bioRxiv : the preprint server for biology最新文献

{"title":"Collagen IV of basement membranes: I. Origin and diversification of COL4 genes enabling animal evolution and adaptation.","authors":"Patrick S Page-McCaw, Elena N Pokidysheva, Carl E Darris, Sergei Chetyrkin, Aaron L Fidler, Julianna Gallup, Prayag Murawala, Julie K Hudson, Sergei Boudko, Billy G Hudson","doi":"10.1101/2023.10.18.563013","DOIUrl":"10.1101/2023.10.18.563013","url":null,"abstract":"<p><p>Collagen IV is a major component of basement membranes, a specialized form of extracellular matrix that enabled the assembly of multicellular epithelial tissues. In mammals, collagen IV assembles from a family of six α-chains (α1 to α6), forming three supramolecular scaffolds: Col-IVα121, Col-IVα345 and Col-IVα121-α556. The α-chains are encoded by six genes (COL4A1-6) that occur in pairs in a head-to-head arrangement. In Alport syndrome, variants in COL4A3, 4 or 5 genes, encoding Col-IVα345 scaffold in glomerular basement membrane (GBM), the kidney ultrafilter, cause progressive renal failure in millions of people worldwide. How variants cause dysfunction remains obscure. Here, we gained insights into Col-IVα345 function by determining its evolutionary lineage, as revealed from phylogenetic analyses and tissue expression of COL4 gene-pairs. We found that the COL4A⟨1|2⟩ gene-pair emerged in basal Ctenophores and Cnidaria phyla and is highly conserved across metazoans. The COL4A⟨1|2⟩ duplicated and arose as the progenitor to the COL4A⟨3|4⟩ gene-pair in cyclostomes, coinciding with emergence of kidney GBM, and expressed and conserved in jawed-vertebrates, except for amphibians, and a second duplication as the progenitor to the COL4A⟨5|6⟩ gene-pair and conserved in jawed-vertebrates. These findings revealed that Col-IVα121 is the progenitor scaffold, expressed ubiquitously in metazoan basement membranes, and which evolved into vertebrate Col-IVα345 and expressed in GBM. The Col-IVα345 scaffold, in comparison, has an increased number of cysteine residues, varying in number with osmolarity of the environment. Cysteines mediate disulfide crosslinks between protomers, an adaptation enabling a compact GBM that withstands the high hydrostatic pressure associated with glomerular ultrafiltration.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71415511","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":"Self-supervised segmentation and characterization of fiber bundles in anatomic tracing data.","authors":"Vaanathi Sundaresan, Julia F Lehman, Chiara Maffei, Suzanne N Haber, Anastasia Yendiki","doi":"10.1101/2023.09.30.560310","DOIUrl":"10.1101/2023.09.30.560310","url":null,"abstract":"<p><p>Anatomic tracing is the gold standard tool for delineating brain connections and for validating more recently developed imaging approaches such as diffusion MRI tractography. A key step in the analysis of data from tracer experiments is the careful, manual charting of fiber trajectories on histological sections. This is a very time-consuming process, which limits the amount of annotated tracer data that are available for validation studies. Thus, there is a need to accelerate this process by developing a method for computer-assisted segmentation. Such a method must be robust to the common artifacts in tracer data, including variations in the intensity of stained axons and background, as well as spatial distortions introduced by sectioning and mounting the tissue. The method should also achieve satisfactory performance using limited manually charted data for training. Here we propose the first deep-learning method, with a self-supervised loss function, for segmentation of fiber bundles on histological sections from macaque brains that have received tracer injections. We address the limited availability of manual labels with a semi-supervised training technique that takes advantage of unlabeled data to improve performance. We also introduce anatomic and across-section continuity constraints to improve accuracy. We show that our method can be trained on manually charted sections from a single case and segment unseen sections from different cases, with a true positive rate of ~0.80. We further demonstrate the utility of our method by quantifying the density of fiber bundles as they travel through different white-matter pathways. We show that fiber bundles originating in the same injection site have different levels of density when they travel through different pathways, a finding that can have implications for microstructure-informed tractography methods. The code for our method is available at https://github.com/v-sundaresan/fiberbundle_seg_tracing.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592842/pdf/nihpp-2023.09.30.560310v1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694680","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":"Loss of CTRP10 results in female obesity with preserved metabolic health.","authors":"Fangluo Chen, Dylan C Sarver, Muzna Saqib, Leandro M Velez, Susan Aja, Marcus M Seldin, G William Wong","doi":"10.1101/2023.11.01.565163","DOIUrl":"10.1101/2023.11.01.565163","url":null,"abstract":"<p><p>Obesity is a major risk factor for type 2 diabetes, dyslipidemia, cardiovascular disease, and hypertension. Intriguingly, there is a subset of metabolically healthy obese (MHO) individuals who are seemingly able to maintain a healthy metabolic profile free of metabolic syndrome. The molecular underpinnings of MHO, however, are not well understood. Here, we report that CTRP10/C1QL2-deficient mice represent a unique female model of MHO. CTRP10 modulates weight gain in a striking and sexually dimorphic manner. Female, but not male, mice lacking CTRP10 develop obesity with age on a low-fat diet while maintaining an otherwise healthy metabolic profile. When fed an obesogenic diet, female <i>Ctrp10</i> knockout (KO) mice show rapid weight gain. Despite pronounced obesity, <i>Ctrp10</i> KO female mice do not develop steatosis, dyslipidemia, glucose intolerance, insulin resistance, oxidative stress, or low-grade inflammation. Obesity is largely uncoupled from metabolic dysregulation in female KO mice. Multi-tissue transcriptomic analyses highlighted gene expression changes and pathways associated with insulin-sensitive obesity. Transcriptional correlation of the differentially expressed gene (DEG) orthologous in humans also shows sex differences in gene connectivity within and across metabolic tissues, underscoring the conserved sex-dependent function of CTRP10. Collectively, our findings suggest that CTRP10 negatively regulates body weight in females, and that loss of CTRP10 results in benign obesity with largely preserved insulin sensitivity and metabolic health. This female MHO mouse model is valuable for understanding sex-biased mechanisms that uncouple obesity from metabolic dysfunction.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157802","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":"Connectional axis of individual functional variability: Patterns, structural correlates, and relevance for development and cognition.","authors":"Hang Yang, Guowei Wu, Yaoxin Li, Xiaoyu Xu, Jing Cong, Haoshu Xu, Yiyao Ma, Yang Li, Runsen Chen, Adam Pines, Ting Xu, Valerie J Sydnor, Theodore D Satterthwaite, Zaixu Cui","doi":"10.1101/2023.03.08.531800","DOIUrl":"10.1101/2023.03.08.531800","url":null,"abstract":"<p><p>The human cerebral cortex exhibits intricate interareal functional synchronization at the macroscale, with substantial individual variability in these functional connections. However, the spatial organization of functional connectivity (FC) variability across the human connectome edges and its significance in cognitive development remain unclear. Here, we identified a connectional axis in the edge-level FC variability. The variability declined continuously along this axis from within-network to between-network connections, and from the edges linking association networks to those linking the sensorimotor and association networks. This connectional axis of functional variability is associated with spatial pattern of structural connectivity variability. Moreover, the connectional variability axis evolves in youth with an increasing flatter axis slope. We also observed that the slope of connectional variability axis was positively related to the performance in the higher-order cognition. Together, our results reveal a connectional axis in functional variability that is linked with structural connectome variability, refines during development, and is relevant to cognition.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c8/8f/nihpp-2023.03.08.531800v1.PMC10028904.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9186956","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":"Next-Generation Breast Organoids Capture Human Organogenesis with High-Resolution Live Imaging.","authors":"Gat Rauner, Nicole C Traugh, Colin J Trepicchio, Meadow E Parrish, Kenan Mushayandebvu, Charlotte Kuperwasser","doi":"10.1101/2023.10.02.560364","DOIUrl":"10.1101/2023.10.02.560364","url":null,"abstract":"<p><p>Organoids have emerged as a powerful tool for modeling tissue growth and diseases. In this study, we introduce a groundbreaking organotypic culture technique that replicates the morphology, scale, and heterogeneity of human breast tissue, and includes a mesenchymal-like stromal component. A standout feature of this approach is the use of long-term live imaging at high temporal resolution to directly observe stem cell dynamics during organogenesis, from single cells to mature organ tissue. The system is adaptable for high throughput applications and allows for genetic manipulation of the cells. Real-time imaging of ex-vivo tissue formation reveals a non-canonical process of ductal-lobular morphogenesis and branching, and de-novo generation of a supportive stroma. Incorporating patient-derived single cells from multiple donors offers an enhanced representation of the spectrum of individual responses and the impacts of distinct exposures. While developed for breast tissue, the principles of this technology can serve as a model for the development of similar systems in other tissues, where organoids do not merely reproduce the tissue, but where their regeneration can also be observed and studied. In addition, this model provides a quantitative experimental system to study mechanisms of embryogenesis, development, and tissue organization where biomechanics plays an important role.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694436","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":"Animal septins contain functional transmembrane domains.","authors":"Jenna A Perry, Michael E Werner, Shizue Omi, Bryan W Heck, Paul S Maddox, Manos Mavrakis, Amy S Maddox","doi":"10.1101/2023.11.20.567915","DOIUrl":"10.1101/2023.11.20.567915","url":null,"abstract":"<p><p>Septins, a conserved family of filament-forming proteins, contribute to eukaryotic cell division, polarity, and membrane trafficking. Septins scaffold other proteins to cellular membranes, but it is not fully understood how septins associate with membranes. We identified and characterized an isoform of <i>Caenorhabditis elegans</i> septin UNC-61 that was predicted to contain a transmembrane domain (TMD). The TMD isoform is expressed in a subset of tissues where the known septins were known to act, and TMD function was required for tissue integrity of the egg-laying apparatus. We found predicted TMD-containing septins across much of opisthokont phylogeny and demonstrated that the TMD-containing sequence of a primate TMD-septin is sufficient for localization to cellular membranes. Together, our findings reveal a novel mechanism of septin-membrane association with profound implications for septin dynamics and regulation.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479601","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":"<i>Inversions Can Accumulate Balanced Sexual Antagonism: Evidence from Simulations and</i> Drosophila <i>Experiments</i>.","authors":"Christopher S McAllester, John E Pool","doi":"10.1101/2023.10.02.560529","DOIUrl":"10.1101/2023.10.02.560529","url":null,"abstract":"<p><p>Chromosomal inversion polymorphisms can be common, but the causes of their persistence are often unclear. We propose a model for the maintenance of inversion polymorphism, which requires that some variants contribute antagonistically to two phenotypes, one of which has negative frequency-dependent fitness. These conditions yield a form of frequency-dependent disruptive selection, favoring two predominant haplotypes segregating alleles that favor opposing antagonistic phenotypes. An inversion associated with one haplotype can reduce the fitness load incurred by generating recombinant offspring, reinforcing its linkage to the haplotype and enabling both haplotypes to accumulate more antagonistic variants than expected otherwise. We develop and apply a forward simulator to examine these dynamics under a tradeoff between survival and male display. These simulations indeed generate inversion-associated haplotypes with opposing sex-specific fitness effects. Antagonism strengthens with time, and can ultimately yield karyotypes at surprisingly predictable frequencies, with striking genotype frequency differences between sexes and between developmental stages. To test whether this model may contribute to well-studied yet enigmatic inversion polymorphisms in <i>Drosophila melanogaster</i>, we track inversion frequencies in laboratory crosses to test whether they influence male reproductive success or survival. We find that two of the four tested inversions show significant evidence for the tradeoff examined, with <i>ln(3R)K</i> favoring survival and <i>ln(3L)Ok</i> favoring male reproduction. In line with the apparent sex-specific fitness effects implied for both of those inversions, <i>ln(3L)Ok</i> was also found to be less costly to the viability and/or longevity of males than females, whereas <i>ln(3R)K</i> was more beneficial to female survival. Based on this work, we expect that balancing selection on antagonistically pleiotropic traits may provide a significant and underappreciated contribution to the maintenance of natural inversion polymorphism.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592935/pdf/nihpp-2023.10.02.560529v2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694590","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":"Programming megakaryocytes to produce engineered platelets for delivering non-native proteins.","authors":"Farhana Islam, Shwan B Javdan, Mitchell R Lewis, James D Craig, Han Wu, Tara L Deans","doi":"10.1101/2023.10.13.562311","DOIUrl":"10.1101/2023.10.13.562311","url":null,"abstract":"<p><p>Platelets are anucleate cells naturally filled with secretory granules that store large amounts of protein to be released in response to certain physiological conditions. Cell engineering can endow platelets with the ability to deliver non-native proteins by modifying them as they develop during the cell fate process. This study presents a strategy to efficiently generate mouse platelets from pluripotent stem cells and demonstrates their potential as bioengineered protein delivery platforms. By modifying megakaryocytes, the progenitor cells of platelets, we successfully engineered platelets capable of packaging and delivering non-native proteins. These engineered platelets can offer flexible delivery platforms to release non-native proteins in a controlled manner upon activation when packaged into α-granules or deliver active enzymes to genetically alter recipient cells. Our findings highlight platelets as a promising tool for protein delivery in cell therapy applications.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592833/pdf/nihpp-2023.10.13.562311v1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694667","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":"Neural substrates of cold nociception in <i>Drosophila</i> larva.","authors":"Atit A Patel, Albert Cardona, Daniel N Cox","doi":"10.1101/2023.07.31.551339","DOIUrl":"10.1101/2023.07.31.551339","url":null,"abstract":"<p><p>Metazoans detect and differentiate between innocuous (non-painful) and/or noxious (harmful) environmental cues using primary sensory neurons, which serve as the first node in a neural network that computes stimulus specific behaviors to either navigate away from injury-causing conditions or to perform protective behaviors that mitigate extensive injury. The ability of an animal to detect and respond to various sensory stimuli depends upon molecular diversity in the primary sensors and the underlying neural circuitry responsible for the relevant behavioral action selection. Recent studies in <i>Drosophila</i> larvae have revealed that somatosensory class III multidendritic (CIII md) neurons function as multimodal sensors regulating distinct behavioral responses to innocuous mechanical and nociceptive thermal stimuli. Recent advances in circuit bases of behavior have identified and functionally validated <i>Drosophila</i> larval somatosensory circuitry involved in innocuous (mechanical) and noxious (heat and mechanical) cues. However, central processing of cold nociceptive cues remained unexplored. We implicate multisensory integrators (Basins), premotor (Down-and-Back) and projection (A09e and TePns) neurons as neural substrates required for cold-evoked behavioral and calcium responses. Neural silencing of cell types downstream of CIII md neurons led to significant reductions in cold-evoked behaviors and neural co-activation of CIII md neurons plus additional cell types facilitated larval contraction (CT) responses. Further, we demonstrate that optogenetic activation of CIII md neurons evokes calcium increases in these neurons. Finally, we characterize the premotor to motor neuron network underlying cold-evoked CT and delineate the muscular basis of CT response. Collectively, we demonstrate how <i>Drosophila</i> larvae process cold stimuli through functionally diverse somatosensory circuitry responsible for generating stimulus-specific behaviors.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/52/50/nihpp-2023.07.31.551339v1.PMC10418107.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10055686","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":"Cell autonomous polarization by the planar cell polarity signaling pathway.","authors":"Alexis T Weiner, Silas Boye Nissen, Kaye Suyama, Bomsoo Cho, Gandhy Pierre-Louis, Jeffrey D Axelrod","doi":"10.1101/2023.09.26.559449","DOIUrl":"10.1101/2023.09.26.559449","url":null,"abstract":"<p><p>Planar Cell Polarity (PCP) signaling polarizes epithelial cells in a plane orthogonal to their apical-basal axis. A core PCP signaling module segregates two distinct molecular subcomplexes to opposite sides of cells and coordinates the direction of polarization between neighboring cells. Homodimers of the atypical cadherin Flamingo are thought to scaffold these subcomplexes and are required for intercellular polarity signaling. Feedback is required for polarization, but whether feedback requires intercellular and/or intracellular pathways is unknown, and traditional genetic tools have limited utility in dissecting these mechanisms. Using novel tools, we show that cells lacking Flamingo, or bearing a homodimerization-deficient Flamingo, do polarize, indicating that functional PCP subcomplexes form and segregate cell-autonomously. We identify feedback pathways and propose a competitive binding-based asymmetry amplifying mechanism that each operate cell-autonomously. The intrinsic logic of PCP signaling is therefore more similar to that in single cell polarizing systems than was previously recognized.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/bc/3e/nihpp-2023.09.26.559449v1.PMC10557733.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41123282","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}