bioRxiv : the preprint server for biology最新文献

{"title":"BIBSNet: A Deep Learning Baby Image Brain Segmentation Network for MRI Scans.","authors":"Timothy J Hendrickson, Paul Reiners, Lucille A Moore, Jacob T Lundquist, Begim Fayzullobekova, Anders J Perrone, Erik G Lee, Julia Moser, Trevor K M Day, Dimitrios Alexopoulos, Martin Styner, Omid Kardan, Taylor A Chamberlain, Anurima Mummaneni, Henrique A Caldas, Brad Bower, Sally Stoyell, Tabitha Martin, Sooyeon Sung, Ermias Fair, Kenevan Carter, Jonathan Uriarte-Lopez, Amanda R Rueter, Essa Yacoub, Monica D Rosenberg, Christopher D Smyser, Jed T Elison, Alice Graham, Damien A Fair, Eric Feczko","doi":"10.1101/2023.03.22.533696","DOIUrl":"10.1101/2023.03.22.533696","url":null,"abstract":"<p><strong>Objectives: </strong>Brain segmentation of infant magnetic resonance (MR) images is vitally important in studying developmental mental health and disease. The infant brain undergoes many changes throughout the first years of postnatal life, making tissue segmentation difficult for most existing algorithms. Here, we introduce a deep neural network BIBSNet (<b>B</b>aby and <b>I</b>nfant <b>B</b>rain <b>S</b>egmentation Neural <b>Net</b>work), an open-source, community-driven model that relies on data augmentation and a large sample size of manually annotated images to facilitate the production of robust and generalizable brain segmentations.</p><p><strong>Experimental design: </strong>Included in model training and testing were MR brain images on 84 participants with an age range of 0-8 months (median postmenstrual ages of 13.57 months). Using manually annotated real and synthetic segmentation images, the model was trained using a 10-fold cross-validation procedure. Testing occurred on MRI data processed with the DCAN labs infant-ABCD-BIDS processing pipeline using segmentations produced from gold standard manual annotation, joint-label fusion (JLF), and BIBSNet to assess model performance.</p><p><strong>Principal observations: </strong>Using group analyses, results suggest that cortical metrics produced using BIBSNet segmentations outperforms JLF segmentations. Additionally, when analyzing individual differences, BIBSNet segmentations perform even better.</p><p><strong>Conclusions: </strong>BIBSNet segmentation shows marked improvement over JLF segmentations across all age groups analyzed. The BIBSNet model is 600x faster compared to JLF and can be easily included in other processing pipelines.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9465054","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":"Desmosome mutations impact the tumor microenvironment to promote melanoma proliferation.","authors":"Maayan Baron, Mohita Tagore, Patrick Wall, Fan Zheng, Dalia Barkley, Itai Yanai, Jing Yang, Maija Kiuru, Richard M White, Trey Ideker","doi":"10.1101/2023.09.19.558457","DOIUrl":"10.1101/2023.09.19.558457","url":null,"abstract":"<p><p>Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic alterations in the desmosome in human cancers, with the strongest signal seen in cutaneous melanoma where desmosomes are mutated in >70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations in desmosome genes associates with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics and protein immunofluorescence suggests that these expression decreases occur in keratinocytes in the microenvironment rather than in primary melanoma cells. In further support of a microenvironmental origin, we find that desmosome gene knockdown in keratinocytes yields markedly increased proliferation of adjacent melanoma cells in keratinocyte/melanoma co-cultures. Similar increases in melanoma proliferation are observed in media preconditioned by desmosome-deficient keratinocytes. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanoma cells for neoplastic transformation.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c3/ff/nihpp-2023.09.19.558457v1.PMC10541613.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41153104","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":"Predicting the effect of CRISPR-Cas9-based epigenome editing.","authors":"Sanjit Singh Batra, Alan Cabrera, Jeffrey P Spence, Jacob Goell, Selvalakshmi S Anand, Isaac B Hilton, Yun S Song","doi":"10.1101/2023.10.03.560674","DOIUrl":"10.1101/2023.10.03.560674","url":null,"abstract":"<p><p>Epigenetic regulation orchestrates mammalian transcription, but functional links between them remain elusive. To tackle this problem, we use epigenomic and transcriptomic data from 13 ENCODE cell types to train machine learning models to predict gene expression from histone post-translational modifications (PTMs), achieving transcriptome-wide correlations of ~ 0.70 - 0.79 for most cell types. Our models recapitulate known associations between histone PTMs and expression patterns, including predicting that acetylation of histone subunit H3 lysine residue 27 (H3K27ac) near the transcription start site (TSS) significantly increases expression levels. To validate this prediction experimentally and investigate how natural vs. engineered deposition of H3K27ac might differentially affect expression, we apply the synthetic dCas9-p300 histone acetyltransferase system to 8 genes in the HEK293T cell line and to 5 genes in the K562 cell line. Further, to facilitate model building, we perform MNase-seq to map genome-wide nucleosome occupancy levels in HEK293T. We observe that our models perform well in accurately ranking relative fold-changes among genes in response to the dCas9-p300 system; however, their ability to rank fold-changes within individual genes is noticeably diminished compared to predicting expression across cell types from their native epigenetic signatures. Our findings highlight the need for more comprehensive genome-scale epigenome editing datasets, better understanding of the actual modifications made by epigenome editing tools, and improved causal models that transfer better from endogenous cellular measurements to perturbation experiments. Together these improvements would facilitate the ability to understand and predictably control the dynamic human epigenome with consequences for human health.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592942/pdf/nihpp-2023.10.03.560674v1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694644","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":"Suppression of epithelial proliferation and tumourigenesis by immunoglobulin A.","authors":"Gregory P Donaldson, Gabriella L Reis, Marwa Saad, Christopher Wichmann, Izabela Mamede, Guo Chen, Nicole L DelGaudio, Dayu Zhang, Begüm Aydin, Caroline E Harrer, Tiago B R Castro, Sergei Grivennikov, Bernardo S Reis, Beth M Stadtmueller, Gabriel D Victora, Daniel Mucida","doi":"10.1101/2023.10.06.561290","DOIUrl":"10.1101/2023.10.06.561290","url":null,"abstract":"<p><p>Immunoglobulin A (IgA) is the most abundant antibody isotype produced across mammals and plays a specialized role in mucosal homeostasis ¹ . Constantly secreted into the lumen of the intestine, IgA binds commensal microbiota to regulate their colonization and function ^2,3 with unclear implications for health. IgA deficiency is common in humans but is difficult to study due to its complex aetiology and comorbidities ^4-8 . Using genetically and environmentally controlled mice, here we show that IgA-deficient animals have increased susceptibility to endogenous colorectal tumours. Cellular and molecular analyses revealed that, in the absence of IgA, colonic epithelial cells induce antibacterial factors and accelerate cell cycling in response to the microbiota. Oral treatment with IgA was sufficient to both reduce steady-state proliferation and protect mice from tumours, but this function was due to antibody structure rather than binding specificity. In both organoid and monolayer culture systems, IgA directly suppressed epithelial growth. Co-immunoprecipitation mass spectrometry and a targeted CRISPR screen identified DMBT1 as an IgA-binding epithelial surface protein required for IgA-mediated suppression of proliferation. Together, IgA and DMBT1 regulate Notch signalling and tune the normal cycling of absorptive colonocyte progenitors. In mice, deleting the transmembrane and cytoplasmic signalling portions of DMBT1 or blocking Notch signalling was sufficient to reverse both the increased proliferation and tumour susceptibility of IgA knockouts. These experiments establish a homeostatic function for IgA in tempering physiological epithelial responses to microbiota to maintain mucosal health.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694708","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":"Nucleolar dynamics are determined by the ordered assembly of the ribosome.","authors":"Jessica Sheu-Gruttadauria, Xiaowei Yan, Nico Stuurman, Ronald D Vale, Stephen N Floor","doi":"10.1101/2023.09.26.559432","DOIUrl":"10.1101/2023.09.26.559432","url":null,"abstract":"<p><p>Ribosome biogenesis occurs in the nucleolus, a nuclear biomolecular condensate that exhibits dynamic biophysical properties thought to be important for function. However, the relationship between ribosome assembly and nucleolar dynamics is incompletely understood. Here, we present a platform for high-throughput fluorescence recovery after photobleaching (HiT-FRAP), which we use to screen hundreds of genes for their impact on dynamics of the nucleolar scaffold nucleophosmin (NPM1). We find that scaffold dynamics and nucleolar morphology respond to disruptions in key stages of ribosome biogenesis. Accumulation of early ribosomal intermediates leads to nucleolar rigidification while late intermediates lead to increased fluidity. We map these biophysical changes to specific ribosomal intermediates and their affinity for NPM1. We also discover that disrupting mRNA processing impacts nucleolar dynamics and ribosome biogenesis. This work mechanistically ties ribosome assembly to the biophysical features of the nucleolus and enables study of how dynamics relate to function across other biomolecular condensates.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/38/02/nihpp-2023.09.26.559432v1.PMC10557630.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41157760","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":"Recognition and Cleavage of Human tRNA Methyltransferase TRMT1 by the SARS-CoV-2 Main Protease.","authors":"Angel D'Oliviera, Xuhang Dai, Saba Mottaghinia, Sophie Olson, Evan P Geissler, Lucie Etienne, Yingkai Zhang, Jeffrey S Mugridge","doi":"10.1101/2023.02.20.529306","DOIUrl":"10.1101/2023.02.20.529306","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The SARS-CoV-2 main protease (M&lt;sup&gt;pro&lt;/sup&gt;, or Nsp5) is critical for the production of functional viral proteins during infection and, like many viral proteases, can also target host proteins to subvert their cellular functions. Here, we show that the human tRNA methyltransferase TRMT1 can be recognized and cleaved by SARS-CoV-2 M&lt;sup&gt;pro&lt;/sup&gt;. TRMT1 installs the &lt;i&gt;N&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt;,&lt;i&gt;N&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt;-dimethylguanosine (m2,2G) modification on mammalian tRNAs, which promotes global protein synthesis and cellular redox homeostasis. We find that M&lt;sup&gt;pro&lt;/sup&gt; can cleave endogenous TRMT1 in human cell lysate, resulting in removal of the TRMT1 zinc finger domain. TRMT1 proteolysis results in elimination of TRMT1 tRNA methyltransferase activity and reduced tRNA binding affinity. Evolutionary analysis shows that the TRMT1 cleavage site is highly conserved in mammals, except in Muroidea, where TRMT1 is likely resistant to cleavage. In primates, regions outside the cleavage site with rapid evolution could indicate adaptation to ancient viral pathogens. Furthermore, we determined the structure of a TRMT1 peptide in complex with M&lt;sup&gt;pro&lt;/sup&gt;, revealing a substrate binding conformation distinct from the majority of available M&lt;sup&gt;pro&lt;/sup&gt;-peptide complexes. Kinetic parameters for peptide cleavage show that the TRMT1(526-536) sequence is cleaved with comparable efficiency to the M&lt;sup&gt;pro&lt;/sup&gt;-targeted nsp8/9 viral cleavage site. Mutagenesis studies and molecular dynamics simulations together indicate that kinetic discrimination occurs during a later step of M&lt;sup&gt;pro&lt;/sup&gt;-mediated proteolysis that follows substrate binding. Our results provide new information about the structural basis for M&lt;sup&gt;pro&lt;/sup&gt; substrate recognition and cleavage, the functional roles of the TRMT1 zinc finger domain in tRNA binding and modification, and the regulation of TRMT1 activity by SARS-CoV-2 M&lt;sup&gt;pro&lt;/sup&gt;. These studies could inform future therapeutic design targeting M&lt;sup&gt;pro&lt;/sup&gt; and raise the possibility that proteolysis of human TRMT1 during SARS-CoV-2 infection suppresses protein translation and oxidative stress response to impact viral pathogenesis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Significance statement: &lt;/strong&gt;Viral proteases can strategically target human proteins to manipulate host biochemistry during infection. Here, we show that the SARS-CoV-2 main protease (M&lt;sup&gt;pro&lt;/sup&gt;) can specifically recognize and cleave the human tRNA methyltransferase enzyme TRMT1, and that cleavage of TRMT1 cripples its ability to install a key modification on human tRNAs that is critical for protein translation. Our structural and functional analysis of the M&lt;sup&gt;pro&lt;/sup&gt;-TRMT1 interaction shows how the flexible M&lt;sup&gt;pro&lt;/sup&gt; active site engages a conserved sequence in TRMT1 in an uncommon binding mode to catalyze its cleavage and inactivation. These studies provide new insights into substrate recognition by SARS-CoV-2 M&lt;sup&gt;pro&lt;/sup&gt; that could help guide future antivi","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2c/aa/nihpp-2023.02.20.529306v3.PMC9980103.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10229544","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":"Functional connectomics reveals general wiring rule in mouse visual cortex.","authors":"Zhuokun Ding, Paul G Fahey, Stelios Papadopoulos, Eric Y Wang, Brendan Celii, Christos Papadopoulos, Andersen Chang, Alexander B Kunin, Dat Tran, Jiakun Fu, Zhiwei Ding, Saumil Patel, Lydia Ntanavara, Rachel Froebe, Kayla Ponder, Taliah Muhammad, J Alexander Bae, Agnes L Bodor, Derrick Brittain, JoAnn Buchanan, Daniel J Bumbarger, Manuel A Castro, Erick Cobos, Sven Dorkenwald, Leila Elabbady, Akhilesh Halageri, Zhen Jia, Chris Jordan, Dan Kapner, Nico Kemnitz, Sam Kinn, Kisuk Lee, Kai Li, Ran Lu, Thomas Macrina, Gayathri Mahalingam, Eric Mitchell, Shanka Subhra Mondal, Shang Mu, Barak Nehoran, Sergiy Popovych, Casey M Schneider-Mizell, William Silversmith, Marc Takeno, Russel Torres, Nicholas L Turner, William Wong, Jingpeng Wu, Wenjing Yin, Szi-Chieh Yu, Dimitri Yatsenko, Emmanouil Froudarakis, Fabian Sinz, Krešimir Josić, Robert Rosenbaum, H Sebastian Seung, Forrest Collman, Nuno Maçarico da Costa, R Clay Reid, Edgar Y Walker, Xaq Pitkow, Jacob Reimer, Andreas S Tolias","doi":"10.1101/2023.03.13.531369","DOIUrl":"10.1101/2023.03.13.531369","url":null,"abstract":"<p><p>Understanding the relationship between circuit connectivity and function is crucial for uncovering how the brain implements computation. In the mouse primary visual cortex (V1), excitatory neurons with similar response properties are more likely to be synaptically connected, but previous studies have been limited to within V1, leaving much unknown about broader connectivity rules. In this study, we leverage the millimeter-scale MICrONS dataset to analyze synaptic connectivity and functional properties of individual neurons across cortical layers and areas. Our results reveal that neurons with similar responses are preferentially connected both within and across layers and areas - including feedback connections - suggesting the universality of the 'like-to-like' connectivity across the visual hierarchy. Using a validated digital twin model, we separated neuronal tuning into feature (what neurons respond to) and spatial (receptive field location) components. We found that only the feature component predicts fine-scale synaptic connections, beyond what could be explained by the physical proximity of axons and dendrites. We also found a higher-order rule where postsynaptic neuron cohorts downstream of individual presynaptic cells show greater functional similarity than predicted by a pairwise like-to-like rule. Notably, recurrent neural networks (RNNs) trained on a simple classification task develop connectivity patterns mirroring both pairwise and higher-order rules, with magnitude similar to those in the MICrONS data. Lesion studies in these RNNs reveal that disrupting 'like-to-like' connections has a significantly greater impact on performance compared to lesions of random connections. These findings suggest that these connectivity principles may play a functional role in sensory processing and learning, highlighting shared principles between biological and artificial systems.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10054929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9664366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell and spatial detection of senescent cells using DeepScence.","authors":"Yilong Qu, Runze Dong, Liangcai Gu, Cliburn Chan, Jichun Xie, Carolyn Glass, Xiao-Fan Wang, Andrew B Nixon, Zhicheng Ji","doi":"10.1101/2023.11.21.568150","DOIUrl":"10.1101/2023.11.21.568150","url":null,"abstract":"<p><p>Accurately identifying senescent cells is essential for studying their spatial and molecular features. We developed DeepScence, a method based on deep neural networks, to identify senescent cells in single-cell and spatial transcriptomics data. DeepScence is based on CoreScence, a senescence-associated gene set we curated that incorporates information from multiple published gene sets. We demonstrate that DeepScence can accurately identify senescent cells in single-cell gene expression data collected both <i>in vitro</i> and <i>in vivo</i>, as well as in spatial transcriptomics data generated by different platforms, substantially outperforming existing methods.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138479560","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":"Within Thermal Scales: The Kinetic and Energetic Pull of Chemical Entropy.","authors":"Josh E Baker","doi":"10.1101/2023.09.20.558706","DOIUrl":"10.1101/2023.09.20.558706","url":null,"abstract":"<p><p>Biological systems are fundamentally containers of thermally fluctuating atoms that through unknown mechanisms are structurally layered across many thermal scales from atoms to amino acids to primary, secondary, and tertiary structures to functional proteins to functional macromolecular assemblies and up. Understanding how the irreversible kinetics (i.e., the arrow of time) of biological systems emerge from the equilibrium kinetics of constituent structures defined on smaller thermal scales is central to describing biological function. Muscle's irreversible power stroke - with its mechanochemistry defined on both the thermal scale of muscle and the thermal scale of myosin motors - provides a clear solution to this problem. Individual myosin motors function as reversible force-generating switches induced by actin binding and gated by the release of inorganic phosphate, P _i . As shown in a companion article, when <i>N</i> individual switches thermally scale up to an ensemble of <i>N</i> switches in muscle, the entropy of a binary system of switches is created. We have shown in muscle that a change in state of this binary system of switches entropically drives actin-myosin binding (the switch) and muscle's irreversible power stroke, and that this simple two-state model accurately accounts for most key aspects of muscle contraction. Extending this observation beyond muscle, here I show that the chemical kinetics of an ensemble of <i>N</i> molecules differs fundamentally from a conventional chemical analysis of <i>N</i> individual molecules, describing irreversible chemical reactions as being pulled into the future by the a priori defined entropy of a binary system rather than being pushed forward by the physical occupancy of chemical states (e.g., mass action).</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10542136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41107536","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":"Inversions Can Accumulate Balanced Sexual Antagonism: Evidence from Simulations and <i>Drosophila</i> Experiments.","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>In(3R)K</i> favoring survival and <i>In(3L)Ok</i> favoring male reproduction. In line with the apparent sex-specific fitness effects implied for both of those inversions, <i>In(3L)Ok</i> was also found to be less costly to the viability and/or longevity of males than females, whereas <i>In(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":"2024-10-10","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}