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Chemically induced partial unfolding of the multifunctional Apurinic/apyrimidinic endonuclease 1. 化学诱导的多功能无尿嘧啶/无嘧啶内切酶1的部分展开。
bioRxiv : the preprint server for biology Pub Date : 2025-03-26 DOI: 10.1101/2023.06.29.547112
Ratan Rai, Olabode I Dawodu, Jingwei Meng, Steven M Johnson, Jonah Z Vilseck, Mark R Kelley, Joshua J Ziarek, Millie M Georgiadis
{"title":"Chemically induced partial unfolding of the multifunctional Apurinic/apyrimidinic endonuclease 1.","authors":"Ratan Rai, Olabode I Dawodu, Jingwei Meng, Steven M Johnson, Jonah Z Vilseck, Mark R Kelley, Joshua J Ziarek, Millie M Georgiadis","doi":"10.1101/2023.06.29.547112","DOIUrl":"10.1101/2023.06.29.547112","url":null,"abstract":"<p><p>Apurinic/apyrimidinic endonuclease I (APE1) acts as both an endonuclease and a redox factor to ensure cell survival. The two activities require different conformations of APE1. As an endonuclease, APE1 is fully folded. As a redox factor, APE1 must be partially unfolded to expose the buried residue Cys65, which reduces transcription factors including AP-1, NF-κB, and HIF-1α and thereby enables them to bind DNA. To determine a molecular basis for partial unfolding associated with APE1's redox activity, we characterized specific interactions of a known redox inhibitor APX3330 with APE1 through waterLOGSY and <sup>1</sup> H- <sup>15</sup> N HSQC NMR approaches using ethanol and acetonitrile as co-solvents. We find that APX3330 binds to the endonuclease active site in both co-solvents and to a distant small pocket in acetonitrile. Prolonged exposure of APE1 with APX3330 in acetonitrile resulted in a time-dependent loss of <sup>1</sup> H- <sup>15</sup> N HSQC chemical shifts (∼35%), consistent with partial unfolding. Regions that are partially unfolded include adjacent N- and C-terminal beta strands within one of the two sheets comprising the core, which converge within the small binding pocket defined by the CSPs. Removal of APX3330 via dialysis resulted in a slow reappearance of the <sup>1</sup> H- <sup>15</sup> N HSQC chemical shifts suggesting that the effect of APX3330 is reversible. APX3330 significantly decreases the melting temperature of APE1 but has no effect on endonuclease activity using a standard assay in either co-solvent. Our results provide insights on reversible partial unfolding of APE1 relevant for its redox function as well as the mechanism of redox inhibition by APX3330.</p><p><strong>Toc graphic: </strong></p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10327033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9865745","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}
引用次数: 0
Human Bone Marrow Adipose Tissue is a Hematopoietic Niche for Leptin-Driven Monopoiesis. 人骨髓脂肪组织是瘦素驱动的造血生态位。
bioRxiv : the preprint server for biology Pub Date : 2025-03-25 DOI: 10.1101/2023.08.29.555167
Zinger Yang Loureiro, Amruta Samant, Anand Desai, Tiffany DeSouza, Haley Cirka, Mai Ceesay, David Kostyra, Shannon Joyce, Lyne Khair, Javier Solivan-Rivera, Rachel Ziegler, Nathalia Ketelut Carneiro, Linus T Tsai, Michael Brehm, Louis M Messina, Katherine A Fitzgerald, Evan D Rosen, Silvia Corvera, Tammy T Nguyen
{"title":"Human Bone Marrow Adipose Tissue is a Hematopoietic Niche for Leptin-Driven Monopoiesis.","authors":"Zinger Yang Loureiro, Amruta Samant, Anand Desai, Tiffany DeSouza, Haley Cirka, Mai Ceesay, David Kostyra, Shannon Joyce, Lyne Khair, Javier Solivan-Rivera, Rachel Ziegler, Nathalia Ketelut Carneiro, Linus T Tsai, Michael Brehm, Louis M Messina, Katherine A Fitzgerald, Evan D Rosen, Silvia Corvera, Tammy T Nguyen","doi":"10.1101/2023.08.29.555167","DOIUrl":"10.1101/2023.08.29.555167","url":null,"abstract":"<p><p>During aging, adipose tissue within the bone marrow expands while the trabecular red marrow contracts. The impact of these changes on blood cell formation remains unclear. To address this question, we performed single-cell and single-nuclei transcriptomic analysis on adipose-rich yellow bone marrow (BMY) and adipose-poor trabecular red marrow (BMR) from human subjects undergoing lower limb amputations. Surprisingly, we discovered two distinct hematopoietic niches, in which BMY contains a higher number of monocytes and progenitor cells expressing genes associated with inflammation. To further investigate these niches, we developed an in-vitro organoid system that maintains features of the human bone marrow. We find cells from BMY are distinct in their expression of the leptin receptor, and respond to leptin stimulation with enhanced proliferation, leading to increased monocyte production. These findings suggest that the age-associated expansion of bone marrow adipose tissue drives a pro-inflammatory state by stimulating monocyte production from a spatially distinct, leptin-responsive hematopoietic stem/progenitor cell population.</p><p><strong>Significance: </strong>This study reveals that adipose tissue within the human bone marrow is a niche for hematopoietic stem and progenitor cells that can give rise to pro-inflammatory monocytes through leptin signaling. Expansion of bone marrow adipose tissue with age and stress may thus underlie inflammageing.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10491256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10570815","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}
引用次数: 0
Human deleterious mutation rate slows adaptation and implies high fitness variance. 人类有害突变率意味着高适应度方差,平均适应度的下降由影响更大的罕见有益突变补偿。
bioRxiv : the preprint server for biology Pub Date : 2025-03-25 DOI: 10.1101/2023.09.01.555871
Joseph Matheson, Ulises Hernández, Jason Bertram, Joanna Masel
{"title":"Human deleterious mutation rate slows adaptation and implies high fitness variance.","authors":"Joseph Matheson, Ulises Hernández, Jason Bertram, Joanna Masel","doi":"10.1101/2023.09.01.555871","DOIUrl":"10.1101/2023.09.01.555871","url":null,"abstract":"<p><p>Each new human has an expected <math> <mrow><msub><mi>U</mi> <mi>d</mi></msub> <mo>=</mo> <mn>2</mn> <mo>-</mo> <mn>10</mn></mrow> </math> new deleterious mutations. Using a novel approach to capture complex linkage disequilibria from high <math> <mrow><msub><mi>U</mi> <mi>d</mi></msub> </mrow> </math> using genome-wide simulations, we confirm that fitness decline due to the fixation of many slightly deleterious mutations can be compensated by rarer beneficial mutations of larger effect. The evolution of increased genome size and complexity have previously been attributed to a similarly asymmetric pattern of fixations, but we propose that the cause might be high <math> <mrow><msub><mi>U</mi> <mi>d</mi></msub> </mrow> </math> rather than the small population size posited as causal by drift barrier theory. High within-population variance in relative fitness is an inevitable consequence of high <math> <mrow><msub><mi>U</mi> <mi>d</mi></msub> <mo>∼</mo> <mn>2</mn> <mo>-</mo> <mn>10</mn></mrow> </math> combined with inferred human deleterious effect sizes; two individuals will typically differ in fitness by 15-40%. The need to compensate for the deluge of deleterious mutations slows net adaptation (i.e. to the external environment) by ~13%-55%. The rate of beneficial fixations is more sensitive to changes in the mutation rate than the rate of deleterious fixations is. As a surprising consequence of this, an increase (e.g. 10%) in overall mutation rate leads to faster adaptation; this puts to rest dysgenic fears about increasing mutation rates due to rising paternal age.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10508744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41163941","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}
引用次数: 0
nELISA: A high-throughput, high-plex platform enables quantitative profiling of the inflammatory secretome. nELISA:一个高通量,高复杂性的平台,可以定量分析炎症分泌组。
bioRxiv : the preprint server for biology Pub Date : 2025-03-24 DOI: 10.1101/2023.04.17.535914
Milad Dagher, Grant Ongo, Nathaniel Robichaud, Jinglin Kong, Woojong Rho, Ivan Teahulos, Arya Tavakoli, Samantha Bovaird, Shahem Merjaneh, Andrew Tan, Kiran Edwardson, Christelle Scheepers, Andy Ng, Andy Hajjar, Baly Sow, Michael Vrouvides, Andy Lee, Philippe DeCorwin-Martin, Shafqat Rasool, Jiamin Huang, Timothy Erps, Spencer Coffin, Yu Han, Srinivas Niranj Chandrasekaran, Lisa Miller, Maria Kost-Alimova, Adam Skepner, Shantanu Singh, Anne E Carpenter, Jeffrey Munzar, David Juncker
{"title":"nELISA: A high-throughput, high-plex platform enables quantitative profiling of the inflammatory secretome.","authors":"Milad Dagher, Grant Ongo, Nathaniel Robichaud, Jinglin Kong, Woojong Rho, Ivan Teahulos, Arya Tavakoli, Samantha Bovaird, Shahem Merjaneh, Andrew Tan, Kiran Edwardson, Christelle Scheepers, Andy Ng, Andy Hajjar, Baly Sow, Michael Vrouvides, Andy Lee, Philippe DeCorwin-Martin, Shafqat Rasool, Jiamin Huang, Timothy Erps, Spencer Coffin, Yu Han, Srinivas Niranj Chandrasekaran, Lisa Miller, Maria Kost-Alimova, Adam Skepner, Shantanu Singh, Anne E Carpenter, Jeffrey Munzar, David Juncker","doi":"10.1101/2023.04.17.535914","DOIUrl":"10.1101/2023.04.17.535914","url":null,"abstract":"<p><p>We present the nELISA, a high-throughput, high-fidelity, and high-plex protein profiling platform. DNA oligonucleotides are used to pre-assemble antibody pairs on spectrally encoded microparticles and perform displacement-mediated detection. Spatial separation between non-cognate antibodies prevents the rise of reagent-driven cross-reactivity, while read-out is performed cost-efficiently and at high-throughput using flow cytometry. nELISA can measure both protein concentration and their post-translational modifications. We assembled an inflammatory panel of 191 targets that were multiplexed without cross-reactivity nor impact on performance vs 1-plex signals, with sensitivities as low as 0.1 pg/mL and measurements spanning 7 orders of magnitude. We then performed a large-scale inflammatory-secretome perturbation screen of peripheral blood mononuclear cells (PBMCs), with cytokines as both perturbagens and readouts, measuring 7,392 samples and generating ~1.4M protein data points in under a week; a significant advance in throughput compared to other highly multiplexed immunoassays. We uncovered 447 significant cytokine responses, including multiple putatively novel ones, that were conserved across donors and stimulation conditions. We validate nELISA for phenotypic screening, where its capacity to faithfully report hundreds of proteins make it a powerful tool across multiple stages of drug discovery.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10153206/pdf/nihpp-2023.04.17.535914v2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9986488","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}
引用次数: 0
Single neuron contributions to the auditory brainstem EEG. 单神经元对听觉脑干脑电图的贡献。
bioRxiv : the preprint server for biology Pub Date : 2025-03-21 DOI: 10.1101/2024.05.29.596509
Paula T Kuokkanen, Ira Kraemer, Christine Koeppl, Catherine E Carr, Richard Kempter
{"title":"Single neuron contributions to the auditory brainstem EEG.","authors":"Paula T Kuokkanen, Ira Kraemer, Christine Koeppl, Catherine E Carr, Richard Kempter","doi":"10.1101/2024.05.29.596509","DOIUrl":"10.1101/2024.05.29.596509","url":null,"abstract":"<p><p>The auditory brainstem response (ABR) is an acoustically evoked EEG potential that is an important diagnostic tool for hearing loss, especially in newborns. The ABR originates from the response sequence of auditory nerve and brainstem nuclei, and a click-evoked ABR typically shows three positive peaks ('waves') within the first six milliseconds. However, an assignment of the waves of the ABR to specific sources is difficult, and a quantification of contributions to the ABR waves is not available. Here, we exploit the large size and physical separation of the barn owl first-order cochlear nucleus magnocellularis (NM) to estimate single-cell contributions to the ABR. We simultaneously recorded NM neurons' spikes and the EEG in owls of both sexes, and found that ≳ 5,000 spontaneous single-cell spikes are necessary to isolate a significant spike-triggered average response at the EEG electrode. An average single-neuron contribution to the ABR was predicted by convolving the spike-triggered average with the cell's peri-stimulus time histogram. Amplitudes of predicted contributions of single NM cells typically reached 32.9 ± 1.1 nV (mean ± SE, range: 2.5 - 162.7 nV), or 0.07 ± 0.02% (median ± SE; range from 0.01% to 1%) of the ABR amplitude. The time of the predicted peak coincided best with the peak of the ABR wave II, independent of the click sound level. Our results suggest that individual neurons' contributions to an EEG can vary widely, and that wave II of the ABR is shaped by NM units.</p><p><strong>Significance statement: </strong>The auditory brainstem response (ABR) is a scalp potential used for the diagnosis of hearing loss, both clinically and in research. We investigated the contribution of single action potentials from auditory brainstem neurons to the ABR and provide direct evidence that action potentials recorded in a first order auditory nucleus, and their EEG contribution, coincide with wave II of the ABR. The study also shows that the contribution of single cells varies strongly across the population.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11160769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141297468","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}
引用次数: 0
Comparative analyses of disease-linked missense mutations in the RNA exosome modeled in budding yeast reveal distinct functional consequences in translation. 对芽殖酵母中模拟的RNA外泌体中与疾病相关的错义突变的比较分析揭示了翻译中不同的功能后果。
bioRxiv : the preprint server for biology Pub Date : 2025-03-19 DOI: 10.1101/2023.10.18.562946
Maria C Sterrett, Lauryn A Cureton, Lauren N Cohen, Ambro van Hoof, Sohail Khoshnevis, Milo B Fasken, Anita H Corbett, Homa Ghalei
{"title":"Comparative analyses of disease-linked missense mutations in the RNA exosome modeled in budding yeast reveal distinct functional consequences in translation.","authors":"Maria C Sterrett, Lauryn A Cureton, Lauren N Cohen, Ambro van Hoof, Sohail Khoshnevis, Milo B Fasken, Anita H Corbett, Homa Ghalei","doi":"10.1101/2023.10.18.562946","DOIUrl":"10.1101/2023.10.18.562946","url":null,"abstract":"<p><p>The RNA exosome is a multi-subunit, evolutionarily conserved ribonuclease complex that is essential for processing, decay and surveillance of many cellular RNAs. Missense mutations in genes encoding the structural subunits of the RNA exosome complex cause a diverse range of diseases, collectively known as RNA exosomopathies, often involving neurological and developmental defects. The varied symptoms suggest that different mutations lead to distinct <i>in vivo</i> consequences. To investigate these functional consequences and distinguish whether they are unique to each RNA exosomopathy mutation, we generated a collection of <i>in vivo</i> models by introducing pathogenic missense mutations in orthologous <i>S. cerevisiae</i> genes. Comparative RNA-seq analysis assessing broad transcriptomic changes in each mutant model revealed that three yeast mutant models, <i>rrp4-G226D, rrp40-W195R</i> and <i>rrp46-L191H,</i> which model mutations in the genes encoding EXOSC2, EXOSC3 and EXOSC5, respectively, had the largest transcriptomic differences. While some transcriptomic changes, particularly in transcripts related to ribosome biogenesis, were shared among mutant models, each mutation also induced unique transcriptomic changes. Thus, our data suggests that while there are some shared consequences, there are also distinct differences in RNA exosome function by each variant. Assessment of ribosome biogenesis and translation defects in the three models revealed distinct differences in polysome profiles. Collectively, our results provide the first comparative analyses of RNA exosomopathy mutant models and suggest that different RNA exosome gene mutations result in <i>in vivo</i> consequences that are both unique and shared across each variant, providing further insight into the biology underlying each distinct pathology.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71415513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dynamically shifting from compositional to conjunctive brain representations supports cognitive task learning. 神经表征动力学揭示了认知任务学习的计算原理。
bioRxiv : the preprint server for biology Pub Date : 2025-03-18 DOI: 10.1101/2023.06.27.546751
Ravi D Mill, Michael W Cole
{"title":"Dynamically shifting from compositional to conjunctive brain representations supports cognitive task learning.","authors":"Ravi D Mill, Michael W Cole","doi":"10.1101/2023.06.27.546751","DOIUrl":"10.1101/2023.06.27.546751","url":null,"abstract":"<p><p>During cognitive task learning, neural representations must be rapidly constructed for novel task performance, then optimized for robust practiced task performance. How the geometry of neural representations changes to enable this transition from novel to practiced performance remains unknown. We hypothesized that practice involves a shift from compositional representations (task-general activity patterns that can be flexibly reused across tasks) to conjunctive representations (task-specific activity patterns specialized for the current task). Functional MRI during learning of multiple complex tasks substantiated this dynamic shift from compositional to conjunctive representations, which was associated with reduced cross-task interference (via pattern separation) and behavioral improvement. Further, we found that conjunctions originated in subcortex (hippocampus and cerebellum) and slowly spread to cortex, extending multiple memory systems theories to encompass cognitive task learning. The strengthening of conjunctive representations hence serves as a computational signature of learning, reflecting cortical-subcortical dynamics that optimize task representations in the human brain.</p><p><strong>Highlights: </strong>Learning shifts multi-task representations from compositional to conjunctive formatsCortical conjunctions uniquely associate with improved behavior and pattern separationThese conjunctions strengthen over separated learning events and index switch costsSubcortical regions are critical for cross-region binding of task rule information.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10327096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9865751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mechanistic Basis for Enhanced Strigolactone Sensitivity in KAI2 Triple Mutant. KAI2三重突变体Strigolactone敏感性增强的机制基础。
bioRxiv : the preprint server for biology Pub Date : 2025-03-18 DOI: 10.1101/2023.01.18.524622
Briana L Sobecks, Jiming Chen, Tanner J Dean, Diwakar Shukla
{"title":"Mechanistic Basis for Enhanced Strigolactone Sensitivity in KAI2 Triple Mutant.","authors":"Briana L Sobecks, Jiming Chen, Tanner J Dean, Diwakar Shukla","doi":"10.1101/2023.01.18.524622","DOIUrl":"10.1101/2023.01.18.524622","url":null,"abstract":"<p><p><i>Striga hermonthica</i> is a parasitic weed that destroys billions of dollars' worth of staple crops every year. Its rapid proliferation stems from an enhanced ability to metabolize strigolactones (SLs), plant hormones that direct root branching and shoot growth. <i>Striga's</i> SL receptor, <i>Sh</i>HTL7, bears more similarity to the staple crop karrikin receptor KAI2 than to SL receptor D14, though KAI2 variants in plants like <i>Arabidopsis thaliana</i> show minimal SL sensitivity. Recently, studies have indicated that a small number of point mutations to HTL7 residues can confer SL sensitivity to <i>At</i>KAI2. Here, we analyze both wild-type <i>At</i>KAI2 and SL-sensitive mutant Var64 through all-atom, long-timescale molecular dynamics simulations to determine the effects of these mutations on receptor function at a molecular level. We demonstrate that the mutations stabilize SL binding by about 2 kcal/mol. They also result in a doubling of the average pocket volume, and eliminate the dependence of binding on certain pocket conformational arrangements. While the probability of certain non-binding SL-receptor interactions increases in the mutant compared with the wild-type, the rate of binding also increases by a factor of ten. All these changes account for the increased SL sensitivity in mutant KAI2, and suggest mechanisms for increasing functionality of host crop SL receptors.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9a/6f/nihpp-2023.01.18.524622v1.PMC9882355.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10657155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Image-based identification and isolation of micronucleated cells to dissect cellular consequences. 基于图像识别和分离微核细胞,剖析细胞后果。
bioRxiv : the preprint server for biology Pub Date : 2025-03-17 DOI: 10.1101/2023.05.04.539483
Lucian DiPeso, Sriram Pendyala, Heather Z Huang, Douglas M Fowler, Emily M Hatch
{"title":"Image-based identification and isolation of micronucleated cells to dissect cellular consequences.","authors":"Lucian DiPeso, Sriram Pendyala, Heather Z Huang, Douglas M Fowler, Emily M Hatch","doi":"10.1101/2023.05.04.539483","DOIUrl":"10.1101/2023.05.04.539483","url":null,"abstract":"<p><p>Recent advances in isolating cells based on visual phenotypes have transformed our ability to identify the mechanisms and consequences of complex traits. Micronucleus (MN) formation is a frequent outcome of genome instability, triggers extensive changes in genome structure and signaling coincident with MN rupture, and is almost exclusively defined by visual analysis. Automated MN detection in microscopy images has proved challenging, limiting discovery of the mechanisms and consequences of MN. In this study we describe two new MN segmentation modules: a rapid model for classifying micronucleated cells and their rupture status (VCS MN), and a robust model for accurate MN segmentation (MNFinder) from a broad range of cell lines. As proof-of-concept, we define the transcriptome of non-transformed human cells with intact or ruptured MN after chromosome missegregation by combining VCS MN with photoactivation-based cell isolation and RNASeq. Surprisingly, we find that neither MN formation nor rupture triggers a strong unique transcriptional response. Instead, transcriptional changes appear correlated with small increases in aneuploidy in these cell classes. Our MN segmentation modules overcome a significant challenge with reproducible MN quantification, and, joined with visual cell sorting, enable the application of powerful functional genomics assays to a wide-range of questions in MN biology.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9610318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
How Occam's razor guides human decision-making. 奥卡姆剃刀如何指导人类决策。
bioRxiv : the preprint server for biology Pub Date : 2025-03-16 DOI: 10.1101/2023.01.10.523479
Eugenio Piasini, Shuze Liu, Pratik Chaudhari, Vijay Balasubramanian, Joshua I Gold
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