bioRxiv : the preprint server for biology最新文献

{"title":"Aging directs the differential evolution of KRAS-driven lung adenocarcinoma.","authors":"Felicia Lazure, Stanislav Drapela, Xiaoxian Liu, John H Lockhart, Hossein Kashfi, Nadir Sarigul, Didem Ilter, Elsa R Flores, Xuefeng Wang, Inna Smalley, Alex Jaeger, Xiaoqing Yu, Ana P Gomes","doi":"10.1101/2025.01.20.633951","DOIUrl":"https://doi.org/10.1101/2025.01.20.633951","url":null,"abstract":"<p><p>Lung adenocarcinoma (LUAD), the most common histological subtype of lung cancer( <i>1, 2</i> ), is a disease of the elderly, with an average age of diagnosis of about 70 years of age( <i>3</i> ). Older age is associated with an increased incidence of KRAS-driven LUAD( <i>4</i> ), a particularly deadly type of LUAD characterized by treatment resistance and relapse. Despite this, our understanding of how old age shapes KRAS-driven LUAD evolution remains incomplete. While the age-related increase in cancer risk was previously ascribed to the accumulation of mutations over time, we are now beginning to consider the role of host biology as an independent factor influencing cancer. Here, we use single-cell RNA-Sequencing of KP (Kras ^G12D/+ ; Trp53 ^flox/flox ) LUAD transplanted into young and old mice to define how old age affects LUAD evolution and map the changes that old age imposes onto LUAD's microenvironment. Our data demonstrates that the aged lung environment steers LUAD evolution towards a primitive stem-like state that is associated with poor prognosis. We ascribe this differential evolution, at least in part, to a population of rare and highly secretory damage-associated alveolar differentiation intermediate (ADI) cells that accumulate in the aged tumor microenvironment (TME) and that dominate the niche signaling received by LUAD cells. Overall, our data puts aging center stage in coordinating LUAD evolution, highlighting the need to model LUAD in its most common context and creating a framework to tailor future cancer therapeutic strategies to the age of the patient to improve outcomes in the largest and most vulnerable LUAD patient population, the elderly.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785146/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082853","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 fractionation dependence of tumor control in proton therapy for early-stage non-small cell lung cancer.","authors":"Jeho Jeong, Vicki T Taasti, Andrew Jackson, Zeno A R Gouw, Charles B Simone, Philippe Lambin, Joseph O Deasy","doi":"10.1101/2025.01.23.632803","DOIUrl":"https://doi.org/10.1101/2025.01.23.632803","url":null,"abstract":"<p><strong>Purpose: </strong>The relative biological effectiveness (RBE) of tumor control for proton beam therapy (PBT) compared to photon radiotherapy (RT) is typically assumed to be independent of fractionation. To test this, we modeled published PBT outcome results for early-stage non-small cell lung cancer (NSCLC) treatments across a range of fractionation schedules.</p><p><strong>Materials and methods: </strong>All published and analyzable cohorts were included (399 patients, 413 treated lesions). Two models were used to fit the data: a previously published tumor simulation model that fits photon RT results of NSCLC across all fractionation regimes and the Fowler LQ model with a kick-off time term. The treatment effect of each cohort was referenced to the photon equivalent dose through mechanistic model simulations in a 2 Gy/weekday scenario, with radiobiological parameters determined to simultaneously best-fit all fractionation results. The tumor control RBE of each published treatment schedule, compared to the modeled photon RT effect of the same schedule, was then estimated.</p><p><strong>Results: </strong>For cohorts whose treatments lasted less than three weeks (i.e., 12 fractions or less), the RBE of PBT was in the range of 1.08 to 1.11. However, for fractionated treatments stretching over four weeks or more (20-25 fractions), the relative effectiveness was much lower, with RBEs in the range of 0.82-0.89. This conclusion was unchanged using the simpler Fowler LQ + time model.</p><p><strong>Conclusions: </strong>The proton RBE for hypo-fractionated schedules was 20-30% higher than for conventional schedules. The derived radiobiological parameters of PBT differ significantly from those of photon RT, indicating that PBT is influenced differentially by radiobiological mechanisms which require further investigation.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082931","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":"Molecular Insights into Fungal Innate Immunity Using the <i>Neurospora crassa - Pseudomonas syringae</i> Model.","authors":"Frances Grace Stark, Mari Torii-Karch, Sudyut Yuvaraj, Lucas Bonometti, Pierre Gladieux, N Louise Glass, Ksenia Krasileva","doi":"10.1101/2025.01.22.633611","DOIUrl":"https://doi.org/10.1101/2025.01.22.633611","url":null,"abstract":"<p><p>Recent comparative genomics and mechanistic analyses support the existence of a fungal immune system. Fungi encode genes with features similar to non-self recognition systems in plants, animals, and bacteria. However, limited functional or mechanistic evidence exists for the surveillance-system recognition of heterologous microbes in fungi. We found that <i>Neurospora</i> species coexist with <i>Pseudomonas</i> in their natural environment. We leveraged two model organisms, <i>Neurospora crassa</i> and <i>Pseudomonas syringae</i> DC3000 (PSTDC3000) to observe immediate fungal responses to bacteria. PSTDC3000 preferentially surrounds <i>N. crassa</i> cells on a solid surface, causing environmental dependent growth responses, bacterial proliferation and varying fungal fitness. Specifically, the Type III secretion system (T3SS) ΔhrcC mutant of PSTDC3000 colonized <i>N. crassa</i> hyphae less well. To dissect initial cellular signaling events within the population of germinated asexual spores (germlings), we performed transcriptomics on <i>N. crassa</i> after PSTDC3000 inoculation. Upon contact with live bacteria, a subpopulation of fungal germlings initiate a response as early as ten minutes post-contact revealing transcriptional differentiation of Reactive Oxygen Species (ROS) mechanisms, trace metal warfare, cell wall remodeling dynamics, multidrug-efflux transporters, secondary metabolite synthesis, and excretion. We dissected mutants of plausible receptors, signaling pathways, and responses that <i>N. crassa</i> uses to detect and mount a defense against PSTDC3000 and found seven genes that influence resistant and susceptibility phenotypes of <i>N. crassa</i> to bacterial colonization. Mutants in genes encoding a ctr copper transporter ( <i>tcu-1</i> ), ferric reductase ( <i>fer-1</i> ), superoxide reductase ( <i>sod-2</i> ), multidrug resistance transporter ( <i>mdr-6</i> ), a secreted lysozyme-Glycoside hydrolase ( <i>lyz</i> ) and the Woronin body tether leashin (NCU02793, <i>lah-1</i> and <i>lah-2</i> ) showed a significant reduction of growth in the presence of bacteria, allowing the bacteria to fully take over the fungal mycelium faster than wildtype. In this study we provide a bacterial-fungal model system within Dikarya that allows us to begin to dissect signaling pathways of the putative fungal immune system.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082935","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":"Hydrogen Sulfide Deficiency and Therapeutic Targeting in Cardiometabolic HFpEF: Evidence for Synergistic Benefit with GLP-1/Glucagon Agonism.","authors":"Jake E Doiron, Mahmoud H Elbatreek, Huijing Xia, Xiaoman Yu, Natalie D Gehred, Tatiana Gromova, Jingshu Chen, Ian H Driver, Naoto Muraoka, Martin Jensen, Smitha Shambhu, W H Wilson Tang, Kyle B LaPenna, Thomas E Sharp, Traci T Goodchild, Ming Xian, Shi Xu, Heather Quiriarte, Timothy D Allerton, Alexia Zagouras, Jennifer Wilcox, Sanjiv J Shah, Josef Pfeilschifter, Karl-Friedrich Beck, Thomas M Vondriska, Zhen Li, David J Lefer","doi":"10.1101/2024.09.16.613349","DOIUrl":"10.1101/2024.09.16.613349","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Heart failure with preserved ejection fraction (HFpEF) is a significant public health concern with limited treatment options. Dysregulated nitric oxide-mediated signaling has been implicated in HFpEF pathophysiology, however, little is known about the role of endogenous hydrogen sulfide (H &lt;sub&gt;2&lt;/sub&gt; S) in HFpEF.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;This study evaluated H &lt;sub&gt;2&lt;/sub&gt; S bioavailability in patients and two animal models of cardiometabolic HFpEF and assessed the impact of H &lt;sub&gt;2&lt;/sub&gt; S on HFpEF severity through alterations in endogenous H &lt;sub&gt;2&lt;/sub&gt; S production and pharmacological supplementation. We also evaluated the effects of the H &lt;sub&gt;2&lt;/sub&gt; S donor, diallyl trisulfide (DATS) in combination with the GLP-1/glucagon receptor agonist, survodutide, in HFpEF.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;HFpEF patients and two rodent models of HFpEF (\"two-hit\" L-NAME + HFD mouse and ZSF1 obese rat) were evaluated for H &lt;sub&gt;2&lt;/sub&gt; S bioavailability. Two cohorts of two-hit mice were investigated for changes in HFpEF pathophysiology: (1) endothelial cell cystathionine-γ-lyase (EC-CSE) knockout; (2) H &lt;sub&gt;2&lt;/sub&gt; S donor, JK-1, supplementation. DATS and survodutide combination therapy was tested in ZSF1 obese rats.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;H &lt;sub&gt;2&lt;/sub&gt; S levels were significantly reduced (i.e., 81%) in human HFpEF patients and in both preclinical HFpEF models. This depletion was associated with reduced CSE expression and activity, and increased SQR expression. Genetic knockout of H &lt;sub&gt;2&lt;/sub&gt; S -generating enzyme, CSE, worsened HFpEF characteristics, including elevated E/e' ratio and LVEDP, impaired aortic vasorelaxation and increased mortality. Pharmacologic H &lt;sub&gt;2&lt;/sub&gt; S supplementation restored H &lt;sub&gt;2&lt;/sub&gt; S bioavailability, improved diastolic function and attenuated cardiac fibrosis corroborating an improved HFpEF phenotype. DATS synergized with survodutide to attenuate obesity, improve diastolic function, exercise capacity, and reduce oxidative stress and cardiac fibrosis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;H &lt;sub&gt;2&lt;/sub&gt; S deficiency is evident in HFpEF patients and conserved across multiple preclinical HFpEF models. Increasing H &lt;sub&gt;2&lt;/sub&gt; S bioavailability improved cardiovascular function, while knockout of endogenous H &lt;sub&gt;2&lt;/sub&gt; S production exacerbated HFpEF pathology and mortality. These results suggest H &lt;sub&gt;2&lt;/sub&gt; S dysregulation contributes to HFpEF and increasing H &lt;sub&gt;2&lt;/sub&gt; S bioavailability may represent a novel therapeutic strategy for HFpEF. Furthermore, our data demonstrate that combining H &lt;sub&gt;2&lt;/sub&gt; S supplementation with GLP-1/glucagon receptor agonist may provide synergistic benefits in improving HFpEF outcomes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Highlights: &lt;/strong&gt;H &lt;sub&gt;2&lt;/sub&gt; S deficiency is evident in both human HFpEF patients and two clinically relevant models. Reduced H &lt;sub&gt;2&lt;/sub&gt; S production by CSE and increased metabolism by SQR impair H &lt;sub&gt;2&lt;/sub&gt; S bioavail","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11429683/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142336133","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":"Oxidative Phosphorylation (OXPHOS) Promotes the Formation and Growth of Melanoma Lung and Brain Metastases.","authors":"Renato A Guerrieri, Grant M Fischer, David A Kircher, Aron Y Joon, Jacob R Cortez, Allie H Grossman, Courtney W Hudgens, Debora A Ledesma, Rossana Lazcano, Christian Yb Onana, Barbara G Knighton, Swaminathan Kumar, Qianghua Hu, Y N Vashisht Gopal, Jennifer L McQuade, Wanleng Deng, Lauren E Haydu, Jeffrey E Gershenwald, Alexander J Lazar, Michael T Tetzlaff, Sheri L Holmen, Michael A Davies","doi":"10.1101/2025.01.23.633049","DOIUrl":"https://doi.org/10.1101/2025.01.23.633049","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Melanoma mortality is driven by the formation and growth of distant metastases. Here, we interrogated the role of tumor oxidative phosphorylation (OXPHOS) in the formation of distant metastases in melanoma. OXPHOS was the most upregulated metabolic pathway in primary tumors that formed distant metastases in the RCAS-TVA mouse model of spontaneous lung and brain metastases, and in melanoma patients that developed brain or other distant metastases. Knockout of PGC1α in melanocytes in the RCAS-TVA melanoma mouse model had no impact on primary tumor formation, but markedly reduced the incidence of lung and brain metastases. Genetic knockout of a component of electron transport chain complex I, NDUFS4, in B16-F10 and D4M-UV2 murine melanoma cell lines did not impact tumor incidence following subcutaneous, intravenous, or intracranial injection, but decreased tumor burden specifically in the lungs and brain. Together, these data demonstrate that OXPHOS is critical for the formation of metastases in melanoma.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Structured abstract: &lt;/strong&gt;&lt;b&gt;Purpose:&lt;/b&gt; Melanoma mortality is driven by the formation and growth of distant metastases. However, the process and pathogenesis of melanoma metastasis remain poorly understood. Here, we interrogate the role of tumor oxidative phosphorylation (OXPHOS) in the formation of distant metastases in melanoma.&lt;b&gt;Experimental Design:&lt;/b&gt; This study includes (1) new RNA-seq analysis of primary melanomas from patients characterized for distant metastasis events; (2) RNA-seq analysis and functional testing of genetic OXPHOS inhibition (PGC1α KO) the RCAS-TVA model, which is the only existing immunocompetent murine model of autochthonous lung and brain metastasis formation from primary melanoma tumors; and (3) functional experiments of genetic OXPHOS inhibition (NDUFS4 KO) in the B16-F10 and D4M-UV2 murine melanoma cell lines, including evaluation of subcutaneous, lung, and brain metastatic site dependencies.&lt;b&gt;Results:&lt;/b&gt; OXPHOS was the most upregulated metabolic pathway in primary tumors that formed distant metastases in the RCAS-TVA mouse model of spontaneous lung and brain metastases, and in melanoma patients that developed brain or other distant metastases. Knockout of PGC1a in melanocytes in the RCAS-TVA melanoma mouse model had no impact on primary tumor formation, but markedly reduced the incidence of lung and brain metastases. Genetic knockout of a component of electron transport chain complex I, NDUFS4, in B16-F10 and D4M-UV2 murine melanoma cell lines did not impact tumor incidence following subcutaneous, intravenous, or intracranial injection, but decreased tumor burden specifically in the lungs and brain.&lt;b&gt;Conclusions:&lt;/b&gt; Together, these data demonstrate that OXPHOS is critical for the formation of metastases in melanoma.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Translational relevance: &lt;/strong&gt;Melanoma is the most aggressive form of skin cancer. One hallmark of this disease is a high risk of distant metastasis forma","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083012","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":"Protein corona formed on lipid nanoparticles compromises delivery efficiency of mRNA cargo.","authors":"Elizabeth Voke, Mariah Arral, Henry J Squire, Teng-Jui Lin, Roxana Coreas, Alison Lui, Anthony T Iavarone, Rebecca L Pinals, Kathryn A Whitehead, Markita Landry","doi":"10.1101/2025.01.20.633942","DOIUrl":"https://doi.org/10.1101/2025.01.20.633942","url":null,"abstract":"<p><p>Lipid nanoparticles (LNPs) are the most clinically advanced nonviral RNA-delivery vehicles, though challenges remain in fully understanding how LNPs interact with biological systems. <i>In vivo</i> , proteins form an associated corona on LNPs that redefines their physicochemical properties and influences delivery outcomes. Despite its importance, the LNP protein corona is challenging to study owing to the technical difficulty of selectively recovering soft nanoparticles from biological samples. Herein, we developed a quantitative, label-free mass spectrometry-based proteomics approach to characterize the protein corona on LNPs. Critically, this protein corona isolation workflow avoids artifacts introduced by the presence of endogenous nanoparticles in human biofluids. We applied continuous density gradient ultracentrifugation for protein-LNP complex isolation, with mass spectrometry for protein identification normalized to protein composition in the biofluid alone. With this approach, we quantify proteins consistently enriched in the LNP corona including vitronectin, C-reactive protein, and alpha-2-macroglobulin. We explore the impact of these corona proteins on cell uptake and mRNA expression in HepG2 human liver cells, and find that, surprisingly, increased levels of cell uptake do not correlate with increased mRNA expression in part likely due to protein corona-induced lysosomal trafficking of LNPs. Our results underscore the need to consider the protein corona in the design of LNP-based therapeutics.</p><p><strong>Abstract figure: </strong></p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083033","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":"Multifaceted Actions of Neurosteroids.","authors":"Ajeet Kumar, Mingxing Qian, Yuanjian Xu, Ann Benz, Douglas F Covey, Charles F Zorumski, Steven Mennerick","doi":"10.1101/2025.01.22.634297","DOIUrl":"https://doi.org/10.1101/2025.01.22.634297","url":null,"abstract":"<p><strong>Background and purpose: </strong>Neurosteroids modulate neuronal function and are promising therapeutic agents for neuropsychiatric disorders. Neurosteroid analogues are approved for treating postpartum depression and are of interest in other disorders. GABA-A receptors are well characterized targets of natural neurosteroids, but other biological pathways are likely relevant to therapeutic mechanisms and/or to off-target effects. We performed hypothesis-generating <i>in silico</i> analyses and broad <i>in vitro</i> biological screens to assess the range of actions of neurosteroids analogues of varying structural attributes.</p><p><strong>Key results: </strong>We employed <i>in silico</i> molecular similarity analysis and network pharmacology to elucidate likely targets. This analysis confirmed likely targets beyond GABA-A receptors. We then functionally screened 19 distinct neurosteroid structures across 78 targets representing interconnected signaling pathways, complemented with a limited screen of kinase activation. Results revealed unanticipated modulation of targets by neurosteroids with some structural selectivity. Many compounds-initiated androgen receptor translocation with little or no enantioselectivity. Modulation of multiple G-protein receptors was also unexpected.</p><p><strong>Conclusions and implications: </strong>Neurosteroids are ascendant treatments in neuropsychiatry, but their full spectrum of actions remains unclear. This virtual and biological screening discovery approach opens new vistas for exploring mechanism of neurosteroids analogues. The multifaceted approach provides an unbiased, holistic exploration of the potential effects of neurosteroids across various molecular targets and provides a platform for future validation studies to aid drug discovery.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082947","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":"17β-Estradiol Counteracts Pathological Microtubule Remodeling To Enhance Cardiac Function.","authors":"Ryan Moon, Neal T Vogel, Jenna B Mendelson, Lynn M Hartweck, John P Carney, Minwoo Kim, Melissa K Gardner, Sasha Prisco, Kurt W Prins","doi":"10.1101/2025.01.22.634271","DOIUrl":"10.1101/2025.01.22.634271","url":null,"abstract":"<p><p>The female-predominate sex hormone 17β-estradiol exerts cardioprotective effects via multiple mechanisms. Available data demonstrate 17β-estradiol modulates microtubule dynamics <i>in vitro</i> , but its effects on pathogenic microtubule remodeling in pressure-overloaded cardiomyocytes are unexplored. Here, we show 17β-estradiol directly blunts microtubule polymerization <i>in vitro</i> , counteracts endothelin-mediated microtubule remodeling in iPSC-cardiomyocytes, and mitigates microtubule stabilization in pulmonary artery banded right ventricular cardiomyocytes. 17β-estradiol treatment blunts cardiomyocyte and nuclear hypertrophy, restores t-tubule architecture, and prevents mislocalization of connexin-43 in RV cardiomyocytes of pulmonary artery banded rats. These cellular phenotypes are paired with significant improvements in RV function. Thus, we propose 17β-estradiol exerts cardioprotective effects via direct modulation of microtubules in addition to its well ascribed signaling functions.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082903","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":"Decoding words during sentence production: Syntactic role encoding and structure-dependent dynamics revealed by ECoG.","authors":"Adam M Morgan, Orrin Devinsky, Werner K Doyle, Patricia Dugan, Daniel Friedman, Adeen Flinker","doi":"10.1101/2024.10.30.621177","DOIUrl":"10.1101/2024.10.30.621177","url":null,"abstract":"<p><p>Sentence production is the uniquely human ability to transform complex thoughts into strings of words. Despite the importance of this process, language production research has primarily focused on single words. However, it remains a largely untested assumption that the principles of word production generalize to more naturalistic utterances like sentences. Here, we investigate this using high-resolution neurosurgical recordings (ECoG) and an overt production experiment where patients produced six words in isolation (picture naming) and in sentences (scene description). We trained machine learning classifiers to identify the unique brain activity patterns for each word during picture naming, and used these patterns to decode which words patients were processing while they produced sentences. Our findings confirm that words share cortical representations across tasks, but reveal a division of labor within the language network. In sensorimotor cortex, words were consistently activated in the order in which they were said in the sentence. However, in inferior and middle frontal gyri (IFG and MFG), the order in which words were processed depended on the syntactic structure of the sentence. Deeper analysis of this pattern revealed a spatial code for representing a word's position in the sentence, with subjects selectively encoded in IFG and objects in MFG. Finally, we argue that the processes we observe in prefrontal cortex may impose a subtle pressure on language evolution, explaining why nearly all the world's languages position subjects before objects.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11565881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142650394","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":"Caliber of zebrafish touch-sensory axons is dynamic in vivo.","authors":"Kaitlin Ching, Alvaro Sagasti","doi":"10.1101/2024.12.04.626901","DOIUrl":"10.1101/2024.12.04.626901","url":null,"abstract":"<p><p>Cell shape is crucial to cell function, particularly in neurons. The cross-sectional diameter, also known as caliber, of axons and dendrites is an important parameter of neuron shape, best appreciated for its influence on the speed of action potential propagation. Many studies of axon caliber focus on cell-wide regulation and assume that caliber is static. Here, we have characterized local variation and dynamics of axon caliber in vivo using the peripheral axons of zebrafish touch-sensing neurons at embryonic stages, prior to sex determination. To obtain absolute measurements of caliber in vivo, we paired sparse membrane labeling with super-resolution microscopy of neurons in live fish. We observed that axon segments had varicose or \"pearled\" morphologies, and thus vary in caliber along their length, consistent with reports from mammalian systems. Sister axon segments originating from the most proximal branch point in the axon arbor had average calibers that were uncorrelated with each other. Axon caliber also tapered across the branch point. Varicosities and caliber, overall, were dynamic on the timescale of minutes, and dynamicity changed over the course of development. By measuring the caliber of axons adjacent to dividing epithelial cells, we found that skin cell division is one aspect of the cellular microenvironment that may drive local differences and dynamics in axon caliber. Our findings support the possibility that spatial and temporal variation in axon caliber could significantly influence neuronal physiology.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879394","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}