Function (Oxford, England)最新文献

{"title":"Proton-Secreting Cells as Drivers of Inflammation and Sperm Dysfunction in LPS-Induced Epididymitis.","authors":"A A S Da Silva, F Barrachina, M C Avenatti, M L Elizagaray, I Bastepe, E Sasso-Cerri, M A Battistone","doi":"10.1093/function/zqaf023","DOIUrl":"10.1093/function/zqaf023","url":null,"abstract":"<p><p>Proton-secreting cells in various organs, such as the kidney and epididymis, regulate pH balance, maintain cellular homeostasis, and support key physiological processes. More recently, these specialized cells have emerged as key contributors to mucosal immunity, orchestrating immune activation. Epididymitis is an inflammatory condition that significantly impacts male fertility, often due to a lack of diagnosis and treatment. This study investigates the role of region-specific epididymal proton-secreting clear cells (CCs) in shaping immune responses during LPS-induced epididymitis in mice. We found that in response to lipopolysaccharide (LPS), CCs rapidly shifted to a proinflammatory phenotype, marked by the upregulation of cytokines and chemokines, alongside the downregulation of genes involved in sperm maturation. Morphological changes in CCs, including increased apical blebs and altered shape across different epididymal segments, suggest their active role in immune responses. Moreover, mononuclear phagocytes reduced their luminal-reaching projections in the proximal epididymis after the LPS challenge. This bacterial antigen triggered dendritic cell migration and neutrophil infiltration in the distal epididymis. These immune landscape alterations contributed to epithelial damage and impaired sperm maturation, as evidenced by decreased sperm motility following LPS intravasal-epididymal injection. Our findings indicate that proton-secreting cells are immune gatekeepers in the epididymis, initiating immune responses and disrupting sperm maturation. This research enhances the understanding of epithelial immunoregulation and will help to develop novel diagnostic and therapeutic strategies for epididymitis and male infertility. Furthermore, insights into CC-mediated immune responses could inform the development of new approaches for male contraception.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210408","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":"Activation of the Carotid Body by Kappa Opioid Receptors Mitigates Fentanyl-Induced Respiratory Depression.","authors":"Ying-Jie Peng, Jayasri Nanduri, Ning Wang, Zheng Xie, Aaron P Fox, Nanduri R Prabhakar","doi":"10.1093/function/zqaf020","DOIUrl":"10.1093/function/zqaf020","url":null,"abstract":"<p><p>Previous studies reported that opioids depress breathing by inhibiting respiratory neural networks in the brainstem. The effects of opioids on sensory inputs regulating breathing are less studied. This study examined the effects of fentanyl and sufentanil on carotid body neural activity, a crucial sensory regulator of breathing. Both opioids stimulated carotid body afferent nerve activity and increased glomus cell [Ca2+]i levels. RNA sequencing and immunohistochemistry revealed a high abundance of κ opioid receptors (KORs) in carotid bodies, but no µ or δ opioid receptors. A KOR agonist, like fentanyl, stimulated carotid body afferents, while a KOR antagonist blocked carotid body activation by fentanyl and KOR agonist. In unanesthetized rats, fentanyl initially stimulated breathing, followed by respiratory depression. A KOR agonist stimulated breathing without respiratory inhibition, and this effect was absent in carotid body-denervated rats. Combining fentanyl with a KOR agonist attenuated respiratory depression in rats with intact carotid body but not in carotid body-denervated rats. These findings highlight previously uncharacterized activation of carotid body afferents by fentanyl via KORs as opposed to depression of brainstem respiratory neurons by µ opioid receptors and suggest that KOR agonists might counteract the central depressive effects of opioids on breathing.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082540","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":"Moving Beyond Barker's Hypothesis Towards New Therapies for the Treatment of Fetal Growth Restriction.","authors":"Laura E Coats, Barbara T Alexander","doi":"10.1093/function/zqaf022","DOIUrl":"10.1093/function/zqaf022","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144182293","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":"Aerobic Capacity and Exercise Mediate Protection Against Hepatic Steatosis via Enhanced Bile Acid Metabolism.","authors":"Benjamin A Kugler, Adrianna Maurer, Xiaorong Fu, Edziu Franczak, Nick Ernst, Kevin Schwartze, Julie Allen, Tiangang Li, Peter A Crawford, Lauren G Koch, Steven L Britton, Kartik Shankar, Shawn C Burgess, John P Thyfault","doi":"10.1093/function/zqaf019","DOIUrl":"10.1093/function/zqaf019","url":null,"abstract":"<p><p>High cardiorespiratory fitness and exercise show evidence of altering bile acid (BA) metabolism and are known to protect or treat diet-induced hepatic steatosis, respectively. Here, we tested the hypothesis that high intrinsic aerobic capacity and exercise both increase hepatic BA synthesis measured by the incorporation of 2H2O. We also leveraged mice with inducible liver-specific deletion of Cyp7a1 (LCyp7a1KO), which encodes the rate-limiting enzyme for BA synthesis, to test if exercise-induced BA synthesis is critical for exercise to reduce hepatic steatosis. The synthesis of hepatic BA, cholesterol, and de novo lipogenesis was measured in rats bred for either high (HCR) or low (LCR) aerobic capacity consuming acute and chronic high-fat diets. HCR rats had increased synthesis of cholesterol and certain BA species in the liver compared to LCR rats. We also found that chronic exercise with voluntary wheel running (VWR) (4 weeks) increased newly synthesized BAs of specific species in male C57BL/6J mice compared to sedentary mice. Loss of Cyp7a1 resulted in fewer new BAs and increased liver triglycerides compared to controls after a 10-week high-fat diet. Additionally, exercise via VWR for 4 weeks effectively reduced hepatic triglycerides in the high-fat diet-fed control male and female mice as expected; however, exercise in LCyp7a1KO mice did not lower liver triglycerides in either sex. These results show that aerobic capacity and exercise increase hepatic BA metabolism, which may be critical for combatting hepatic steatosis.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804996","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":"Science Is at a Crossroads-and Physiology With It: A Statement from the APS Chief Executive Officer.","authors":"Scott Steen","doi":"10.1093/function/zqaf025","DOIUrl":"10.1093/function/zqaf025","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12199138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Perspective on \"Signal Transduction Pathway Mediating Carotid Body Dependent Sympathetic Activation and Hypertension by Chronic Intermittent Hypoxia\".","authors":"Gary C Sieck","doi":"10.1093/function/zqaf012","DOIUrl":"10.1093/function/zqaf012","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560177","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":"KATP Channels as Target for Remodeling Connectivity in Type 2 Diabetes.","authors":"Fei Kang, Herbert Y Gaisano","doi":"10.1093/function/zqaf013","DOIUrl":"10.1093/function/zqaf013","url":null,"abstract":"","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931611/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652383","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":"Response of the Nephron Arterial Network and Its Interactions to Acute Hypertension: A Simulation.","authors":"Donald J Marsh, Niels-Henrik Holstein-Rathlou","doi":"10.1093/function/zqae049","DOIUrl":"10.1093/function/zqae049","url":null,"abstract":"<p><p>We simulated the dynamics of a group of 10 nephrons supplied from an arterial network and subjected to acute increases in blood pressure. Arterial lengths and topology were based on measurements of a vascular cast. The model builds on a previous version exercised at a single blood pressure with 2 additional features: pressure diuresis and the effect of blood pressure on efferent arteriolar vascular resistance. The new version simulates autoregulation, and reproduces tubule pressure oscillations. Individual nephron dynamics depended on mean arterial pressure and the axial pressure gradient required to cause blood flow through the arteries. Rhythmic blood withdrawal into afferent arterioles caused blood flow fluctuations in downstream vessels. Blood pressure dependent changes in nephron dynamics affected synchronization metrics. The combination of vascular pressure gradients and oscillations created a range of arterial pressures at the origins of the 10 afferent arterioles. Because arterial blood pressure in conscious animals has ${1}/{f}$ dynamics, we applied an arterial pressure pattern with such dynamics to the model. Amplitude of tubule pressure oscillations were affected by the ${1}/{f}$ blood pressure fluctuations, but the oscillation frequencies did not change. The pressure gradients required to deliver blood to all afferent arterioles impose a complexity that affects nephrons according to their locations in the network, but other interactions compensate to ensure the stability of the system. The sensitivity of nephron response to location on the network, and the constancy of the tubular oscillation frequency provide a spatial and time context.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142636214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Hands-On Introduction to Data Analytics for Biomedical Research.","authors":"Joshua Pickard, Victoria E Sturgess, Katherine O McDonald, Nicholas Rossiter, Kelly B Arnold, Yatrik M Shah, Indika Rajapakse, Daniel A Beard","doi":"10.1093/function/zqaf015","DOIUrl":"10.1093/function/zqaf015","url":null,"abstract":"<p><p>Artificial intelligence (AI) applications are having increasing impacts in the biomedical sciences. Modern AI tools enable uncovering hidden patterns in large datasets, forecasting outcomes, and numerous other applications. Despite the availability and power of these tools, the rapid expansion and complexity of AI applications can be daunting, and there is a conspicuous absence of consensus on their ethical and responsible use. Misapplication of AI can result in invalid, unclear, or biased outcomes, exacerbated by the unfamiliarity of many biomedical researchers with the underlying mathematical and computational principles. To address these challenges, this review and tutorial paper aims to achieve three primary objectives: (1) highlight prevalent data science applications in biomedical research, including data visualization, dimensionality reduction, missing data imputation, and predictive model training and evaluation; (2) provide comprehensible explanations of the mathematical foundations underpinning these methodologies; and (3) guide readers on the effective use and interpretation of software tools for implementing these methods in biomedical contexts. While introductory, this guide covers core principles essential for understanding advanced applications, empowering readers to critically interpret results, assess tools, and explore the potential and limitations of machine learning in their research. Ultimately, this paper serves as a practical foundation for biomedical researchers to confidently navigate the growing intersection of AI and biomedicine.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11999024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812953","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":"Aryl Hydrocarbon Receptor Activation Promotes Effector CD4+ T Cell Homeostasis and Restrains Salt-Sensitive Hypertension.","authors":"Patrick A Molina, Claudia J Edell, Luke S Dunaway, Cailin E Kellum, Rachel Q Muir, Melissa S Jennings, Jackson C Colson, Carmen De Miguel, Megan K Rhoads, Ashlyn A Buzzelli, Laurie E Harrington, Selene Meza-Perez, Troy D Randall, Davide Botta, Dominik N Müller, David M Pollock, Craig L Maynard, Jennifer S Pollock","doi":"10.1093/function/zqaf001","DOIUrl":"10.1093/function/zqaf001","url":null,"abstract":"<p><p>Excess dietary salt and salt-sensitivity contribute to cardiovascular disease. Distinct T cell phenotypic responses to high salt and hypertension, as well as influences from environmental cues, are not well understood. The aryl hydrocarbon receptor (AhR) is activated by dietary ligands, promoting T cell and systemic homeostasis. We hypothesized that activating AhR supports CD4+ homeostatic functions, such as cytokine production and mobilization, in response to high salt intake while mitigating salt-sensitive hypertension. In the intestinal mucosa, we demonstrate that a high-salt diet (HSD) is a key driving factor, independent of hypertension, in diminishing interleukin 17A (IL-17A) production by CD4+ T (Th17) cells without disrupting circulating cytokines associated with Th17 function. Previous studies suggest that hypertensive patients and individuals on a HSD are deficient in AhR ligands or agonistic metabolites. We found that activating AhR augments Th17 cells during experimental salt-sensitive hypertension. Further, we demonstrate that activating AhR in vitro contributes to sustaining Th17 cells in the setting of excess salt. Using photoconvertible Kikume Green-Red mice, we also revealed that HSD drives CD4+ T cell mobilization. Next, we found that excess salt augments T cell mobilization markers, validating HSD-driven T cell migration. Also, we found that activating AhR mitigates HSD-induced T cell migration markers. Using telemetry in a model of experimental salt-sensitivity, we found that activating AhR prevents the development of salt-sensitive hypertension. Collectively, stimulating AhR through dietary ligands facilitates immunologic and systemic functions amid excess salt intake and restrains the development of salt-sensitive hypertension.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142959688","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}