Function (Oxford, England)最新文献

{"title":"A Hands-On Introduction to Data Analytics for Biomedical Research.","authors":"Joshua Pickard, Victoria E Sturgess, Katherine McDonald, Nicholas Rossiter, Kelly Arnold, Yatrik M Shah, Indika Rajapakse, Daniel A Beard","doi":"10.1093/function/zqaf015","DOIUrl":"https://doi.org/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":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","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":"https://doi.org/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) vs. 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/6 J 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":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143804996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lentivirus mediated trophoblast specific Deptor knockdown increases transplacental system A and system L amino acid transport and fetal growth in mice.","authors":"Avery Kramer, Owen R Vaughan, Kenneth Barentsen, Johann Urschitz, Theresa L Powell, Thomas Jansson, Fredrick J Rosario","doi":"10.1093/function/zqaf018","DOIUrl":"https://doi.org/10.1093/function/zqaf018","url":null,"abstract":"<p><p>Mechanistic target of rapamycin (mTOR) signaling is a positive regulator of human placental function including System A/L amino acid transport activity. Placental mTOR signaling is inhibited in fetal growth restriction (FGR) and activated in fetal overgrowth in women, however the causes of these changes in placental mTOR signaling are unknown. DEP-domain containing mTOR-interacting protein (DEPTOR) is an endogenous inhibitor of mTOR. We tested the hypothesis that trophoblast-specific Deptor knockdown activates placental mTOR signaling and amino acid transport and causes fetal overgrowth. Using lentiviral transduction of blastocyst trophectoderm with a small hairpin RNA, we achieved 47% knockdown of placental Deptor mRNA expression, without altering fetal Deptor mRNA expression. Trophoblast-specific Deptor knockdown activated placental mTORC1 and mTORC2 signaling and increased trophoblast plasma membrane (TPM) LAT1 and SNAT2 protein abundance, and TPM System L and System A transporter activity. In addition, Deptor knockdown increased in vivo transplacental System A and L amino acid transport and stimulated placental and fetal growth. In human FGR, placental DEPTOR protein expression was higher and negatively correlated with birth weight and microvillus plasma membrane System A activity. In conclusion, we provide mechanistic evidence that DEPTOR regulates placental mTOR signaling and amino acid transport and fetal growth in vivo. We speculate that modulation of placental Deptor is a promising target for intervention in pregnancies characterized by abnormal placental function and fetal growth.</p>","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","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":"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}

{"title":"Phosphatases Control the Duration and Range of cAMP/PKA Microdomains.","authors":"Filippo Conca, Doruk Kaan Bayburtlu, Mauro Vismara, Nicoletta C Surdo, Alessandra Tavoni, Leonardo Nogara, Adamo Sarra, Stefano Ciciliot, Giulietta Di Benedetto, Liliana F Iannucci, Konstantinos Lefkimmiatis","doi":"10.1093/function/zqaf007","DOIUrl":"10.1093/function/zqaf007","url":null,"abstract":"<p><p>The spatiotemporal interplay between the second messenger cyclic AMP (cAMP) and its main effector, protein kinase A (PKA), is crucial for the pleiotropic nature of this cascade. To maintain a high degree of specificity, the cAMP/PKA axis is organised into functional units called microdomains, precisely distributed within the cell. While the subcellular allocation of PKA is guaranteed by a family of tethers called A-Kinase-anchoring Proteins (AKAPs), the mechanisms underlying the efficient confinement of a microdomain's functional effects are not fully understood. Here, we used FRET-based sensors to detect cAMP levels and PKA-dependent phosphorylation within specific subcellular compartments. We find that cellular cAMP levels may depend on different mechanisms and are responsible for the activation of local PKA enzymes. On the other hand, the dephosphorylating actions of phosphatases dictate the duration of the microdomain's effects. To test the range of action of PKA microdomains, we used rigid aminoacidic nanorulers to distance our FRET sensors from their original location for 10 or 30 nm. Interestingly, we established that cAMP levels do not affect the spatial range of the microdomain while on the contrary, phosphatase activity provides a functional boundary for phosphorylated PKA targets. Finally, using the same strategy to distance phosphatases from the mitochondria, we found that enzymes close to the outer mitochondrial membrane produced a fragmented phenotype that was not observed when phosphatases were moved to 30 nm from the organelle's surface. Our findings contribute to the design of a picture where 2 microdomain-forming events have distinct roles. Cyclic AMP elevations trigger the initial activation of subcellular PKA moieties, while the temporal and spatial extent of the PKA's actions are regulated by phosphatases.</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/PMC11931618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477291","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":"Role of Pannexin 1, P2X7, and CFTR in ATP Release and Autocrine Signaling by Principal Cells of the Epididymis.","authors":"Kéliane Brochu, Aram Minas, Larissa Berloffa Belardin, Christine Légaré, Sylvie Breton","doi":"10.1093/function/zqaf016","DOIUrl":"10.1093/function/zqaf016","url":null,"abstract":"<p><p>Extracellular adenosine triphosphate (ATP) is a signaling molecule that acts as a paracrine and autocrine modulator of cell function. Here, we characterized the role of luminal ATP in the regulation of epithelial principal cells (PCs) in the epididymis, an understudied organ that plays crucial roles in male reproduction. We previously showed that ATP secretion by PCs is part of a complex communication system that ensures the establishment of an optimal luminal acidic environment in the epididymis. However, the molecular mechanisms regulating ATP release and the role of ATP-mediated signaling in PCs acidifying functions are not fully understood. In other cell types, pannexin 1 (PANX-1) has been associated with ATP-induced ATP release through the interaction with the purinergic P2X7 receptor. Here, we show that PANX-1 and P2X7 are located in the apical membrane of PCs in the mouse epididymis. Functional analysis using the immortalized epididymal PC cell line (DC2) and the mouse epididymis perfused in vivo showed that (1) PANX-1 and P2X7 participate in ATP release by DC2 cells, together with cystic fibrosis transmembrane conductance regulator (CFTR); (2) several ATP-activated P2Y and P2X purinergic receptors are expressed in DC2 cells; (3) the nonhydrolyzable ATP analog ATPγS induces a dose-dependent increase in intracellular Ca2+ concentration in DC2 cells, a process that is mainly mediated by P2X7; and (4) perfusion of the epididymal lumen in vivo with ATPγS induces the internalization of apical sodium-hydrogen exchanger 3 (NHE3) in PCs. Altogether, this study shows that luminal ATP, regulated by CFTR, PANX-1, and P2X7, modulates sodium-proton exchange in PCs in an autocrine manner through activation of purinergic receptor-mediated intracellular calcium signaling.</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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does Anybody Really Know What Time It Is?","authors":"David M Pollock","doi":"10.1093/function/zqaf011","DOIUrl":"10.1093/function/zqaf011","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/PMC11931613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143560179","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}