Function (Oxford, England)最新文献

Sequentially constrained randomization in preclinical animal studies. 临床前动物研究的顺序约束随机化。

IF 3.8

Function (Oxford, England) Pub Date : 2025-10-08 DOI: 10.1093/function/zqaf046

Joseph Rigdon, Michael Walkup, David Amar, Matthew T Wheeler, Laurie J Goodyear, Sue Bodine, Karyn Esser, Denise Esserman, Michael E Miller

{"title":"Sequentially constrained randomization in preclinical animal studies.","authors":"Joseph Rigdon, Michael Walkup, David Amar, Matthew T Wheeler, Laurie J Goodyear, Sue Bodine, Karyn Esser, Denise Esserman, Michael E Miller","doi":"10.1093/function/zqaf046","DOIUrl":"https://doi.org/10.1093/function/zqaf046","url":null,"abstract":"Randomization is a key component to scientific inquiry as it facilitates unbiased estimation of treatment effects via balancing of measured and unmeasured prognostic variables across treatment groups. Recent reports have noted that randomization is lacking in animal studies, threatening internal validity. Animal studies often involve rodents (mice or rats) sent in small batches to laboratories or bred on site in litters. Randomizing half of each batch to treatment and half to control (simple randomization) is a viable strategy to implementing randomization in animal studies, however experimenters may be concerned about chance imbalances, given the smaller sample sizes utilized in animal studies, in key prognostic variables, e.g., baseline weight. Constrained randomization, wherein key prognostic factors are balanced within each batch, may offer benefits over simple randomization, especially if it were sequential, i.e., could take balance of previous batches into account when randomly assigning treatment in current batch. Adjusting for prognostic variables in a statistical model is a way to address imbalances, independent of choice of randomization scheme. In simulations designed to mimic realistic scenarios, all methods of randomization tested led to unbiased treatment effect estimation, with model adjustment reducing standard errors and improving statistical power in all scenarios. Treatment effects in unadjusted and adjusted models were nearly an order of magnitude closer to each other in sequentially constrained randomization compared to simple randomization, yielding more robust findings.","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254016","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}

引用次数: 0

Sex Differences in Renal Mitochondrial Respiration and H2O2 Emission in Young Dahl Salt-Sensitive Rats. 幼龄达尔盐敏感大鼠肾脏线粒体呼吸和H2O2排放的性别差异。

IF 3.8

Function (Oxford, England) Pub Date : 2025-10-07 DOI: 10.1093/function/zqaf045

Chun Yang, Devanshi D Dave, Sri Rahavi Boovarahan, Satoshi Shimada, Aron Geurts, Ranjan K Dash, Allen W Cowley

{"title":"Sex Differences in Renal Mitochondrial Respiration and H2O2 Emission in Young Dahl Salt-Sensitive Rats.","authors":"Chun Yang, Devanshi D Dave, Sri Rahavi Boovarahan, Satoshi Shimada, Aron Geurts, Ranjan K Dash, Allen W Cowley","doi":"10.1093/function/zqaf045","DOIUrl":"https://doi.org/10.1093/function/zqaf045","url":null,"abstract":"Sexual dimorphism has a significant influence on physiology, disease susceptibility, and therapeutic responses, yet its impact on kidney mitochondrial function remains poorly understood. We hypothesized that sex differences in kidney mitochondrial function would parallel those observed in other organs, where females often exhibit higher oxidative capacity and lower oxidative stress. To test this, we measured the kinetics of oxidative phosphorylation (OXPHOS) and hydrogen peroxide (H2O2) emission in isolated cortical and outer medullary (OM) mitochondria from young male and female Dahl salt-sensitive (SS) rats fed a low-salt diet. Contrary to our hypothesis, male cortical mitochondria showed significantly higher O2 consumption during ATP synthesis (OXPHOS) than females when fueled by either complex I- or complex II-linked substrates. Cortical H2O2 emission was also greater in males, under both forward and reverse electron transport fueled by succinate. This difference was consistent with an increase in Complex IV protein abundance despite no changes in mitochondrial DNA copy number or markers of mitochondrial dynamics. In the OM, both mitochondrial respiration and H2O2 emission were higher than in the cortex, but no sex differences were observed. Analysis of kidney transporter protein abundance revealed a sex-specific \"downstream shift\" in nephron transport function. Males showed a greater sodium reabsorption potential in the proximal tubules (PT) and reduced capacity in distal segments. The elevated cortical OXPHOS activity in males likely supports these higher PT transport demands. These results indicate that sex differences in renal mitochondrial function diverge from those in other organs, suggesting that kidney-specific energetic demands override systemic maternal inheritance and sex hormone effects. The higher cortical H2O2 emission in males may contribute to a greater susceptibility to kidney injury and salt sensitivity.","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145240511","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}

引用次数: 0

Gastrocnemius myofiber type and mitochondrial alterations associated with peripheral artery disease severity. 腓肠肌肌纤维类型和线粒体改变与外周动脉疾病严重程度相关。

IF 3.8

Function (Oxford, England) Pub Date : 2025-10-06 DOI: 10.1093/function/zqaf047

Kate Kosmac, Rena Dana Wang, Jada Stewart, Parminder Kaur, Ahmed Ismaeel, Haseeb Ahsan, Lisa Hartnell, Esther E Dupont-Versteegden, Mary M McDermott, Robert L Sufit, Luigi Ferrucci, Charlotte A Peterson

{"title":"Gastrocnemius myofiber type and mitochondrial alterations associated with peripheral artery disease severity.","authors":"Kate Kosmac, Rena Dana Wang, Jada Stewart, Parminder Kaur, Ahmed Ismaeel, Haseeb Ahsan, Lisa Hartnell, Esther E Dupont-Versteegden, Mary M McDermott, Robert L Sufit, Luigi Ferrucci, Charlotte A Peterson","doi":"10.1093/function/zqaf047","DOIUrl":"https://doi.org/10.1093/function/zqaf047","url":null,"abstract":"The extent of walking impairment varies among individuals with peripheral artery disease (PAD), which may reflect differences in the adaptability of lower extremity muscles to ischemia-reperfusion injury characteristic of the disease. Analyses of gastrocnemius muscle biopsies from 113 individuals with PAD (mean ankle-brachial index (ABI) = 0.65 ± 0.13, 38 (33.6%) women, 76 (67.2%) Black) showed a wide range of myofiber type distributions (9.6%-82.6% type 1 myofibers). The abundance of oxidative type 1 myofibers negatively correlated with ABI (r=-0.22, p = 0.02), a measure of PAD severity. The abundance of type 1 myofibers also negatively correlated to 2a/x myofiber abundance (r=-0.76, p < 0.001). Eighty % of participants had NCAM + myofibers, a potential indicator of myofiber denervation. Overall, 3.2% of total myofibers were NCAM + . Of 113 muscle biopsies, 86 (76.1%) contained type 1 myofibers with regions lacking intermyofibrillar mitochondria (IMFM-), which may represent formation of target myofibers. In type 1 myofiber IMFM- areas, 77.8% contained 2x myosin heavy chain (MyHC) and/or the autophagy marker LC3. Electron microscopy within one muscle with IMFM- myofibers confirmed sarcomere disruption in IMFM- regions. These analyses support the possibility of type 2 myofibers transitioning to type 1 in PAD and suggest IMFM- target fibers may represent visualization of this process for the first time. Because type 1 myofibers are more resistant to oxidative damage, results suggest the possibility that a higher proportion of type 1 myofibers in PAD with increasing disease severity may be a compensatory mechanism to maintain muscle.","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234183","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}

引用次数: 0

Acidic Offense: Proton-Secreting Cells Orchestrate Inflammation and Sperm Damage in Epididymitis. 酸性攻击：在附睾炎中质子分泌细胞协调炎症和精子损伤。

IF 3.8

Function (Oxford, England) Pub Date : 2025-09-16 DOI: 10.1093/function/zqaf044

Ming Wang, Zhenyu Zhou, Sudhanshu Bhushan

引用次数: 0

Modeling Pain Without Injury: Inherited Rodent Models as Mechanistic Windows into Chronic Pain. 无损伤疼痛建模：遗传啮齿动物模型作为慢性疼痛的机制窗口。

IF 3.8

Function (Oxford, England) Pub Date : 2025-09-16 DOI: 10.1093/function/zqaf043

Luiz F Ferrari, Norman E Taylor

{"title":"Modeling Pain Without Injury: Inherited Rodent Models as Mechanistic Windows into Chronic Pain.","authors":"Luiz F Ferrari, Norman E Taylor","doi":"10.1093/function/zqaf043","DOIUrl":"https://doi.org/10.1093/function/zqaf043","url":null,"abstract":"Chronic pain is a multifactorial condition often accompanied by comorbidities such as anxiety, depression, and cardiovascular dysfunction. Traditional injury-based models have provided valuable mechanistic insights but are limited in their ability to capture the spontaneous, polygenic, and systemic nature of human chronic pain. Inherited pain models, such as consomic rat strains, transgenic mice, and recombinant inbred panels, offer a unique advantage towards bridging this translational gap: they enable the study of pain-related mechanisms in the absence of experimental injury, reducing confounding effects and better reflecting clinical complexity. These models serve as powerful platforms to investigate neuroimmune signaling, oxidative stress, and epigenetic regulation, and to explore how these pathways interact with sex, stress, and systemic comorbidities. Importantly, while referred to as \"inherited pain models\", these systems are not designed to model pain transmission across generations, but rather to uncover genetically-driven susceptibility to pain and its mechanistic basis. Many of the mechanisms identified in these models overlap with findings from human genome-wide association studies (GWAS), reinforcing their translational relevance. Beyond mechanistic discovery, inherited pain models can be used for the identification of biomarkers, the study of gene-environment interactions, and the development of mechanism-based therapies. Integration with multi-omics technologies and patient-derived systems further enhance their utility. This review highlights how these models are reshaping the field by enabling biologically-informed approaches to diagnosis, prevention, and treatment, thus laying the foundations for a more precise and proactive era in pain medicine.","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093038","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}

引用次数: 0

The Amount of Releasable Insulin Depends on Continuous Oxidative Phosphorylation. 胰岛素的释放量取决于持续的氧化磷酸化。

IF 3.8

Function (Oxford, England) Pub Date : 2025-09-15 DOI: 10.1093/function/zqaf033

Carolin Tappe, Manjitha Parambath, Julia Reschke, Ingo Rustenbeck

{"title":"The Amount of Releasable Insulin Depends on Continuous Oxidative Phosphorylation.","authors":"Carolin Tappe, Manjitha Parambath, Julia Reschke, Ingo Rustenbeck","doi":"10.1093/function/zqaf033","DOIUrl":"10.1093/function/zqaf033","url":null,"abstract":"The consensus or canonical model of glucose-stimulated insulin secretion provides that the metabolism of glucose closes KATP channels by increase of the ATP/ADP ratio and that the ensuing depolarization-induced Ca2+ influx through voltage-dependent Ca2+ channels represents the immediate signal for the onset of exocytosis. However, it has been shown earlier that the depolarization-induced secretion can be suppressed by inhibition of the oxidative phosphorylation, pointing to an energy-requiring step presumably located downstream of Ca2+ influx. Here, we have investigated the relation between oxidative phosphorylation and the insulinotropic effect of K+ depolarization to better localize the energy-requiring step. The specific inhibitor of the mitochondrial F1FO ATPase, oligomycin, concentration-dependently and time-dependently inhibited the insulin secretion elicited by a strong K+ depolarization (40 mm). Perifusion with 4 µg/mL of oligomycin for 20, 10, or 5 min prior to the K+ depolarization reduced the amount of insulin secreted from freshly isolated islets from control value to about 5% with a half-time of 1.6 min. 0.4 µg/mL of oligomycin required more time for comparable effects. Cultured islets were less susceptible to the inhibitory action of oligomycin than fresh islets, corresponding to their significantly higher ATP/ADP ratio. The perifusion with oligomycin prior to the K+ depolarization did not decrease the depolarization-elevated cytosolic Ca2+ concentration and did not affect the resting plasma membrane potential and the extent of depolarization by 40 mm KCl. In conclusion, the exocytotic machinery of the beta cell requires a continuously running oxidative phosphorylation to remain responsive to the Ca2+ signal for granule fusion.","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144692665","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

Chronic Stress Induces Sex-Specific Renal Mitochondrial Dysfunction in Mice. 慢性应激诱导小鼠肾线粒体功能障碍。

IF 3.8

Function (Oxford, England) Pub Date : 2025-09-15 DOI: 10.1093/function/zqaf041

Noelle I Frambes, Alexia M Crockett, Amelia M Churillo, Alaina Mullaly, Molly Maranto, Cameron Folk, Lisa A Freeburg, Reilly T Enos, Eliana Cavalli, Susan K Wood, Francis G Spinale, Fiona Hollis, Michael J Ryan

{"title":"Chronic Stress Induces Sex-Specific Renal Mitochondrial Dysfunction in Mice.","authors":"Noelle I Frambes, Alexia M Crockett, Amelia M Churillo, Alaina Mullaly, Molly Maranto, Cameron Folk, Lisa A Freeburg, Reilly T Enos, Eliana Cavalli, Susan K Wood, Francis G Spinale, Fiona Hollis, Michael J Ryan","doi":"10.1093/function/zqaf041","DOIUrl":"10.1093/function/zqaf041","url":null,"abstract":"Chronic psychological stress has been linked to renal disease and is also associated with the development of hypertension. However, the mechanisms by which chronic stress alters renal function and promotes hypertension is unclear. This study tested the hypothesis that chronic stress causes impaired renal mitochondrial function that can lead to increased arterial pressure. Adult male and female C57BL/6 mice were exposed to a chronic unpredictable stress (CUS), or non-stress control, protocol for 28 consecutive days. The protocol models mild, persistent, and variable stress that is a common occurrence in daily life. The CUS protocol induced anxiety relevant behaviors in both male and female mice. CUS increased blood pressure in both sexes, but the increase was greater in female mice. Renal mitochondrial function was unchanged by CUS in male mice. In contrast, renal mitochondrial function was impaired in the proestrus phase of the estrous cycle in female mice. Female mice exposed to CUS had low renal progesterone. Impaired mitochondrial function correlated with low renal progesterone, which correlated with increased blood pressure. Renal sex steroids were unchanged by CUS in males. Urinary albumin excretion was significantly increased in female mice exposed to CUS. CUS did not affect urinary albumin excretion in male mice exposed to CUS. These data show a direct role for CUS in causing an increase in blood pressure. The mechanisms causing increased pressure in CUS-exposed mice are sex-dependent, with low renal progesterone leading to impaired renal mitochondrial function as a potential mechanism underlying the elevated pressure in female mice.","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":"6 5","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093049","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

Leading the Understanding of Lymphatic Function. 引领对淋巴功能的认识。

IF 3.8

Function (Oxford, England) Pub Date : 2025-09-15 DOI: 10.1093/function/zqaf038

Walter L Murfee, Jerome W Breslin, Brant E Isakson

引用次数: 0

Beyond the Microbiome: The Gut's Role in Hypertension. 超越微生物组：肠道在高血压中的作用。

IF 3.8

Function (Oxford, England) Pub Date : 2025-09-15 DOI: 10.1093/function/zqaf037

Wenjun Deng, Mengying Zhu, Isaac Lloyd, Manaswini Nedunuri, Chen Zhou, Wenting Liu, Yawen Li, Qi Li, Xinyue Wang, Qiangxiang Zhang, Tania Akter Jhuma, Jing Li, Tao Yang

{"title":"Beyond the Microbiome: The Gut's Role in Hypertension.","authors":"Wenjun Deng, Mengying Zhu, Isaac Lloyd, Manaswini Nedunuri, Chen Zhou, Wenting Liu, Yawen Li, Qi Li, Xinyue Wang, Qiangxiang Zhang, Tania Akter Jhuma, Jing Li, Tao Yang","doi":"10.1093/function/zqaf037","DOIUrl":"10.1093/function/zqaf037","url":null,"abstract":"This review emphasizes the importance of investigating the gut itself-beyond microbiota-centered studies in the context of hypertension. Since the initial discovery of the connection between gut microbiota and blood pressure regulation, research has increasingly focused on understanding the role of gut microbiota and exploring strategies to modify it for better blood pressure management. The intestine as an organ has received comparatively less attention. Yet, hypertension-associated intestinal pathological changes are well documented in both rodent models and human patients. Research to restore the intestinal function may serve as a valuable but unexplored therapeutic target. This underscores the need for a summary of our understanding of the gut's intrinsic physiological and pathological roles in hypertension. To address this, we structured our review to (1) revisit the physiological functions of the intestine; (2) describe the pathological changes that are associated with hypertension; (3) summarize available current studies targeting to restore intestinal function for blood pressure control; and (4) discuss knowledge gaps and future opportunities.","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980939","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

Degeneracy Explains Diversity in Interneuronal Regulation of Pattern Separation in Heterogeneous Dentate Gyrus Networks. 退化解释了异质齿状回网络中模式分离的神经元间调节的多样性。

IF 3.8

Function (Oxford, England) Pub Date : 2025-09-15 DOI: 10.1093/function/zqaf035

Sarang Saini, Rishikesh Narayanan

{"title":"Degeneracy Explains Diversity in Interneuronal Regulation of Pattern Separation in Heterogeneous Dentate Gyrus Networks.","authors":"Sarang Saini, Rishikesh Narayanan","doi":"10.1093/function/zqaf035","DOIUrl":"10.1093/function/zqaf035","url":null,"abstract":"Pattern separation, the ability of a network to distinguish similar inputs by transforming them into distinct outputs, was postulated by the Marr-Albus theory to be realized by divergent feedforward excitatory connectivity. Yet, there is evidence for strong but differential regulation of pattern separation by local circuit connectivity. How do we reconcile the conflicting views on local-circuit regulation of pattern separation in circuits receiving divergent feedforward connectivity? Here, we quantitatively examined a population of heterogeneous dentate gyrus (DG) spiking networks where identically divergent feedforward connectivity was enforced. We generated 20 000 random DG networks constructed with thousands of functionally validated, heterogeneous single-neuron models of 4 different DG neuronal subtypes. We recorded network outputs to morphed sets of input patterns and applied quantitative metrics that we developed to assess pattern separation performance of each network. Surprisingly, only 47 of these 20 000 networks (0.23%) manifested effective pattern separation showing that divergent feedforward connectivity alone does not guarantee pattern separation. Instead, our analyses unveiled strong contributions from the 3 interneuron subtypes toward granule cell sparsity and pattern separation, with pronounced network-to-network variability in such contributions. We traced this variability to differences in local synaptic weights across pattern-separating networks, highlighting synaptic degeneracy as a key mechanism that explains diversity in interneuronal regulation of pattern separation. Finally, we found heterogeneous DG networks to be more resilient to synaptic jitter compared to their homogeneous counterparts. Together, our findings reconcile conflicting evidence by revealing degeneracy in DG circuits, whereby similar pattern separation efficacy can arise through diverse interactions among granule cells and interneurons.","PeriodicalId":73119,"journal":{"name":"Function (Oxford, England)","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762491","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