FASEB BioAdvances

Background: Canadian biomedical core facilities (BCFs) provide researchers with access to advanced tools and unique technical expertise, essential for research. However, their role, sustainability, and impact remain poorly understood. We report on the evolution of model and existing state of Canadas 205 BCFs, examining challenges and benefits. Methods: Cross referencing of national databases by the Canadian Innovation Fund (CFI), and from data collected by the Canadian Network of Scientific Platforms (CNSP) allowed he identification of BCFs. Hand curation of these lists validated that cores are operational. To ensure cores not listed by CFI/CNSP were captured, research intensive institutions in Canada were independently searched to identify active cores. Results: There are currently 205 active and operational BCFs located across 9 provinces, which can be further stratified into 9 technical domains that describe the nature of services they provide. Quebec (80 cores) and Ontario (75 cores) have the highest confluence of BCFs, with Quebec having a higher ratio of cores per capita. Conclusions: While our data establishes the ubiquity of Canadian BCFs, we highlight substantial challenges including sustainability, governance, evaluation and the recognition of support for core scientists. Here, we establish a framework to address these challenges and to inform best practice, to optimize creation of impactful, accessible and functional biomedical core facilities.

The mitochondrial fatty acid synthesis (mtFAS) pathway is a highly conserved process in mitochondria implicated in metabolic state sensing. Aberrant functioning of this pathway leads to neurodegenerative diseases in humans. Animal experiments indicates that the mtFAS pathway is essential in mammals, and mtFAS inactivation leads to neuronal cell death. Nuclear encoded mitochondrial 3-ketoacyl-acyl carrier protein reductase (KAR) is a heterotetrameric enzyme in this process, consisting of two CBR4 and two HSD17B8 polypeptides. CBR4 works as the catalytic subunit of the enzyme. Here, we provide evidence that CBR4 function is essential in mammals. In contrast, a skeletal muscle-specific Cbr4 KO in mice did not result in any measurable defects in muscle strength and endurance, and the overall structure of the muscle remained unchanged. The Cbr4 KO did not affect the lipoylation process in quadriceps muscle samples, and high-resolution respirometry analysis of soleus muscle samples showed no defects in mitochondrial respiration capacity. The lack of a phenotype of a muscle-specific Cbr4 KO is consistent with previous reports on a lack of effects of mtFAS inactivation in muscle and re-iterates the question about the existence of bypass mechanisms that can alleviate mtFAS deficiencies in non-neuronal cell types.

PurposeDiscussions surrounding the biomedical faculty job market often focus on applicant competitiveness and external metrics such as number of publications and funding records. Consequently, there is typically less discussion about applicant readiness, the point at which applicants perceive themselves as prepared to enter the market. Since 2018 our group, the Faculty Job Market Collaboration (FJMC), has conducted annual end-of-cycle surveys of biomedical faculty job applicants, producing the largest longitudinal dataset on this process to date. MethodsWe employed a mixed-methods design examining faculty applicants in biological science fields in North America. Regression analyses were conducted on a longitudinal dataset of 729 respondents across multiple hiring cycles. To determine how applicants evaluated their own preparation, qualitative interviews were conducted with a separate cohort of biomedical postdoctoral applicants during the 2024-2026 job cycles. ResultsOur findings demonstrate that rather than depending on a single quantitative threshold, readiness is a multifaceted construct shaped by actionable and interpersonal drivers. Key factors influencing an applicants perceived readiness include taking agency to submit applications, receiving explicit support from a mentor, incorporating strategic use of artificial intelligence tools into application preparation, and their career stage. ConclusionBy distinguishing individual readiness from systemic assumptions of market competitiveness, this study highlights a blind spot in academic workforce development. Our results suggest that applicants can achieve readiness and successful outcomes through different combinations of support, strategy, and timing rather than a uniform metric profile. By integrating quantitative and qualitative data, our study provides an evidence-based framework for understanding applicant readiness and offers practical guidance to help trainees navigate the increasingly competitive academic job market. Teaser TextOur mixed-model analysis of the biomedical faculty job market is designed to help prospective faculty candidates assess their readiness to enter the job market. By integrating multiple indicators of academic productivity, funding success, and professional experience, our study provides evidence-based benchmarks that can guide applicants in evaluating their competitiveness and identifying areas for further development before pursuing faculty positions.

Tyrosol, a natural polyphenolic compound, has been identified as a potent cellular antioxidant. It mitigates oxidative stress-induced damage in skeletal muscle cells and facilitates the recovery of intracellular adenosine triphosphate (ATP), suggesting a beneficial role in maintaining cellular energy homeostasis. Creatine, widely used to enhance muscle strength by augmenting the phosphagen system, promotes intracellular ATP production but yields relatively modest improvements in endurance. In this study, we investigated the effects of combined supplementation of tyrosol (CreaSol) and creatine monohydrate (CM) on muscle endurance and strength in mice. Following a 4-week exercise training and intragastric intervention, muscle strength and exercise endurance were evaluated through four consecutive forelimb grip strength tests and exhaustive weighted swimming tests at 24-hour intervals. Compared with creatine monohydrate supplementation alone, the co-administration of CreaSol and creatine monohydrate significantly enhanced grip strength (+28.1%) and swimming endurance (+51.5%). More importantly, following consecutive exhaustive exercise, the combined group exhibited superior recovery capacity, demonstrating significantly attenuated declines in both strength and endurance compared to the creatine monohydrate-only group. We conclude that CreaSol not only effectively improves exercise performance in mice, but also significantly enhances the efficacy of creatine monohydrate in improving muscle strength and endurance, as well as reducing fatigue during consecutive high-intensity exercise.

IntroductionThe acquisition of National Institutes of Health (NIH) grants is an increasingly competitive undertaking. Many early-career biomedical investigators lack sufficient grant writing skills. This pragmatic, 2x2 factorial, group-randomized trial tested the effects of coaching duration and mode of engagement of participants scientific mentors in a grant writing coaching group intervention on grant application outcomes. MethodsA national US sample of 367 faculty and postdoctoral fellows, organized into 76 coaching groups across 6 cohorts (2020-2022), was randomized to 1 of 4 arms that differed by coaching duration (5 months vs 5 months plus 18 months of access to 1:1 coaching) and mode of scientific mentor engagement (structured vs unstructured). Primary outcomes were national-level grant application submissions and awards, and success rate among submitters, assessed via surveys and verified through award databases 30 months after study initiation. ResultsAmong 271 faculty and 96 postdoctoral fellows, 69% submitted at least 1 national application and 32% were awarded at least 1 grant. Submission rates did not differ by experimental arm. Among faculty, the structured engagement of a mentor in coaching was associated with significantly higher odds of any award (adjusted OR = 1.87) and any NIH mentored career development (K) award (adjusted OR = 3.32), and with higher success rates for these proposal types. Extended coaching duration showed a positive but not statistically significant association with faculty awards after adjustment. Neither factor significantly affected outcomes for postdoctoral fellows. Faculty success rates exceeded national NIH-reported success rates for research project grants equivalent to the R01 mechanism (43% vs 17.6%) and K awards (51% vs 36.5%). ConclusionParticipation in a national, cross-institutional, group coaching model yielded high grant submission outcomes, and award rates were higher relative to NIH benchmarks. Structured integration of scientific mentors with the coaching intervention had a greater effect than extended coaching duration on faculty outcomes.

Effective mentorship is essential for strengthening the STEMM (Science, Technology, Engineering, Mathematics, and Medicine) workforce, yet empirical evidence on how mentorship networks are structured and linked to career success remains limited. Here, we analyze mentorship networks among recipients of NIH career development (K) awards to characterize network size, mentor roles, and their associations with mentee-reported outcomes, including potential variation by sociodemographic characteristics. We found that K-awardees rely on mentors beyond their primary advisor, who play varying roles beyond being a Research mentor. Different mentor roles led to different types of mentoring outcomes; while Research mentors were associated with research-related outcomes such as Publications and Grants, career- and psychosocial-related mentoring outcomes were more likely to come from other types of mentors, such as Coaches, Connectors, and Sponsors. Larger networks, as well as having Peer and Identity mentors are additively beneficial for researchers who identify as underrepresented in science more than their counterparts. This study provides large-scale evidence on how mentorship network configurations relate to early-career grant success.

BackgroundThe delayed effects of radiation exposure on the heart often manifest as cardiac fibrosis and diastolic dysfunction, which can develop years after exposure. However, no FDA-approved serological biomarker is available to assess the risk of individuals for developing radiation-related heart disease (RRHD). ObjectivesSerum pro-N-cadherin (PNC) has shown promise as a marker for predicting the onset of heart failure in the general population. We hypothesize that serum PNC levels will correlate with the risk of RRHD following radiation exposure. MethodsWe examined male non-human primates (NHPs) exposed to total-body irradiation (TBI) and unirradiated controls from the Wake Forest University radiation late effects cohort. NHPs exhibited cardiac fibrosis scores ranging from less severe (F0-1) to more severe (F2-3). Cardiac tissue samples collected at necropsy, median 6.8 years post-irradiation, were stained for PNC by immunohistochemistry. PNC was quantified in longitudinal serum samples collected 2, 1 and 0 years before necropsy. The associations of serum PNC levels with cardiac fibrosis scores and echocardiographic parameters were examined. ResultsHistological examinations showed aberrant localization of PNC in NHPs with cardiac fibrosis. Elevated serum PNC levels significantly correlated with severe cardiac fibrosis (AUC = 0.81, p = 0.006) and echocardiogram parameters of diastolic dysfunction. Cardiac fibrosis was the only measured comorbidity with a significant difference in serum PNC. ConclusionsOur results demonstrate that serum PNC significantly correlates with cardiac fibrosis and diastolic dysfunction in irradiated NHPs. These findings pave the way for future clinical studies to develop serum PNC as a biomarker of RRHD in humans. HIGHLIGHTSO_LIRadiation-related heart disease is an often under-recognized complication of radiation exposure and radiation therapy, which has no FDA-approved biomarkers for assessing risk. C_LIO_LIOur results reveal that serum pro-N-cadherin is a biomarker of cardiac fibrosis and diastolic dysfunction in non-human primates that survived radiation exposure. C_LIO_LIThis study lays the foundation for further research into the development of serum pro-N-cadherin as a biomarker for assessing the risk of radiation-related heart disease in humans. C_LI

Undergraduate research experiences offer important paths into scientific research careers, yet students do not experience them uniformly. For Black women, these experiences occur within racialized and gendered environments that may shape whether they perceive research careers as attainable. Yet little is known about these influences, including how mentors, role models, and institutional contexts, could support or limit Black womens beliefs about research career attainability. To advance our understanding of these influences, we conducted interviews with 23 Black women who participated in undergraduate research at 18 institutions in the United States, including historically Black colleges and universities (HBCUs) and predominantly White institutions (PWIs). We conducted qualitative content analysis to understand Black women undergraduate researchers perceptions of the attainability of a scientific research career, including the influences of their mentors, role models, and institutional context. Three main themes emerged. First, Black women undergraduates varied in the importance they placed on sharing racial and gender identities with mentors and role models; some viewed such similarities as highly meaningful while others described them as less influential. Second, Black women undergraduates described that mentors and role models who shared similar life experiences, values, attitudes, or beliefs contributed to perceptions that scientific research careers were attainable, regardless of gender or racial similarity. Third, institutional context (HBCU, PWI) shaped how mentoring and role modeling influenced Black women undergraduates perceptions of research career attainability. We conclude by offering recommendations for individuals seeking to support Black women in undergraduate research and in their pursuit of research careers.

Thymosin {beta}4 (T{beta}4) is a conserved acidic polypeptide with 43-amino acids participating in multiple pathophysiological processes. In this study in vivo effects of T{beta}4 on liver regeneration are investigated in carbon-tetrachloride (CCL4) induced rodent animal liver jury models. Results illustrate that exogenous T{beta}4 treatment significantly reduced CCL4-rendered liver necrosis around central vein. At 48 hours after CCL4 insults hepatocytes proliferation occur mainly around the periportal area, while hepatocytes proliferation around the necrosis area is prominently increased by exogenous T{beta}4 treatment. The holistic proliferation level of liver tissues are also enhanced by exogenous T{beta}4. Hepatocyte proliferation activities negatively correlate with the necrosis extent of the liver tissue. These results suggested firstly exogenous T{beta}4 treatment could enhance liver regeneration and exhibit prosperous potential for application in clinical conditions such as liver transplantation.

Adipose tissue (body fat) is increasingly recognized as a dynamic organ system essential to human health, with distinct depots that serve specialized biological functions. However, this understanding is not reflected in traditional human anatomy curricula, where adipose tissue is typically introduced only as connective tissue and treated in dissection as an obstacle to be removed rather than a structure worthy of study. Anatomy dissection courses have been identified as a source of negative weight bias in medical students, with students reporting disgust toward adipose tissue and frustration with its removal to visualize course-required anatomical structures. Here, we hypothesize that reframing adipose tissue as a functional organ system within anatomy curricula may improve students understanding of human anatomy and mitigate these negative perceptions. To test this, we created a human adipose atlas (AdipoAtlas) by identifying and photographing macroscopic adipose depots in an anatomical donor and organizing these images into an anatomical reference with evidence-based functional descriptions. The atlas was integrated into a human anatomy dissection course, followed by a survey assessing students perceptions of adipose tissue and attitudes related to weight bias, with a concurrent non-dissection anatomy course serving as a control. Students in the adipose-inclusive course reported more positive perceptions and improved understanding of adipose tissue as a multifunctional organ system, while responses related to weight-based discrimination and broader attitudes toward body size were similar between groups. These results support our hypothesis that integrating adipose tissue into anatomy education improves anatomical understanding and may reduce negative weight-related perceptions.

BackgroundCatecholamines play a central role in cardiac performance, coordinating myocardial contractility, conduction, metabolism, and electrophysiological stability. In the heart, their actions have been attributed primarily to sympathetic nerve terminals and circulating adrenal catecholamines. The discovery of an intrinsic non-neuronal cholinergic system within cardiomyocytes challenges this neurocentric paradigm and raises the possibility that cardiomyocytes also possess an intrinsic catecholaminergic programme. Here, we investigated whether cardiomyocytes possess an intrinsic catecholaminergic programme and its contribution to cardiomyocyte homeostasis and stress responses. MethodsWe investigated catecholamine biosynthesis and handling in human induced pluripotent stem cell-derived cardiomyocytes, adult mouse cardiomyocytes, H9C2 cells, rat ventricular tissue, and Langendorff-perfused mouse hearts. Protein expression of catecholamine biosynthetic enzymes and vesicular monoamine transporters was assessed by immunoblotting and immunohistochemistry, while vesicular monoamine uptake was evaluated using fluorescent false neurotransmitters. Functional consequences of catecholamine biosynthesis inhibition were examined using pharmacological approaches, assessing cell viability, apoptosis, organelle homeostasis, metabolic signalling, and cardiac electrophysiology. ResultsTyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine {beta}-hydroxylase, and vesicular monoamine transporters were detected in cardiomyocytes across models. Expression of catecholamine biosynthetic enzymes increased following ischaemia-reperfusion injury in rat heart tissue (TH p=0.008, AADC p=0.031, DBH p=0.008). Pharmacological inhibition of catecholamine biosynthesis caused dose-dependent reductions in cardiomyocyte viability (p<0.0001), increased apoptosis, organelle stress, and mitochondrial dysfunction, with greater effects under oxidative stress. Mechanistically, catecholamine depletion suppressed mTORC1 signalling and activated LKB1-AMPK-ULK1 pathways. In Langendorff-perfused hearts, tyrosine hydroxylase inhibition induced ventricular arrhythmias in 5 of 6 hearts, including sustained ventricular tachycardia, polymorphic ventricular tachycardia, and ventricular fibrillation. ConclusionsThese findings identify cardiomyocytes as previously unrecognised catecholamine-competent cells expressing intrinsic machinery for catecholamine biosynthesis and vesicular handling. Disruption of this pathway compromises metabolic and organelle homeostasis, activates energy-stress and autophagy-related signalling, and promotes malignant ventricular arrhythmias. Intrinsic cardiomyocyte catecholamine biology therefore represents a non-neuronal regulatory axis essential for myocardial resilience and electrical stability, with potential relevance to ischaemic injury and stress-induced dysfunction.

PurposeTo investigate whether rapamycin can regulate microglial activation and polarization via mTOR and its downstream signals via autophagy both in vivo and in vitro. MethodsThe in vivo study used wild type C57BL/6 mice that were intraperitoneally injected with rapamycin (2 mg/kg) plus ONC. The BV2 cell line was used in the in vitro study and the cells were incubated with rapamycin (50 nM) or transfected with a specific mTOR-targeting small interfering RNA (si-mTOR). Immunohistochemical staining was used to observe the changes in the morphology and cell surface area of microglia and Weste blotting analysis was used for detection of the changes in the proteins related autophagy, microglia polarization and mTOR pathway after the retinal tissue or the cell samples were collected. ResultsThese results indicate that rapamycin increases autophagy and M2 polarization by inhibiting p-mTOR in wild-type C57BL/6 mice in vivo. In the BV2 cell line, rapamycin and si-mTOR can enhance autophagy and promote M2 polarization by inhibiting the p-mTOR/p-Unc-51-like kinase 1 (p-ULK1) pathway. ConclusionsIn conclusion, this work contributes to the understanding of the complex interplay among rapamycin, autophagy and microglial activation/polarization, highlights the downstream signaling pathway of mTOR, and highlights the potential therapeutic effects of autophagy-modulating drugs in retinal neuroinflammation and neurodegeneration after TON.

Systemic inflammatory diseases can be influenced by dietary intake, with gastrointestinal dysfunction driving both metabolic and behavioural changes mirroring the altered inflammatory profile. Additionally, the use of live biotherapeutic products (LBPs) shows promise for treating metabolic and inflammatory diseases, but their efficacy is limited by poor persistence in inflamed gut environments. Designed to utilize inflammatory byproducts, the LBP EcN::ttr has proven efficacy in the treatment of acute and chronic colitis, however its effects on the metabolic and behavioural patterns remain uncharacterized. We evaluated the effects of EcN::ttr on mice fed a proinflammatory omega-6 PUFA-rich diet. EcN::ttr-treated mice exhibited notable changes in the gut, including an improved expression of tight junction protein occludin, accompanied by reduced serum lipopolysaccharide (LPS) - binding protein, indicating protection against endotoxemia. EcN::ttr improved insulin sensitivity compared to the parental strain, associated with increased hepatic insulin receptor expression and reduced GSK3{beta} activation and endoplasmic reticulum stress. Secondary bile acids in mice treated with EcN::ttr were more abundant, with increases in those associated with resolving diarrhea and bile acid detoxification. Behavioural assessment highlighted a normalization of long-term memory along with a reduction of stress management behaviours. Altogether, EcN::ttr restores gut-liver-brain axis function through coordinated modulation of inflammation, barrier integrity, and bile acid metabolism. HighlightsO_LILive Biotherapeutic Product EcN::ttr, designed with a fitness advantage to survive inflammation, and provides protection against a proinflammatory omega 6-rich diet C_LIO_LIAdministration of EcN::ttr improved metabolic outcomes including increasing insulin sensitivity C_LIO_LIEcN::ttr increased the abundance of secondary bile acids including those that modulate bile acid detoxification C_LIO_LIBehavioural parameters were normalized in mice given EcN::ttr C_LIO_LIEcN::ttr partially normalizes gut-liver-brain axis through restoring barrier integrity, modulating inflammation and improving secondary bile acid metabolism C_LI

Artificial intelligence (AI) development is concentrated within private firms, yet their participation in scientific publishing remains poorly understood. We conducted a bibliometric analysis of all 317 AI unicorn startups (1998-2025). Only 1,389 eligible peer-reviewed publications and 688 preprints involving some leading startup contributions were identified. More than half of startups (52.4%) produced no qualifying scientific output, and only 24 firms (7.6%) produced any highly cited papers ([&ge;]200 citations). Scientific influence was highly concentrated: the top 10% of firms accounted for 96.8% of citations, while three startups accounted for 92 of 134 firm-attributed highly cited papers. Firm valuation was not associated with publication productivity or highly cited output, whereas funding raised showed weak associations. Overall, participation in formal scientific communication among AI unicorn startups is negligible, comprising only 0.1% of the overall AI literature in 2025. Most leading developers of AI technology do not engage with the scientific literature, raising concerns for the transparency, reproducibility, and accountability of this rapidly moving innovation frontier.

ObjectiveTo investigate and clarify the role of Ginsenoside Ro (GRo) in diabetic cardiomyopathy (DiaCM) and to elucidate the molecular mechanism by which GRo ameliorates DiaCM. Methods[circled1] The construct of type 2 diabetic mouse model. The bought C57BL/6 male mice were housed in a specific pathogen-free (SPF) animal facility and randomly divided into control, STZ (model), STZ + GRo, and control+GRo groups. The STZ (model) and STZ + GRo groups were fed a high-fat and high-glucose diet combined with intraperitoneal injection of streptozotocin (STZ). The control and control + GRo groups were fed a normal diet, while the control + GRo and STZ + GRo groups were treated with GRo via oral gavage. Then, all groups were evaluated for cardiac function and structure by small animal echocardiography and histological staining including hematoxylin and eosin (HE) and Massons trichrome staining to screen and confirm diabetic cardiomyopathy in mice. Finally, immunofluorescence staining of cilia in mouse heart tissue was performed to determine whether GRo inhibits abnormal ciliary growth. [circled2] The construct of cell models. First, the CCK-8 (Cell Counting Kit-8) assay was used to separately evaluate the cytotoxicity of GRo and the combination of TGF-{beta}1 and PA in myocardial fibroblasts and cardiomyocytes. Subsequently, mouse myocardial fibroblast lines (MCFs) were treated with transforming growth factor-beta 1 (TGF-{beta}1), and H9c2 cardiomyocytes were treated with palmitic acid (PA). Both cell types then received the GRo treatment. [circled3] Molecular and cellular testing. Firstly, we measured serum levels of cardiac injury markers (CK-MB, MYO, and TNNI3), glutathione (GSH), and malondialdehyde (MDA). Secondly, we examined the expression of myocardial fibrosis-related genes (Col1a1, etc.), myocardial hypertrophy markers (Nppa, etc.), cilia-specific genes (Pkd1, etc.), and oxidative stress-related genes (Nrf2, etc.) in both animal and cell samples by Western blotting and RT-qPCR. Finally, we used immunofluorescence staining of myocardial fibroblasts to detect cilia length and phalloidin staining of cardiomyocytes to measure their cross-sectional area. [circled4] The correlation mechanism. Firstly, the cilia-specific inhibitory drug HIP-4 was used to disrupt cilia homeostasis by inhibiting cilia growth. Secondly, small activating RNA (saRNA) was used to upregulate the Pkd1 gene to verify whether GRo exerts its anti-fibrotic effects through the inhibition of PC1. Results[circled1] Animal level. A diabetic cardiomyopathy mouse model was successfully established by combining STZ injection with a high-fat and high-glucose diet, and treatment with GRo significantly ameliorated the associated symptoms. [circled2] Cellular level. We successfully established a myocardial fibrosis model by treating myocardial fibroblasts with TGF-{beta}1, and a myocardial hypertrophy model by treating cardiomyocytes with PA. Immunofluorescence staining demonstrated that GRo significantly decreased cilia length in the fibrosis model, while phalloidin staining showed that GRo significantly attenuated the increase in cardiomyocyte cross-sectional area. [circled3] Molecular level. Compared with the model group, GRo treatment significantly reduced serum levels of cardiac injury markers (CK-MB, MYO and TNNI3), glutathione (GSH) and malondialdehyde (MDA). Western blotting and RT-qPCR analyses of both animal and cell samples revealed that GRo markedly alleviated indicators of myocardial fibrosis and hypertrophy, while also suppressing cilia-specific genes and oxidative stress-related genes. Overall, GRo significantly ameliorated the markers associated with myocardial fibrosis and hypertrophy, and inhibited cilia-specific protein expression as well as oxidative stress parameters. [circled4] The correlation mechanism. The cilia-specific drug hedgehog pathway inhibitor 4 (HPI-4) was used to revealed that cilia homeostasis is closely linked to myocardial fibrosis and shortened cilia inhibit the fibrosis progression. Furthermore, upregulation of the Pkd1 gene by small activating RNA demonstrated that PC1 overexpression abrogates the therapeutic effect of GRo. Finally, GRo can alleviate DiaCM.

BACKGROUNDAlong with advancing age comes declines in physical, cognitive, and cardiovascular function. This diminished capacity may lead to decreased ability to perform activities of daily living, disability onset, and loss of independence. Exercise is a regenerative medicine therapy that can mitigate this loss of function. High intensity interval training (HIIT) is an aerobic exercise paradigm consisting of intense activity periods interspersed with bouts of active recovery. Previously we demonstrated that HIIT preserved physical function in adult, middle-aged, and older male mice. However, whether HIIT preserves physical, cognitive, and cardiovascular function, mitigates frailty, and improves brain and heart health in older adult female mice remains unknown. HYPOTHESISCognitive, physical, and cardiovascular function in older adult female C57BL/6 will be preserved in exercised mice (HIIT) versus sedentary control (SED). METHODSMice (HIIT and SED, both n=9, 24m at end) were tested pre/post-intervention for physical (rotarod, treadmill, grip meter, inverted cling, voluntary wheel running, activity monitor), cognitive (open field, novel object recognition, puzzle box, y-maze), and cardiovascular (blood pressure, echocardiogram) function, body composition, and whole body calorimetry. The mice underwent 14-weeks of HIIT training with progressive volume and intensity. RESULTSHIIT significantly (p<0.05) increased or preserved function in many tests including: aerobic capacity (+71% HIIT versus, vs, no change, NC, in SED), four limb strength/endurance (-67% SED vs -28% HIIT), forelimb strength (-16% SED vs NC HIIT), overall motor function (NC SED vs +39% HIIT), executive function (NC SED vs +73% HIIT), and exploratory behavior, which improved across multiple tests with HIIT while remaining unchanged in SED. HIIT also reduced both systolic blood pressure by 12% (-17 mmHg) and mean arterial pressure by -16 mmHg. In addition, HIIT significantly reduced cardiac fibrosis, increased muscle fiber type 2a percentage, reduced IL-1{beta} expression in the hypothalamus, and mitigated frailty onset. CONCLUSIONHIIT significantly reduced age-related functional loss in all three domains assessed while preventing frailty onset in older adult females and improving markers of brain and heart health.

Pulmonary arterial hypertension (PAH) is a devastating disease with poor outcome affecting relatively young subjects. The arachidonic acid (AA) metabolite, 15-hydroxyeicosatetraenoic acid (15-HETE), has been implicated in the pathogenesis of hypoxia-induced PAH. We tested the hypothesis that genetic deletion of GPR39, the target receptor for 15-HETE, will attenuate PAH. We subjected wild-type (WT) and GPR39 KO to 4 weeks of hypoxia versus normoxia, after which right ventricular and systemic hemodynamics were measured. Immunohistochemistry of lung was performed for pulmonary arteriolar thickness as well as capillary and pericyte density. Lung tissue was also analyzed for AA and 15-HETE levels as well as signaling events (mRNA and protein levels) downtream of GPR39 activation. Unlike WT mice, GPR39 KO mice did not develop PAH. They also exhibited markedly less pulmonary ateriolar remodeling and greater pulmonary capillary density. mRNA expression of genes in the Gq, Gs and G12/13 pathways were upregulated in the WT mice while GPR39 KO hypoxic showed no change in these genes. WT and not GPR39 KO hypoxic mice exhibited enhanced AKT phosphorylation. Downstream of the phosphatidylinositol 3-kinase-AKT pathway, endothelial nitric oxide synthetase was upregulated in both WT hypoxia and GPR39 KO hypoxia mice, while sonic hedgehog was upregulated only in WT hypoxia mice. We conclude that hypoxia-induced aberrant signaling is markedly attenuated with genetic deletion of GPR39, which is associated with less pulmonary arteriolar remodeling and greater capillary density, thus preventing PAH. These results suggest that pharmacological inhibition of GPR39 may offer a novel treatment for PAH.

Skeletal muscle homeostasis depends on the coordinated regulation of protein turnover and mitochondrial quality control; however, the molecular mechanisms linking these processes remain unclear. In this study, we examined the physiological role of leucine aminopeptidase 3 (LAP3), a post-proteolytic aminopeptidase, using constitutive LAP3-deficient mice. LAP3 deficiency preferentially affected skeletal muscle, causing reduced muscle mass and mitochondrial enlargement in both sexes. Female LAP3-deficient mice also showed reduced myofiber size, impaired endurance capacity, increased energy expenditure, elevated lipid oxidation, and lipid droplet accumulation adjacent to the mitochondria. Proteomic analyses revealed remodeling of pathways related to lipid metabolism and protein homeostasis. Consistent with these findings, LAP3 deficiency increased the expression of Pink1 and Tax1bp1 and promoted the accumulation of ubiquitinated proteins, suggesting alterations in mitochondrial quality control and proteostatic regulation. In cultured myogenic cells, LAP3 localized to mitochondrial fractions, and both LAP3 knockdown and overexpression altered mitochondrial morphology. Taken together, these results identify LAP3 as a regulator of skeletal muscle homeostasis and support a role for LAP3 in linking intracellular peptide turnover to mitochondrial homeostasis, with female skeletal muscle showing greater susceptibility to LAP3 deficiency.

Hypoxia (low oxygen availability) is a common environmental stressor in estuarine ecosystems that negatively affects fish survival as well as physiological and behavioral responses. However, the effects of hypoxia on the brain remains poorly understood, particularly in non-model species. Here, we investigated how prolonged hypoxia influences neural, vascular, and molecular responses in the brain of the speckled sanddab (Citharichthys stigmaeus), an ecologically relevant estuarine flatfish. Fish were exposed to normoxic or hypoxic conditions for seven days, and responses were assessed using histological analyses of neural proliferation and vascular structure, alongside transcriptomic and proteomic profiling. Hypoxia increased neural cell proliferation and progenitor activation in the hypothalamic nucleus recessus lateralis (NRL) and optic tectum, while reducing survival of newly generated cells. At the tissue level, hypoxia induced region-specific vascular remodeling, characterized by increased vessel area and vessel number without evidence of widespread endothelial proliferation. At the molecular level, transcriptomic and proteomic analyses revealed consistent enrichment of biological processes related to stress responses, development, metabolism, and cellular homeostasis, despite limited overlap between individual genes and proteins. Gene- and protein-level analyses further indicated activation of hypoxia-responsive pathways, including HIF signaling and oxidative stress protection, alongside selective metabolic reprogramming. Together, these findings demonstrate that hypoxia induces multi-level changes in the brain, linking neural plasticity, vascular remodeling, and molecular responses. This integrated response likely supports brain function under reduced oxygen availability in dynamic estuarine environments and highlights the role of the brain in regulating responses to environmental stress.

Retractions of scientific articles reflect a rising research integrity risk in biomedical research, and continued citation of retracted articles poses a downstream risk to research that built upon unreliable studies. Few studies have examined the structural risk factors embedded in how the research enterprise is organized. Here, we apply an analytical risk assessment framework to structural risk factors associated with retracted articles and the propagation of their citations to ten broad fields of biomedical research, collectively accounting for 14% of biomedicine. We pronounced field-specific differences in retraction rates and citations to retracted articles, and show that multiple retractions from single authors occur far more often than chance would predict. By subdividing fields into finer-grained topics with machine learning network clustering, we find that individual authors can reach large proportions of the literature within their topics through citations, and that retraction risk is positively associated with author productivity. Across these fields, 22% of the literature cites authors with at least one retracted article, and 6% cite work from authors with multiple prior retractions. Together, these factors lead to a concentration of risk within topics, which is only partially explained by the uneven distribution of authors with multiple retractions. Despite these quantifiable vulnerabilities, the risk has not yet been fully realized: most topics cite retracted work no more than baseline. Our findings thus reveal both a latent network vulnerability to the rapid dissemination of questionable results and a measurable resilience that has so far kept this possibility in check. The scientific community would particularly benefit from targeted efforts to test and strengthen reproducibility in high-risk scientific topics.