Genetic influence on vascular smooth muscle cell apoptosis.

Vascular smooth muscle cell (VSMC) proliferation, migration, and apoptosis play important roles in many physiological processes and pathological conditions. To identify genetic influences on VSMC behavior, we measured these traits and undertook genome-wide association studies in primary umbilical artery-derived VSMCs from >2000 individuals. Although there were no genome-wide significant associations for VSMC proliferation or migration, genetic variants at two genomic loci (7p15.3 and 7q32.3) showed highly significant associations with VSMC apoptosis (P = 1.95 × 10-13 and P = 7.47 × 10-9, respectively). The lead variant at the 7p51.3 locus was associated with increased expression of the GSDME and PALS2 genes in VSMCs. Knockdown of GSDME or PALS2 in VSMCs attenuated apoptotic cell death. A protein co-immunoprecipitation assay indicated that GSDME complexed with PALS2. PALS2 knockdown attenuated activated caspase-3 and GSDME fragmentation, whilst GSDME knockdown also reduced activated caspase-3. These findings provide new insights into the genetic regulation of VSMC apoptosis, with potential utility for therapeutic development.

Implementing a scoping review to explore sport officials' mental health.

Introduction: Sport officials are tasked with applying rules, maintaining fairness, and ensuring athlete safety. However, sport officials experience anxiety, burnout, and non-accidental violence, with the incidence of these events increasing worldwide. This has led to rising attrition rates among sport officials, with many sport organizations concerned for their operational capacity. The effects of anxiety, burnout, and non-accidental violence might contribute to or be indicative of sport officials' negative mental health outcomes. To develop a clear understanding of how sport officials' mental health is affected by their occupation, it is necessary to identify the mental health outcomes and predictors they experience, and to what extent. The purpose of this scoping review was to identify and examine the empirical research and policy documents surrounding sport officials' mental health. Method: One thousand, two hundred six articles were identified across four databases: PubMed, Web of Science, SportDiscus, and PsycINFO. Next, a policy search was conducted on the respective international governing body websites from English-speaking countries for the 60 included sports. Following screening, 18 studies and one policy document met the inclusion criteria for exploring sport officials' mental health. Results: Participants (N = 7,941) in the studies were mainly European male soccer and basketball referees. Most studies utilized quantitative inquiry (n = 15) rather than qualitative methods (n = 2) or framework development (n = 1). The research demonstrated that sport officials frequently experienced negative mental health outcomes and predictors including anxiety, depression, burnout, lower mental health literacy, and high levels of stigmatization towards mental health. Discussion: These outcomes were influenced by gender/sex, age, and experience. There is a need to explore personal and environmental (including occupational) factors that cause or contribute to sport officials' mental health symptoms and disorders.

Network-based prioritization and validation of regulators of vascular smooth muscle cell proliferation in disease.

Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize vascular diseases causing heart attack and stroke. Here we elucidate molecular determinants governing VSMC proliferation by reconstructing gene regulatory networks from single-cell transcriptomics and epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. We compared gene regulatory network rewiring between injury-responsive and nonresponsive VSMCs, which suggested shared transcription factors but differing target loci between VSMC states. Through in silico perturbation analysis, we identified and prioritized previously unrecognized regulators of proliferation, including RUNX1 and TIMP1. Moreover, we showed that the pioneer transcription factor RUNX1 increased VSMC responsiveness and that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signaling. Both RUNX1 and the TIMP1-CD74 axis were expressed in human VSMCs, showing low levels in normal arteries and increased expression in disease, suggesting clinical relevance and potential as vascular disease targets.