Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls.
View Article and Find Full Text PDFBackground: Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the pulmonary arteries, increased vascular resistance, and right-sided heart failure. Genome-wide association studies of idiopathic/heritable PAH established novel genetic risk variants, including conserved enhancers upstream of transcription factor (TF) containing 2 independent signals. SOX17 is an important TF in embryonic development and in the homeostasis of pulmonary artery endothelial cells (hPAEC) in the adult.
View Article and Find Full Text PDFPulmonary arterial hypertension (PAH) is a progressive disease predominantly targeting pre-capillary blood vessels. Adverse structural remodelling and increased pulmonary vascular resistance result in cardiac hypertrophy and ultimately failure of the right ventricle. Recent whole-genome and whole-exome sequencing studies have identified as a novel risk gene in PAH, with a dominant mode of inheritance and incomplete penetrance.
View Article and Find Full Text PDFThe two-pore potassium channel, TRESK has been implicated in nociception and pain disorders. We have for the first time investigated TRESK function in human nociceptive neurons using induced pluripotent stem cell-based models. Nociceptors from migraine patients with the F139WfsX2 mutation show loss of functional TRESK at the membrane, with a corresponding significant increase in neuronal excitability.
View Article and Find Full Text PDFTwo-pore domain K (K) channels generate K leak current, which serves a vital role in controlling and modulating neuronal excitability. This diverse family of K channels exhibit distinct expression and function across neuronal tissues. TWIK-related spinal cord K channel (TRESK) is a K channel with a particularly enriched role in sensory neurons and pain pathways.
View Article and Find Full Text PDFConstipation and fecal impaction are conditions of the bowel whose prevalence increases with age. Limited information is known about how these conditions manifest; however, functional deficits are likely to be due to changes in signaling within the bowel. This study investigated the effects of age on colonic mucosal melatonin (MEL) release and the consequences this had on colonic motility.
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