Chew Weng Cheng

The World Health Organization (WHO) Global Measles and Rubella Laboratory Network (GMRLN) collects molecular and epidemiological data to monitor progress towards the elimination of measles and rubella. This report summarises global trends from the data collected through the Measles virus Nucleotide Surveillance (MeaNS2) and Rubella virus Nucleotide Surveillance (RubeNS2) websites up to 2025, with a particular focus on measles virus (MeV). The analysis of MeaNS2 sequence submissions demonstrates substantial regional variations in the proportion of cases sequenced and predominant genotypes reported. Following a steep decrease in measles cases during the COVID-19 pandemic, numbers of reported cases and sequences have both rebounded. Only two of the 24 MeV genotypes originally recognised have been reported globally since 2021: B3 and D8. In response to the decrease in the genetic diversity of circulating strains, the number of sequences submitted for sub-genomic regions other than the N-450 used for genotyping has increased since 2022. The number of sequences submitted to RubeNS2 for rubella virus (RuV) is 10-fold lower than that reported for MeV, due to fewer detected cases and technical challenges of RuV sequencing. Only 59 RuV sequences of genotypes 1G and 2B have been reported since 2022. Continued investment in laboratory capacity, data quality, surveillance, epidemiological investigation, and vaccination programmes remain essential for sustaining the global measles and rubella elimination initiative.

Somatic cell DNA mutations accumulate with age, and can give cells a survival advantage, resulting in their clonal expansion over time. We know that these mutations can lead to cancer, but the growing application of next-generation sequencing across multiple ‘healthy’ tissues has revealed their ubiquity and relevance to noncancer pathology. Indeed, these mutations may play a role in cardiovascular disease (CVD), particularly in the progression of atherosclerosis and other vascular diseases. This review examines the impact of somatic mutations in both blood and cardiovascular tissues, focusing particularly on clonal hematopoiesis of indeterminate potential (CHIP), and its association with systemic inflammation. CHIP mutations, present in hematopoietic stem cells and their progeny, have been associated with increased risk of CVD, possibly by promoting pro-inflammatory pathways that drive atherosclerosis, although some data suggest CHIP may also arise due to an inflammatory milieu. These somatic variants, and non-CHIP variants, have been detected in atherosclerotic plaques, raising questions about their direct role in atherogenesis and vascular remodeling. Understanding the current research on somatic mutations in blood and cardiovascular tissues may uncover new insights into CVD progression and highlight potential therapeutic targets.

Exercise orchestrates an interorgan communication network, in which skeletal muscle releases signaling molecules known as myokines that contribute to exercise training-induced adaptations. We identified the muscle-derived metabolite beta-aminoisobutyric acid (BAIBA) as a regulator of adipose and hepatic metabolic responses to exercise. Here, we demonstrate that BAIBA regulates muscle metabolism, morphology and function via peroxisome proliferator-activated receptor delta (PPARδ) to determine exercise performance in mice. BAIBA mitigates muscle dysfunction in a mouse model of diabetes. Physiologically, BAIBA exists as D- and L- enantiomers. We identify L-BAIBA as the primary mediator of muscular effects. Knockdown of L-BAIBA’s biosynthetic enzyme, 4-aminobutyrate aminotransferase, in mouse hindlimb muscle impairs exercise-induced adaptations and performance gains. L-BAIBA regulates human myotube fibertype and differentiation markers through Mas-related G-protein coupled receptor D. In humans, plasma L-BAIBA correlates with aerobic fitness and increases with endurance exercise training. BAIBA acts through the PGC1α-BAIBA-PPARδ axis to facilitate muscle adaptation and exercise performance.

Background: Pathological remodelling of native vascular smooth muscle cells (VSMC) within the arterial wall is a key contributor to vascular disease. A driver of this remodelling is platelet-derived growth factor BB (PDGF-BB) and its signalling via activation of the store-operated calcium ion channel, ORAI1. Here, we investigated if there are associations of ORAI1 polymorphisms with human cardiovascular disease. Methods and results: We conducted candidate gene association analysis and revealed that a missense ORAI1 variant (rs3741596, S218G) associates with an increased risk of hospital-diagnosed peripheral vascular disease, generalised atherosclerosis, acute ischaemic heart disease, and atrioventricular and left bundle-branch block in White British UK Biobank participants. Rs3741596 is also associated with higher circulating platelet counts and reduced total triglyceride levels. Functional analysis of the effects of rs3741596 S218G variant on ORAI1 channel function, via introduction of the S218G ORAI1 variant in HEK293 cells using CRISPR/Cas9 and investigation of its effects on store-operated calcium entry (SOCE), showed significantly enhanced SOCE compared to wild type cells, suggesting that the S218G variant enhances ORAI1 function. Conclusions: Our results reveal an association between an ORAI1 missense variant and hospitalisation for peripheral vascular disease, generalised atherosclerosis, acute ischaemic heart disease, and atrioventricular and left bundle-branch block. These findings provide a novel insight into the role of ORAI1 in vascular remodelling and highlight its potential as a treatment target for vascular pathologies.

The large membrane protein PIEZO1 assembles as trimers to form exceptional mechanical force-sensing ion channels of eukaryotes. When these channels are activated by force, cell membrane permeability to calcium ions and other ions increases rapidly, coupling force to cell function through ionic control. In humans and other species, PIEZO1 is both widely expressed and functional across major systems that include the cardiovascular, haematological and musculoskeletal systems, thereby serving diverse needs. In this narrative review of the scientific literature, we address what has been learned about PIEZO1 from associations of its gene variation with human characteristics. A particular physiological importance of PIEZO1 is emerging in lymphatics and thus in the control of tissue fluid homeostasis with relevance to the disease conditions of non-immune fetal hydrops and generalized lymphatic dysplasia. Other vascular relevance is seen in lower limb venous varicosities. PIEZO1 may be non-essential in red blood cells but the amplification of its function by gene variation quite selectively alters these cells, leading to haemolytic anaemia and other related disturbances that may be only mildly adverse and confer survival advantage. We speculate on what else might be learned in humans, guided by knowledge from PIEZO1 studies in mice, and describe how knowledge accumulated to date highlights new opportunities for PIEZO1 understanding and pathways to patient benefit.

During recent decades, changes in lifestyle have led to widespread nutritional obesity and its related complications. Remodelling adipose tissue as a therapeutic goal for obesity and its complications has attracted much attention and continues to be actively explored. The endothelium lines all blood vessels and is close to all cells, including adipocytes. The endothelium has been suggested to act as a paracrine organ. We explore the role of endothelial insulin-like growth factor-1 receptor (IGF-1R), as a paracrine modulator of white adipose phenotype. We show that a reduction in endothelial IGF-1R expression in the presence of high-fat feeding in male mice leads to depot-specific beneficial white adipose tissue remodelling, increases whole-body energy expenditure and enhances insulin sensitivity via a non-cell-autonomous paracrine mechanism. We demonstrate that increased endothelial malonate may be contributory and that malonate prodrugs have potentially therapeutically relevant properties in the treatment of obesity-related metabolic disease.

BACKGROUND: Women with heart failure and reduced ejection fraction (HFrEF) have greater symptoms and a lower quality of life compared with men; however, the role of noncardiac mechanisms remains poorly resolved. We hypothesized that differences in skeletal muscle pathology between men and women with HFrEF may explain clinical heterogeneity. METHODS: Muscle biopsies from both men (n=22) and women (n=16) with moderate HFrEF (New York Heart Association classes I–III) and age- and sex-matched controls (n=18 and n=16, respectively) underwent transcriptomics (RNA-sequencing), myofiber structural imaging (histology), and molecular signaling analysis (gene/protein expression), with serum inflammatory profiles analyzed (enzyme-linked immunosorbent assay). Two-way ANOVA was conducted (interaction sex and condition). RESULTS: RNA-sequencing identified 5629 differentially expressed genes between men and women with HFrEF, with upregulated terms for catabolism and downregulated terms for mitochondria in men. mRNA expression confirmed an effect of sex ( P IGF1 expression was higher ( P P _interaction P _interaction HIF1α , ESR1 , VEGF (vascular endothelial growth factor), and PGC1α expression ( P P <0.05). CONCLUSIONS: Sex differences in muscle pathology in HFrEF exist, with men showing greater abnormalities compared with women related to the transcriptome, fiber phenotype, capillarity, and circulating factors. These preliminary data question whether muscle pathology is a primary mechanism contributing to greater symptoms in women with HFrEF and highlight the need for further investigation.

How cardiovascular activity interacts with lipid homeostasis is incompletely understood. We postulated a role for blood flow acting at endothelium in lipid regulatory organs. Transcriptome analysis was performed on livers from mice engineered for deletion of the flow-sensing PIEZO1 channel in endothelium. This revealed unique up-regulation of Cyp7a1 , which encodes the rate-limiting enzyme for bile synthesis from cholesterol in hepatocytes. Consistent with this effect were increased gallbladder and plasma bile acids and lowered hepatic and plasma cholesterol. Elevated portal fluid flow acting via endothelial PIEZO1 and genetically enhanced PIEZO1 conversely suppressed Cyp7a1 . Activation of hepatic endothelial PIEZO1 channels promoted phosphorylation of nitric oxide synthase 3, and portal flow-mediated suppression of Cyp7a1 depended on nitric oxide synthesis, suggesting endothelium-to-hepatocyte coupling via nitric oxide. PIEZO1 variants in people were associated with hepatobiliary disease and dyslipidemia. The data suggest an endothelial force sensing mechanism that controls lipid regulation in parenchymal cells to modulate whole-body lipid homeostasis.