Obesity and related metabolic disturbances including diabetes, hypertension and hyperlipidemia predict future cognitive decline. Asia has a high prevalence of both obesity and metabolic disease, potentially amplifying the future burden of dementia in the region. We aimed to investigate the impact of adiposity and metabolic risk on cognitive function in Asian populations, using an epidemiological analysis and a two-sample Mendelian Randomization (MR) study. The Health for Life in Singapore (HELIOS) Study is a population-based cohort of South-East-Asian men and women in Singapore, aged 30-84 years. We analyzed 8769 participants with metabolic and cognitive data collected between 2018 and 2021. Whole-body fat mass was quantified with Dual X-Ray Absorptiometry (DEXA). Cognition was assessed using a computerized cognitive battery. An index of general cognition ' g ' was derived through factor analysis. We tested the relationship of fat mass indices and metabolic measures with ' g ' using regression approaches. We then performed inverse-variance-weighted MR of adiposity and metabolic risk factors on ' g ', using summary statistics for genome-wide association studies of BMI, visceral adipose tissue (VAT), waist-hip-ratio (WHR), blood pressure, HDL cholesterol, triglycerides, fasting glucose, HbA1c, and general cognition. Participants were 58.9% female, and aged 51.4 (11.3) years. In univariate analysis, all 29 adiposity and metabolic measures assessed were associated with ' g ' at P < 0.05. In multivariable analyses, reduced ' g ' was consistently associated with increased visceral fat mass index and lower HDL cholesterol (P < 0.001), but not with blood pressure, triglycerides, or glycemic indices. The reduction in ' g ' associated with 1SD higher visceral fat, or 1SD lower HDL cholesterol, was equivalent to a 0.7 and 0.9-year increase in chronological age respectively (P < 0.001). Inverse variance MR analyses showed that reduced ' g ' is associated with genetically determined elevation of VAT, BMI and WHR (all P < 0.001). In contrast, MR did not support a causal role for blood pressure, lipid, or glycemic indices on cognition. We show an independent relationship between adiposity and cognition in a multi-ethnic Asian population. MR analyses suggest that both visceral adiposity and raised BMI are likely to be causally linked to cognition. Our findings have important implications for preservation of cognitive health, including further motivation for action to reverse the rising burden of obesity in the Asia-Pacific region. The Nanyang Technological University-the Lee Kong Chian School of Medicine, National Healthcare Group, National Medical Research Council, Ministry of Education, Singapore.

Maternal emotional distress symptoms, including life satisfaction, anxiety and depressed mood, are worse in Severely Obese (SO) than lean pregnancy and may alter placental genes regulating fetal glucocorticoid exposure and placental growth. We hypothesised that the associations between increased maternal distress symptoms and changes in placental gene expression including IGF2 and genes regulating fetal glucocorticoid exposure are more pronounced in SO pregnancy. We also considered whether there were sex-specific effects. Placental mRNA levels of 11β-HSDs, NR3C1-α, NR3C2, ABC transporters, mTOR and the IGF2 family were measured in term placental samples from 43 lean (BMI≤25kg/m(2)) and 50 SO (BMI≥40kg/m(2)) women, in whom distress symptoms were prospectively evaluated during pregnancy. The mRNA levels of genes with a similar role in regulating fetal glucocorticoid exposure were strongly inter-correlated. Increased maternal distress symptoms associated with increased NR3C2 and IGF2 isoform 1(IGF2-1) in both lean and SO group (p≤0.05). Increased distress was associated with higher ABCB1 and ABCG2 mRNA levels in SO but lower ABCB1 and higher 11β-HSD1 mRNA levels in lean (p≤0.05) suggesting a protective adaptive response in SO placentas. Increased maternal distress associated with reduced mRNA levels of ABCB1, ABCG2, 11β-HSD2, NR3C1-α and IGF2-1 in placentas of female but not male offspring. The observed sex differences in placental responses suggest greater vulnerability of female fetuses to maternal distress with potentially greater fetal glucocorticoid exposure and excess IGF2. Further studies are needed to replicate these findings and to test whether this translates to potentially greater negative outcomes of maternal distress in female offspring in early childhood.

The actin cytoskeleton in eukaryotic cells undergoes drastic rearrangement during mitosis. The actin cytoskeleton changes are most obvious in the adherent cells where the actin stress fibres are disassembled and the cortical actin network becomes more prominent with concomitant increase in cell rigidity as cells round up and enter mitosis. While the regulatory connections between the actin cytoskeleton and the early mitotic events are apparent, the mechanisms that govern these links are not well understood. Here, we report that LIMK1 and LIMK2, the downstream effectors of RhoA/ROCK, regulate centrosome integrity and astral microtubules organization respectively. Surprisingly, LIMK1 and cofilin are not involved downstream of RhoA/ROCK in the regulation of astral microtubule organization. Instead, we find LIMK2 acts via TPPP in the regulation of astral microtubule, while both LIMK1 and LIMK2 affect centrosome focusing. Both phenotypes are tightly coupled to spindle orientation in the mitotic cells. Thus, our results reveal a novel regulatory link between the actin cytoskeleton and the mitotic spindle during the early stages of mitosis.

Background.: Both maternal obesity and disordered mood have adverse effects on pregnancy outcome. We hypothesized that maternal very severe obesity (SO) is associated with increased anxiety and depression (A&D) symptoms during pregnancy, with adverse effects on gestational weight gain (GWG), postpartum mood and postpartum weight retention (PPWR) and explored any mediation by circulating glucocorticoids.Method.: We measured A&D symptoms with validated questionnaires at weeks 17 and 28 of pregnancy and 3 months postpartum in 135 lean [body mass index (BMI) ⩽25 kg/m²] and 222 SO (BMI ⩾40 kg/m²) pregnant women. Fasting serum cortisol was measured by radioimmunoassay; GWG and PPWR were recorded.Results.: A&D symptoms were higher in the SO group during pregnancy and postpartum despite adjusting for multiple confounders including previous mental health diagnosis (p< 0.05), and were non-linearly correlated with total GWG (anxietyR²= 0.06,p= 0.037; depressionR²= 0.09,p= 0.001). In the SO group only, increased maternal anxiety (β= 0.33,p= 0.03) and depression (β= 0.19,p= 0.04) symptoms at week 17 of pregnancy were associated with increased PPWR, independent of total GWG and breastfeeding. Anxiety symptoms at week 28 of pregnancy, but not depression, were non-linearly correlated with serum cortisol level at week 36 of pregnancy (R²= 0.06,p= 0.02). Cortisol did not mediate the link between A&D symptoms and GWG.Conclusions.: Maternal SO was associated with increased A&D symptoms, and with adverse effects on GWG and PPWR independent of circulating glucocorticoids. Strategies to optimize GWG and postpartum weight management in SO women should include assessment and management of maternal mood in early pregnancy.

Asian people are under-represented in population-based, clinical, and genomic research. To address this gap, we have initiated the Health for Life in Singapore (HELIOS) longitudinal cohort study, comprising comprehensive behavioural, phenotypic, and genomic measurements from 10,004 Asian men and women of Chinese, Indian or Malay background. Phenotyping has been carried out using validated approaches, that are internationally interoperable. Health record linkage enriches both baseline phenotyping and evaluation of prospective outcomes. The integrated multi-omics data include whole-genome and RNA sequencing, quantification of DNA methylation, and metabolomic profiling. Our data reveal extensive lifestyle, physiological, genomic, and molecular diversity between the distinct Asian ethnic groups, and the biological interconnectivity between functional layers. This includes characterisation of divergent patterns of genome regulation between Asian individuals, that correlate with differences in educational attainment, dietary quality, and adiposity, and which overlap transcription factors and DNA methylation sites linked to the development of diabetes and other chronic diseases. Our unique HELIOS Asian Precision Medicine cohort study represents a state-of-the-art platform to enable biomedical researchers to understand the aetiology and pathogenesis of diverse disease outcomes in Asia, and to generate insights that have the potential to improve health outcomes for Asian populations globally.