Vinculin controls talin engagement with the actomyosin machinery

The link between extracellular-matrix-bound integrins and intracellular F-actin is essential for cell spreading and migration. Here, we demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link. By expressing structure-based talin mutants in talin null cells, we show that while the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the central ABS2 is essential for focal adhesion (FA) maturation. Thus, although ABS2 mutants support cell spreading, the cells lack FAs, fail to polarize and exert reduced force on the surrounding matrix. ABS2 is inhibited by the preceding mechanosensitive vinculin-binding R3 domain, and deletion of R2R3 or expression of constitutively active vinculin generates stable force-independent FAs, although cell polarity is compromised. Our data suggest a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vinculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilizes FAs

Couple concordance in diabetes, hypertension and dyslipidaemia in urban India and Pakistan and associated socioeconomic and household characteristics and modifiable risk factors

Background: Concordance in chronic disease status has been observed within couples. In urban India and Pakistan, little is known about couple concordance in diabetes, hypertension, and dyslipidaemia and associated socioeconomic characteristics and modifiable risk factors.Methods: We analysed cross-sectional data from 2548 couples from the Centre for cArdio-metabolic Risk Reduction in South Asia cohort in Chennai, Delhi and Karachi. We estimated couple concordance in presence of ≥1 of diabetes, hypertension and dyslipidaemia (positive concordance: both spouses (W+H+); negative concordance: neither spouse (W-H-); discordant wife: only wife (W+H-); or discordant husband: only husband (W-H+)). We assessed associations of five socioeconomic and household characteristics, and six modifiable risk factors with couple concordance using multinomial logistic regression models with couples as the unit of analysis (reference: W-H-).Results: Of the couples, 59.4% (95% CI 57.4% to 61.3%) were concordant in chronic conditions (W+H+: 29.2% (95% CI 27.4% to 31.0%); W-H-: 30.2% (95% CI 28.4%- to 32.0%)); and 40.6% (95% CI 38.7% to 42.6%) discordant (W+H-: 13.1% (95% CI 11.8% to 14.4%); W-H+: 27.6% (95% CI 25.9% to 29.4%)). Compared with couples with no conditions (W-H-), couples had higher relative odds of both having at least one condition if they had higher versus lower levels of: income (OR 2.03 (95% CI 1.47 to 2.80)), wealth (OR 2.66 (95% CI 1.98 to 3.58)) and education (wives\u27 education: OR 1.92 (95% CI 1.29 to 2.86); husbands\u27 education: OR 2.98 (95% CI 1.92 to 4.66)) or weight status (overweight or obesity in both spouses ORs 7.17 (95% CI 4.99 to 10.30)).Conclusions: Positive couple concordance in major chronic conditions is high in urban India and Pakistan, especially among couples with relatively higher socioeconomic position. This suggests that prevention and management focusing on couples at high risk for concordant chronic conditions may be effective and more so in higher socioeconomic groups