Structure and mechanism of acetolactate decarboxylase

Acetolactate decarboxylase catalyzes the conversion of both enantiomers of acetolactate to the (R)-enantiomer of acetoin, via a mechanism that has been shown to involve a prior rearrangement of the non-natural (R)-enantiomer substrate to the natural (S)-enantiomer. In this paper, a series of crystal structures of ALDC complex with designed transition state mimics are reported. These structures, coupled with inhibition studies and site-directed mutagenesis provide an improved understanding of the molecular processes involved in the stereoselective decarboxylation/protonation events. A mechanism for the transformation of each enantiomer of acetolactate is proposed

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Eye movements during rapid pointing under risk,” Vision Res

Abstract We recorded saccadic eye movements during visually-guided rapid pointing movements under risk. We intended to determine whether saccadic end points are necessarily tied to the goals of rapid pointing movements or whether, when the visual features of a display and the goals of a pointing movement are different, saccades are driven by low-level features of the visual stimulus. Subjects pointed at a stimulus configuration consisting of a target region and a penalty region. Each target hit yielded a gain of points; each penalty hit incurred a loss of points. Late responses were penalized. The luminance of either target or penalty region was indicated by a disk which differed significantly from the background in luminance, while the other region was indicated by a thin circle. In subsequent experiments, we varied the visual salience of the stimulus configuration and found that manual responses followed near-optimal strategies maximizing expected gain, independent of the salience of the target region. We suggest that the final eye position is partially pre-programmed prior to hand movement initiation. While we found that manipulations of the visual salience of the display determined the end point of the initial saccade we also found that subsequent saccades are driven by the goal of the hand movement

Facial electromyographic responses to emotionally significant visual images: differences between light and heavy drinkers

Fifty participants took part in an experiment designed to investigate individual differences in the effects of alcohol on facial EMG responses to emotionally significant stimuli. Participants took part in two experimental sessions during which they viewed emotionally negative and emotionally positive visual images. In one session they consumed alcohol (0.5 g/kg bodyweight) whilst in the other they consumed soft drink. We classified each participant as a light or heavy drinker on the basis of their self-reported alcohol consumption. Negatively valenced images elicited increases in both frontalis and corrugator activity but alcohol did not moderate this effect either in light or heavy drinkers. Nevertheless, heavy drinkers did respond more strongly to the negatively valenced images and this supports the view that responses to negative emotional stimuli may play a part in the development of heavy drinking as a result of negative reinforcement processes