New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Cerebral gray and white matter changes and clinical course in metachromatic leukodystrophy

OBJECTIVE: Metachromatic leukodystrophy (MLD) is a rare metabolic disorder leading to demyelination and rapid neurologic deterioration. As therapeutic options evolve, it seems essential to understand and quantify progression of the natural disease. The aim of this study was to assess cerebral volumetric changes in children with MLD in comparison to normal controls and in relation to disease course. METHOD: Eighteen patients with late-infantile MLD and 42 typically developing children in the same age range (20–59 months) were analyzed in a cross-sectional study. Patients underwent detailed genetic, biochemical, electrophysiologic, and clinical characterization. Cerebral gray matter (GM) and white matter (WM) volumes were assessed by multispectral segmentation of T1- and T2-weighted MRI. In addition, the demyelinated WM (demyelination load) was automatically quantified in T2-weighted images of the patients, and analyzed in relation to the clinical course. RESULTS: WM volumes of patients did not differ from controls, although their growth curves were slightly different. GM volumes of patients, however, were on average 10.7% (confidence interval 6.0%–14.9%, p < 0.001) below those of normally developing children. The demyelination load (corrected for total WM volume) increased with disease duration (p < 0.003) and motor deterioration (p < 0.001). CONCLUSION: GM volume in patients with MLD is reduced when compared with healthy controls, already at young age. This supports the notion that, beside demyelination, neuronal dysfunction caused by neuronal storage plays an additional role in the disease process. The demyelination load may be a useful noninvasive imaging marker for disease progression and may serve as reference for therapeutic intervention

Characterization of a Radical SAM Oxygenase for the Ether Crosslinking in Darobactin Biosynthesis

International audienceDarobactin A is a ribosomally synthesized, post-translationally modified peptide (RiPP) with potent and broad-spectrum anti-Gram-negative antibiotic activity. The structure of darobactin A is characterized by an ether and C-C crosslinking. However, the specific mechanism of the crosslink formation, especially the ether crosslink, remains elusive. Here, using in vitro enzyme assays, we demonstrate that both crosslinks are formed by the DarE radical S-adenosylmethionine (SAM) enzyme in an O2-dependent manner. The relevance of the observed activity to darobactin A biosynthesis was demonstrated by proteolytic transformation of the DarE product into darobactin A. Furthermore, DarE assays in the presence of 18O2 or [18O]water demonstrated that the oxygen of the ether crosslink originates from O2 and not from water. These results demonstrate that DarE is a radical SAM enzyme that uses oxygen as a co-substrate in its physiologically relevant function. Since radical SAM enzymes are generally considered to function under anaerobic environments, the discovery of a radical SAM oxygenase represents a significant change in the paradigm and suggests that these radical SAM enzymes function in aerobic cells. Also, the study revealed that DarE catalyzes the formation of three distinct modifications on DarA; ether and C-C crosslinks and α,β-desaturation. Based on these observations, possible mechanisms of the DarE-catalyzed reactions are discussed

Genome- and metabolome-guided discovery of marine BamA inhibitors revealed a dedicated darobactin halogenase

Darobactins represent a class of ribosomally synthesized and post-translationally modified peptide (RiPP) antibiotics featuring a rare bicyclic structure. They target the Bam-complex of Gram-negative bacteria and exhibit in vivo activity against drug-resistant pathogens. First isolated from Photorhabdus species, the corresponding biosynthetic gene clusters (BGCs) are widespread among γ-proteobacteria, including the genera Vibrio, Yersinia, and Pseudoalteromonas (P.). While the organization of the BGC core is highly conserved, a small subset of Pseudoalteromonas carries an extended BGC with additional genes. Here, we report the identification of brominated and dehydrated darobactin derivatives from P. luteoviolacea strains. The marine derivatives are active against multidrug-resistant (MDR) Gram-negative bacteria and showed solubility and plasma protein binding ability different from darobactin A, rendering it more active than darobactin A. The halogenation reaction is catalyzed by DarH, a new class of flavin-dependent halogenases with a novel fold

The Fraction of Cool-core Clusters in X-Ray versus SZ Samples Using Chandra Observations

We derive and compare the fractions of cool-core clusters in the Planck Early Sunyaev–Zel'dovich sample of 164 clusters with $z\leqslant 0.35$ and in a flux-limited X-ray sample of 100 clusters with $z\leqslant 0.30$, using Chandra observations. We use four metrics to identify cool-core clusters: (1) the concentration parameter, which is the ratio of the integrated emissivity profile within 0.15 r 500 to that within r 500; (2) the ratio of the integrated emissivity profile within 40 kpc to that within 400 kpc; (3) the cuspiness of the gas density profile, which is the negative of the logarithmic derivative of the gas density with respect to the radius, measured at 0.04 r 500; and (4) the central gas density, measured at 0.01 r 500. We find that the sample of X-ray-selected clusters, as characterized by each of these metrics, contains a significantly larger fraction of cool-core clusters compared to the sample of SZ-selected clusters (44% ± 7% versus 28% ± 4% using the concentration parameter in the 0.15–1.0 r 500 range, 61% ± 8% versus 36% ± 5% using the concentration parameter in the 40–400 kpc range, 64% ± 8% versus 38% ± 5% using the cuspiness, and 53% ± 7% versus 39 ± 5% using the central gas density). Qualitatively, cool-core clusters are more X-ray luminous at fixed mass. Hence, our X-ray, flux-limited sample, compared to the approximately mass-limited SZ sample, is overrepresented with cool-core clusters. We describe a simple quantitative model that uses the excess luminosity of cool-core clusters compared to non-cool-core clusters at fixed mass to successfully predict the observed fraction of cool-core clusters in X-ray-selected samples. © 2017. The American Astronomical Society. All rights reserved