Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Anterior chest wall in axial spondyloarthritis : imaging, interpretation, and differential diagnosis

Anterior chest wall (ACW) inflammation is not an uncommon finding in patients with axial spondyloarthritis (ax-SpA) and reportedly occurs in 26% of these patients. Radiologists may only be familiar with spinal and peripheral joint imaging, possibly due to the inherent challenges of ACW imaging on some cross-sectional imaging modalities. Knowledge of relevant joint anatomy and the location of sites of inflammation allows the interpreting radiologist to better plan appropriate imaging tests and imaging planes. Accurate assessment of disease burden, sometimes in the absence of clinical findings, may alert the treating rheumatologist, allowing a better estimation of disease burden, increased accuracy of potential imaging scoring systems, and optimize assessment and response to treatment. This article reviews salient anatomy and various imaging modalities to optimize diagnosis, important differential diagnoses, and the interpretation of ACW imaging findings in ax-SpA

Structures and stabilization of kinetoplastid-specific split rRNAs revealed by comparing leishmanial and human ribosomes.

The recent success in ribosome structure determination by cryoEM has opened the door to defining structural differences between ribosomes of pathogenic organisms and humans and to understand ribosome-targeting antibiotics. Here, by direct electron-counting cryoEM, we have determined the structures of the Leishmania donovani and human ribosomes at 2.9 Å and 3.6 Å, respectively. Our structure of the leishmanial ribosome elucidates the organization of the six fragments of its large subunit rRNA (as opposed to a single 28S rRNA in most eukaryotes, including humans) and reveals atomic details of a unique 20 amino acid extension of the uL13 protein that pins down the ends of three of the rRNA fragments. The structure also fashions many large rRNA expansion segments. Direct comparison of our human and leishmanial ribosome structures at the decoding A-site sheds light on how the bacterial ribosome-targeting drug paromomycin selectively inhibits the eukaryotic L. donovani, but not human, ribosome

Structures and stabilization of kinetoplastid-specific split rRNAs revealed by comparing leishmanial and human ribosomes.

The recent success in ribosome structure determination by cryoEM has opened the door to defining structural differences between ribosomes of pathogenic organisms and humans and to understand ribosome-targeting antibiotics. Here, by direct electron-counting cryoEM, we have determined the structures of the Leishmania donovani and human ribosomes at 2.9 Å and 3.6 Å, respectively. Our structure of the leishmanial ribosome elucidates the organization of the six fragments of its large subunit rRNA (as opposed to a single 28S rRNA in most eukaryotes, including humans) and reveals atomic details of a unique 20 amino acid extension of the uL13 protein that pins down the ends of three of the rRNA fragments. The structure also fashions many large rRNA expansion segments. Direct comparison of our human and leishmanial ribosome structures at the decoding A-site sheds light on how the bacterial ribosome-targeting drug paromomycin selectively inhibits the eukaryotic L. donovani, but not human, ribosome

Lightcurve analysis of five main-belt asteroids : 3446 Combes,(9410) 1995 BJ1,(17780) 1998 FY13,(24491) 2000 YT 123, and 28341 Bingaman

An observing campaign was conducted among teams at the University of Maryland, College Park, and in Malta to determine the rotation period of 3446 Combes during 2019 March and April. Lightcurve analysis using MPO Canopus of the asteroid was conducted in order to determine its rotation period. Using the eight nights of data, 3446 Combes was found to have a rotation period of 5.6990 ± 0.0005 h and an amplitude of 0.18 mag. The University of Maryland team also observed four additional asteroids that serendipitously appeared in the images: (9410) 1995 BJ, (17780) 1998 FY13, (24491) 2000 YT123, and 28341 Bingaman. These were observed only one night each and only the raw data for them are presented.peer-reviewe