The DRD2 TaqIA polymorphism associated with changed midbrain volumes in healthy individuals

The human DRD2 gene is located on chromosome 11q22-q23 and contains one specific functional polymorphism called TaqIA, which characteristically presents two alleles referred to as A1 and A2. Evidence indicates that the A1 allele impacts brain dopaminergic function and may confer an increased risk of developing Parkinson's disease. However, possible morphological changes underlying such genetic variant remain to be clarified. The aim of this study was to provide an in vivo demonstration of changes in brain structures associated with the TaqIA polymorphism of the DRD2 gene. Optimized voxel-based morphometry (VBM) was applied to high-resolution MR brain images of 70 healthy controls divided into two groups according to their DRD2 genotype (A1/A2, n = 15; A2/A2, n = 55). Compared with individuals' homozygous for the A2 allele, the A1 carriers had significantly smaller areas of a specific part of the midbrain, encompassing the substantia nigra bilaterally. Our findings showed an association of the DRD2 TaqIA polymorphism with the changed volumes of a specific subcortical region strongly involved in the dopaminergic system.     

Thermoluminescence characteristics of lithium borosilicate glass doped with Sm2O3

Lithium borosilicate glass composite (SiO₂–Li₂CO₃–H₃BO₃) doped with various concentrations of Sm₂O₃ (0–0.7 mole %) was prepared using the melt quenching method. The investigated thermoluminescence (TL) characteristics of the prepared system revealed that the highest TL response was obtained for this glass composite at 0.05 mol% Sm₂O₃. In this study, the 0.05 mol% Sm₂O₃‐doped lithium borosilicate glass composite was subjected to detailed dosimetric investigation in terms of its annealing condition, dose–response, and minimum detectable dose. The reproducibility of the response, thermal characteristics, and optical fading were also studied. The obtained results showed that the prepared glass composite had a linear dose–response over the wide gamma dose range 2Gy to 2 kGy, as well as reasonable thermal fading and excellent reproducibility. These attributes render the composite under investigation promising for utilization in radiation detection.     

Bayesian Peak Picking for NMR Spectra

Protein structure determination is a very important topic in structural genomics,which helps people to understand varieties of biological functions such as protein-protein interactions,protein–DNA interactions and so on.Nowadays,nuclear magnetic resonance(NMR) has often been used to determine the three-dimensional structures of protein in vivo.This study aims to automate the peak picking step,the most important and tricky step in NMR structure determination.We propose to model the NMR spectrum by a mixture of bivariate Gaussian densities and use the stochastic approximation Monte Carlo algorithm as the computational tool to solve the problem.Under the Bayesian framework,the peak picking problem is casted as a variable selection problem.The proposed method can automatically distinguish true peaks from false ones without preprocessing the data.To the best of our knowledge,this is the first effort in the literature that tackles the peak picking problem for NMR spectrum data using Bayesian method.     

Structures of the alkanesulfonate monooxygenase MsuD provide insight into C–S bond cleavage,substrate scope,and an unexpected role for the tetramer

Bacterial two-component flavin-dependent monooxygenases cleave the stable C–S bond of environmental and anthropogenic organosulfur compounds. The monooxygenase MsuD converts methanesulfonate (MS⁻) to sulfite, completing the sulfur assimilation process during sulfate starvation, but the mechanism of this conversion remains unclear. To explore the mechanism of C–S bond cleavage, we report a series of crystal structures of MsuD from Pseudomonas fluorescens in different liganded states. This report provides the first crystal structures of an alkanesulfonate monooxygenase with a bound flavin and alkanesulfonate, elucidating the roles of the active site lid, the protein C terminus, and an active site loop in flavin and/or alkanesulfonate binding. These structures position MS⁻ closest to the flavin N5 position, consistent with an N5-(hydro)peroxyflavin mechanism rather than a classical C4a-(hydro)peroxyflavin mechanism. A fully enclosed active site is observed in the ternary complex, mediated by interchain interaction of the C terminus at the tetramer interface. These structures identify an unexpected function of the protein C terminus in this protein family in stabilizing tetramer formation and the alkanesulfonate-binding site. Spurred by interest from the crystal structures, we conducted biochemical assays and molecular docking that redefine MsuD as a small- to medium-chain alkanesulfonate monooxygenase. Functional mutations verify the sulfonate-binding site and reveal the critical importance of the protein C terminus for monooxygenase function. These findings reveal a deeper understanding of MsuD’s functionality at the molecular level and consequently how it operates within its role as part of the sulfur assimilation pathway.     

Comprehensive gene panels provide advantages over clinical exome sequencing for Mendelian diseases

BackgroundTo understand the contribution of Mendelian mutations to the burden of undiagnosed diseases that are suspected to be genetic in origin, we developed a next-generation sequencing-based multiplexing assay that encompasses the ~3000 known Mendelian genes. This assay, which we term the Mendeliome, comprises 13 gene panels based on clinical themes, covering the spectrum of pediatric and adult clinical genetic medicine. We explore how these panels compare with clinical whole exome sequencing (WES).ResultsWe tested 2357 patients referred with suspected genetic diagnoses from virtually every medical specialty. A likely causal mutation was identified in 1018 patients, with an overall clinical sensitivity of 43 %, comparing favorably with WES. Furthermore, the cost of clinical-grade WES is high (typically more than 4500 US dollars), whereas the cost of running a sample on one of our panels is around 75–150 US dollars, depending on the panel. Of the “negative” cases, 11 % were subsequently found by WES to harbor a likely causal mutation in a known disease gene (largely in genes identified after the design of our assay), as inferred from a representative sample of 178. Although our study population is enriched for consanguinity, 245 (24 %) of solved cases were autosomal dominant and 35 (4 %) were X-linked, suggesting that our assay is also applicable to outbred populations.ConclusionsDespite missing a significant number of cases, the current version of the Mendeliome assay can account for a large proportion of suspected genetic disorders, and provides significant practical advantages over clinical WES.

Electronic supplementary material

The online version of this article (doi:10.1186/s13059-015-0693-2) contains supplementary material, which is available to authorized users.     

The Ethanol-Induced Stimulation of Rat Duodenal Mucosal Bicarbonate Secretion In Vivo Is Critically Dependent on Luminal Cl–

Alcohol may induce metabolic and functional changes in gastrointestinal epithelial cells, contributing to impaired mucosal barrier function. Duodenal mucosal bicarbonate secretion (DBS) is a primary epithelial defense against gastric acid and also has an important function in maintaining the homeostasis of the juxtamucosal microenvironment. The aim in this study was to investigate the effects of the luminal perfusion of moderate concentrations of ethanol in vivo on epithelial DBS, fluid secretion and paracellular permeability. Under thiobarbiturate anesthesia, a ∼30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ in rats. The effects on DBS, duodenal transepithelial net fluid flux and the blood-to-lumen clearance of ⁵¹Cr-EDTA were investigated. Perfusing the duodenum with isotonic solutions of 10% or 15% ethanol-by-volume for 30 min increased DBS in a concentration-dependent manner, while the net fluid flux did not change. Pre-treatment with the CFTR inhibitor CFTR_inh172 (i.p. or i.v.) did not change the secretory response to ethanol, while removing Cl⁻ from the luminal perfusate abolished the ethanol-induced increase in DBS. The administration of hexamethonium (i.v.) but not capsazepine significantly reduced the basal net fluid flux and the ethanol-induced increase in DBS. Perfusing the duodenum with a combination of 1.0 mM HCl and 15% ethanol induced significantly greater increases in DBS than 15% ethanol or 1.0 mM HCl alone but did not influence fluid flux. Our data demonstrate that ethanol induces increases in DBS through a mechanism that is critically dependent on luminal Cl⁻ and partly dependent on enteric neural pathways involving nicotinic receptors. Ethanol and HCl appears to stimulate DBS via the activation of different bicarbonate transporting mechanisms.