Fine Mapping of the NRG1 Hirschsprung's Disease Locus

The primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ∼350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR

Accurate Effective Stress Measures: Predicting Creep Life for 3D Stresses Using 2D and 1D Creep Rupture Simulations and Data

Abstract Operating structural components experience complex loading conditions resulting in 3D stress states. Current design practice estimates multiaxial creep rupture life by mapping a general state of stress to a uniaxial creep rupture correlation using effective stress measures. The data supporting the development of effective stress measures are nearly always only uniaxial and biaxial, as 3D creep rupture tests are not widely available. This limitation means current effective stress measures must extrapolate from 2D to 3D stress states, potentially introducing extrapolation error. In this work, we use a physics-based, crystal plasticity finite element model to simulate uniaxial, biaxial, and triaxial creep rupture. We use the virtual dataset to assess the accuracy of current and novel effective stress measures in extrapolating from 2D to 3D stresses and also explore how the predictive accuracy of the effective stress measures might change if experimental 3D rupture data was available. We confirm these conclusions, based on simulation data, against multiaxial creep rupture experimental data for several materials, drawn from the literature. The results of the virtual experiments show that calibrating effective stress measures using triaxial test data would significantly improve accuracy and that some effective stress measures are more accurate than others, particularly for highly triaxial stress states. Results obtained using experimental data confirm the numerical findings and suggest that a unified effective stress measure should include an explicit dependence on the first stress invariant, the maximum tensile principal stress, and the von Mises stress

Significance of the Myxovirus resistance A (MxA) gene - 123C>A single-nucleotide polymorphism in suppressed interferon ß induction of severe acute respiratory syndrome coronavirus infection

Myxovirus resistance A (MxA) is an antiviral protein induced by interferon a and ß (IFN-α, IFN-β) that can inhibit viral replication. The minor alleles of the -88G>T and -123C>A MxA promoter single-nucleotide polymorphisms (SNPs) are associated with increased promoter activity and altered response to IFN-α and IFN-β treatment. Here, we demonstrate that the -123A minor allele provided stronger binding affinity to nuclear proteins extracted from IFN-β-untreated cells than did the wild-type allele, whereas the -88T allele showed preferential binding after IFN-β stimulation. Endogenous IFN-α and IFN-β induction can be suppressed in severe acute respiratory syndrome (SARS) Coronavirus infection. In support of our in vitro findings, a large case-control genetic-association study for SARS Coronavirus infection confirmed that the -123A minor-allele carriers were significantly associated with lower risk of SARS Coronavirus infection, whereas the -88T minorallele carriers were insignificant after adjustment for confounding effects. This suggests that -123C>A plays a more important role in modulating basal MxA expression, thus contributing more significantly to innate immune response against viral infections that suppress endogenous IFN-α and IFN-β induction such as SARS Coronavirus. © 2010 by the Infectious Diseases Society of America. All rights reserved.link_to_subscribed_fulltex

Suppression of diet-induced hypercholesterolaemia by saponins from panax notoginseng in rats

Panax notoginseng saponins (PNS) are major active constituents of P. notoginseng. This study investigated the mechanisms of the hypocholesterolaemic and atheroscleroprotective effects of PNS. It was found that treatment of PNS (30 or 100 mg/kg/day, p.o.) could significantly reduce elevated serum total cholesterol, triacylglycerol, low-density lipoprotein cholesterol and atherogenic index induced by feeding rats with high cholesterol diet for 28 days. High-density lipoprotein cholesterol could also be increased by PNS treatment. Additionally, PNS significantly enhanced the hypercholesterolaemia-induced reduction of superoxide dismutase activity in the liver. In hypercholesterolaemic rats, PNS significantly improved the endothelium-dependent vasodilatation, acetylcholine-induced nitric oxide production and endothelial nitric oxide synthase mRNA expression in a dose-dependent manner. It also significantly reversed the hypercholesterolaemia-induced changes in mRNA expressions of cholesterol 7α-hydroxylase and peroxisome proliferator-activated receptor α but not HMG-CoA reductase. The findings provided evidence for using PNS to prevent the development of hypercholesterolaemia and atherosclerosis. The hypocholesterolaemic activity of PNS is likely to be resulted from inducing the biosynthesis of bile acids from cholesterol and promoting the β-oxidation of fatty acids in the liver. The vasoprotective function of PNS may be brought about by increasing the gene expression of eNOS in endothelial cells, its antioxidative activity, or both

Photocytotoxicity and Magnetic Relaxivity Responses of Dual-Porous γ-Fe₂O₃@<i>meso</i>-SiO₂ Microspheres

Novel high magnetization microspheres with porous γ-Fe₂O₃ core and porous SiO₂ shell were synthesized using a templating method, whereas the size of the magnetic core and the thickness of the porous shell can be controlled by tuning the experimental parameters. By way of an example, as-prepared γ-Fe₂O₃@<i>meso</i>-SiO₂ microspheres (170 nm) display excellent water-dispersity and show photonic characteristics under externally applied a magnetic field. The magnetic property of the γ-Fe₂O₃ porous core enables the microspheres to be used as a contrast agent in magnetic resonance imaging with a high <i>r</i>₂ (76.5 s^–1 mM^–1 Fe) relaxivity. The biocompatible composites possess a large BET surface area (222.3 m²/g), demonstrating that they can be used as a bifunctional agent for both MRI and drug carrier. Because of the high substrate loading of the magnetic, dual-porous materials, only a low dosage of the substrate will be acquired for potential practical applications. Hydrophobic zinc­(II) phthalocyanine (ZnPC) photosensitizing molecules have been encapsulated into the dual-porous microspheres to form γ-Fe₂O₃@<i>meso</i>-SiO₂–ZnPC microspheres. Biosafety, cellular uptake in HT29 cells, and in vitro MRI of these nanoparticles have been demonstrated. Photocytotoxicity (λ > 610 nm) of the HT29 cells uptaken with γ-Fe₂O₃@<i>meso</i>-SiO₂–ZnPC microspheres has been demonstrated for 20 min illumination