Genome wide association for substance dependence: convergent results from epidemiologic and research volunteer samples

<p>Abstract</p> <p>Background</p> <p>Dependences on addictive substances are substantially-heritable complex disorders whose molecular genetic bases have been partially elucidated by studies that have largely focused on research volunteers, including those recruited in Baltimore. Maryland. Subjects recruited from the Baltimore site of the Epidemiological Catchment Area (ECA) study provide a potentially-useful comparison group for possible confounding features that might arise from selecting research volunteer samples of substance dependent and control individuals. We now report novel SNP (single nucleotide polymorphism) genome wide association (GWA) results for vulnerability to substance dependence in ECA participants, who were initially ascertained as members of a probability sample from Baltimore, and compare the results to those from ethnically-matched Baltimore research volunteers.</p> <p>Results</p> <p>We identify substantial overlap between the home address zip codes reported by members of these two samples. We find overlapping clusters of SNPs whose allele frequencies differ with nominal significance between substance dependent <it>vs </it>control individuals in both samples. These overlapping clusters of nominally-positive SNPs identify 172 genes in ways that are never found by chance in Monte Carlo simulation studies. Comparison with data from human expressed sequence tags suggests that these genes are expressed in brain, especially in hippocampus and amygdala, to extents that are greater than chance.</p> <p>Conclusion</p> <p>The convergent results from these probability sample and research volunteer sample datasets support prior genome wide association results. They fail to support the idea that large portions of the molecular genetic results for vulnerability to substance dependence derive from factors that are limited to research volunteers.</p

Induction of the interleukin 6/ signal transducer and activator of transcription pathway in the lungs of mice sub-chronically exposed to mainstream tobacco smoke

<p>Abstract</p> <p>Background</p> <p>Tobacco smoking is associated with lung cancer and other respiratory diseases. However, little is known about the global molecular changes that precede the appearance of clinically detectable symptoms. In this study, the effects of mainstream tobacco smoke (MTS) on global transcription in the mouse lung were investigated.</p> <p>Methods</p> <p>Male C57B1/CBA mice were exposed to MTS from two cigarettes daily, 5 days/week for 6 or 12 weeks. Mice were sacrificed immediately, or 6 weeks following the last cigarette. High density DNA microarrays were used to characterize global gene expression changes in whole lung. Microarray results were validated by Quantitative real-time RT-PCR. Further analysis of protein synthesis and function was carried out for a select set of genes by ELISA and Western blotting.</p> <p>Results</p> <p>Globally, seventy nine genes were significantly differentially expressed following the exposure to MTS. These genes were associated with a number of biological processes including xenobiotic metabolism, redox balance, oxidative stress and inflammation. There was no differential gene expression in mice exposed to smoke and sampled 6 weeks following the last cigarette. Moreover, cluster analysis demonstrated that these samples clustered alongside their respective controls. We observed simultaneous up-regulation of <it>interleukin 6 </it>(<it>IL-6</it>) and its antagonist, <it>suppressor of cytokine signalling </it>(<it>SOCS3</it>) mRNA following 12 weeks of MTS exposure. Analysis by ELISA and Western blotting revealed a concomitant increase in total IL-6 antigen levels and its downstream targets, including phosphorylated signal transducer and activator of transcription 3 (Stat3), basal cell-lymphoma extra large (BCL-XL) and myeloid cell leukemia 1 (MCL-1) protein, in total lung tissue extracts. However, in contrast to gene expression, a subtle decrease in total SOCS3 protein was observed after 12 weeks of MTS exposure.</p> <p>Conclusion</p> <p>Global transcriptional analysis identified a set of genes responding to MTS exposure in mouse lung. These genes returned to basal levels following smoking cessation, providing evidence to support the benefits of smoking cessation. Detailed analyses were undertaken for IL-6 and its associated pathways. Our results provide further insight into the role of these pathways in lung injury and inflammation induced by MTS.</p

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Composition dependence of ferroelectric and piezoelectric properties of epitaxial (1 - x)Ba(Zr <inf>0.2</inf> Ti <inf>0.8</inf> )O <inf>3</inf> -x(Ba <inf>0.7</inf> Ca <inf>0.3</inf> )TiO <inf>3</inf> thin films prepared by pulsed laser deposition

Abstract Lead-free (1 - x)Ba(Zr 0.2 Ti 0.8 )O 3 -x(Ba 0.7 Ca 0.3 )TiO 3 (BZT-xBCT) (x = 0.3, 0.4, 0.5, 0.6, 0.7) thin films were deposited on SrRuO 3 (SRO)-electroded (0 0 1)-oriented SrTiO 3 (STO) single crystal substrates by pulsed laser deposition (PLD). X-ray diffraction and selected area electron diffraction (SAED) patterns verified epitaxial growth for all the thin films. High ferroelectric activities were evidenced by the well-defined polarization-electric field hysteresis loops. Both structural and physical properties of the thin films demonstrated a strong composition dependence and an MPB-like behaviour was found at around x = 0.5, which is in agreement with that of its bulk counterparts. The superior ferroelectric and piezoelectric responses were attained at x = 0.5 with remanent polarization P r of 17.8 μC/cm 2 and piezoelectric coefficient d 33 of 100 ± 5 pm/V

Mechanical activation on phosphogypsum: hydrosodalite system

The application of phosphogypsum in the production of binding materials is problematic because of phosphate, fluorine and other soluble impurities. These impurities influence the strength development of binding materials and during operating time can be released (efflorescence) from binding materials’ products. For these reasons, it is important to neutralize the above-mentioned impurities. The objective of the work was to investigate the neutralization process of the acid impurities of hemihydrate phosphogypsum (obtained from Kovdor apatite mine) with zeolite hydrosodalite. Mechanical activation together with the neutralizing zeolite additive was used in this research. Mechanical activation was carried out in a ball mill. Two types of samples were formed: one type with non-milled mixtures and the second type with milled mixtures. The additive of 0, 3, 5, and 10% of hydrosodalite was chosen. This paper describes the process of adsorbing of hazardous phosphate impurities by hydrosodalite. The compressive strength of phosphogypsum specimens with hydrosodalite additives subjected to mechanical treatment was higher as compared to the specimens without mechanical activation and additive of hydrosodalite. In this case pH values of milled mixture with hydrosodalite become neutral for these samples. It was determined that the mixture of phosphogypsum with hydrosodalite under mechanical treatment is an effective additive for neutralizing the acidic phosphogypsum mediumKauno technologijos universitetasVandens ūkio ir žemėtvarkos fakultetasVytauto Didžiojo universiteta