Material quality characterization of CdZnTe substrates for HgCdTe epitaxy

Cd1-xZnxTe (CZT) substrates were studied to investigate their bulk and surface properties. Imperfections in CZT substrates affect the quality of Hg1-xCdxTe (MCT) epilayers deposited on them and play a role in limiting the performance of infrared (IR) focal plane arrays. CZT wafers were studied to investigate their bulk and surface properties. Transmission and surface x-ray diffraction techniques, utilizing both a conventional closed-tube x-ray source as well as a synchrotron radiation source, and IR transmission microspectroscopy, were used for bulk and surface investigation. Synchrotron radiation offers the capability to combine good spatial resolution and shorter exposure times than conventional x-ray sources, which allows for high-resolution mapping of relatively large areas in an acceptable amount of time. Information on the location of grain boundaries and precipitates was also obtained. The ultimate goal of this work is to understand the defects in CZT substrates and their effects on the performance and uniformity of MCT epilayers and then to apply this understanding to produce better infrared detectors

Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis

Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding vascular disease, as maintenance of a cells' epigenetic profile is essential for maintaining cellular phenotype. Global hypomethylation of proliferating aortic SMCs and concomitant decrease of DNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by ‘genomic convergence' for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2′-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P = 0.017, OR = 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex diseas

Submicron Structures Fabrication and Research

Contains reports on twelve research projects.Lawrence Livermore Laboratory (Subcontract 2069209)Joint Services Electronics Program (Contract DAAG29-C-0104)U.S. Navy - Office of Naval Research (Contract N00014-79-C-0908)Joint Services Electronics Program (Contract DAAG29-80-C-0104)Harkness FoundationI.B.M.U.S. Department of Energy (Contract DE-ACO2-80-E10179)National Science Foundation (Grant ECS80-17705

Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: Findings from the Avon Longitudinal Study of Parents and Children (ALSPAC)

© The Author 2014. Maternal smoking during pregnancy has been found to influence newborn DNA methylation in genes involved in fundamental developmental processes. It is pertinent to understand the degree to which the offspring methylomeis sensitive to the intensity and duration of prenatal smoking. An investigation of the persistence of offspring methylation associated with maternal smoking and the relative roles of the intrauterine and postnatal environment is alsowarranted. In the Avon Longitudinal Study of Parents and Children, we investigated associations between prenatal exposure to maternal smoking and offspring DNA methylation at multiple time points in approximately 800 mother-offspring pairs. In cord blood, methylation at 15 CpG sites in seven gene regions (AHRR, MYO1G, GFI1, CYP1A1, CNTNAP2, KLF13 and ATP9A) was associated with maternal smoking, and a dose-dependent response was observed in relation to smoking duration and intensity. Longitudinal analysis of blood DNA methylation in serial samples at birth, age 7 and 17 years demonstrated that some CpG sites showed reversibility of methylation (GFI1, KLF13 and ATP9A), whereas others showed persistently perturbed patterns (AHRR, MYO1G, CYP1A1 and CNTNAP2). Of those showing persistence, we explored the effect of postnatal smoke exposure and found that the major contribution to altered methylation was attributed to a critical window of in utero exposure. A comparison of paternal and maternal smoking and offspring methylation showed consistently stronger maternal associations, providing further evidence for causal intrauterine mechanisms. These findings emphasize the sensitivity of the methylome to maternal smoking during early development and the long-term impact of such exposure

Omega-3 fatty acids and genome-wide interaction analyses reveal DPP10-pulmonary function association

Rationale: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health. Objective: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility. Methods: Associations of n-3 PUFA biomarkers (a-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV1, FVC, and FEV1/FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNPassociations and their interactions with n-3PUFAs. Results: DPA and DHA were positively associated with FEV1 and FVC (P < 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P-2df = 9.4 x 10(-9) across discovery and replication cohorts). The rs11693320-A allele (frequency, similar to 80%) was associated with lower FVC (P-SNP = 2.1 x 10(-9); beta(SNP) = 2161.0 ml), and the association was attenuated by higher DHA levels (P-SNPxDHA interaction = 2.1x10(-7); beta(SNPxDHA interaction) = 36.2 ml). Conclusions: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction

Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence

Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency = 44-77%) was associated with increased risk of nicotine dependence at P = 3.7 x 10(-8) (odds ratio (OR) = 1.06 and 95% confidence interval (CI) = 1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N = 48,931) using heavy vs never smoking as a proxy phenotype (P = 3.6 x 10(-4), OR = 1.05, and 95% CI = 1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N = 60,586, meta-analysis P = 0.0095, OR = 1.05, and 95% CI = 1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N = 166, P = 2.3 x 10(-26)) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N = 103, P = 3.0 x 10(-6)) and the independent Brain eQTL Almanac (N = 134, P = 0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.Peer reviewe

Genomic and epigenetic evidence for oxytocin receptor deficiency in autism

<p>Abstract</p> <p>Background</p> <p>Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders.</p> <p>Methods</p> <p>We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR).</p> <p>Results</p> <p>Our analysis revealed a genomic deletion containing the oxytocin receptor gene, <it>OXTR </it>(MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate <it>OXTR </it>expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that <it>OXTR </it>mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls.</p> <p>Conclusion</p> <p>Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of <it>OXTR </it>in the development of the disorder.</p> <p>See the related commentary by Gurrieri and Neri: <url>http://www.biomedcentral.com/1741-7015/7/63</url></p

Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits

Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (r(g) = 0.40-1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking