A Haplotype-Based Permutation Approach in Gene-Based Testing

The soaring cost of health care is the biggest public health issue facing our country today. Development of strategies that improve the delivery of health care by identifying high risk individuals for a disease is a major approach to better utilize limited medical resources. Incorporating genomic data into risk stratification models is an essential component for creating these diagnostic and treatment strategies. Although initially applied to just small subsets of disease, advances in technology are making it economically feasible to utilize a patient's genomic data in a wider range of medical disorders. Current genetic association studies are crucial for identifying which loci to include in these models. Genome Wide Association Studies (GWAS) are a valuable tool for identifying genetic variants associated with disease. Commonly, each SNP is initially independently tested in a GWAS with a univariate analysis. By combining the effects of multiple alleles, multivariate analysis of GWAS may increase power to detect associations and, thus, identify additional risk loci. We employ a haplotype block analysis within genes boundaries for a newly developed gene-based method, “GeneBlock”. GeneBlock is compared in a power analysis with two previously published permutation algorithms (GWiS and Fisher) and a simulation method (Vegas). All methods are tested in an Alzheimer Disease GWAS consisting of 1334 cases and 1475 controls. Results from the Alzheimer’s analysis were subsequently compared with haplotype and univariate analysis. Power analyses shows both GeneBlock and GWiS as more powerful methods than Vegas and Fisher. A combinational approach involving the selection of the lowest p-value from Vegas, GWiS, and Geneblock has higher power than any individual method even when controlling for the additional multiple comparisons. Fisher and Vegas identify no significant genes in the Alzheimer’s GWAS, while GWiS and Geneblock identified four (PRDM16, ARHGEF16, HLA-DRA, TRAF1) and three (C17orf51, MGC29506, SLC23A1) respectively. The combination method is also most powerful in the real GWAS data; it identified all seven of the above significant genes. Comparing single, haplotype, and gene level analyses revealed that only about 1/3 of the top 100 genes are shared, indicating a large variance in results between methods

Galactic interstellar 18O/17O ratios - a radial gradient?

(Abridged) Our aim is to determine 18O/17O abundance ratios across the entire Galaxy. These provide a measure of the amount of enrichment by high-mass versus intermediate-mass stars. Such ratios, derived from the C18O and C17O J=1-0 lines alone, may be affected by systematic errors. Therefore, the C18O and C17O (1-0), (2-1), and (3-2), as well as the 13CO (1-0) and (2-1) lines, were observed towards 18 prominent galactic targets (a total of 25 positions). The combined dataset was analysed with an LVG model, accounting for optical depth effects. The data cover galactocentric radii R between 0.1 and 16.9 kpc (solar circle at 8.5 kpc). Near the centre of the Galaxy, 18O/17O = 2.88 +/- 0.11. For the galactic disc out to an R of ca. 10 kpc, 18O/17O = 4.16 +/- 0.09. At ca. R = 16.5 kpc, 18O/17O = 5.03 +/- 0.46. Assuming that 18O is synthesised predominantly in high-mass stars (M > 8 Msun), while C17O is mainly a product of lower-mass stars, the ratio from the inner Galaxy indicates a dominance of CNO-hydrogen burning products that is also apparent in the C- and N-isotope ratios. The high 18O/17O value of the solar system (5.5) relative to that of the ambient ISM suggests contamination by nearby high-mass stars during its formation. High values in the metal-poor environment of the outer Galaxy are not matched by the low values observed towards the even more metal-poor LMC. Apparently, the outer Galaxy cannot be considered as an intermediate environment between the solar neighbourhood and the ISM of small metal-poor galaxies. The apparent 18O/17O gradient along the galactic disc and the discrepancy between outer disc and LMC isotope ratios may be explained by different ages of the respective stellar populations.Comment: Accepted by Astron. & Astroph.; 10 pages + 4 pages on-line material (figs

The interstellar C18O/C17O ratio in the solar neighbourhood: The rho Oph cloud

Observations of up to ten carbon monoxide (CO and isotopomers) transitions are presented to study the interstellar C18O/C17O ratio towards 21 positions in the nearby (d~140pc) low-mass star forming cloud rho Oph. A map of the C18O J=1-0 distribution of parts of the cloud is also shown. An average 12C18O/12C17O isotopomeric ratio of 4.11 +/- 0.14, reflecting the 18O/17O isotope ratio, is derived from Large Velocity Gradient (LVG) calculations. From LTE column densities we derive a ratio of 4.17 +/-0.26. These calculations also show that the kinetic temperature decreases from about 30 K in the cloud envelope to about 10 K in the cloud cores. This decrease is accompanied by an increase of the average molecular hydrogen density from 10^4 cm-3 to >10^5 cm-3. Towards some lines of sight C18O optical depths reach values of order unity.Comment: 13 pages, 9 figures; accepted for publication in A&

Antecedentes da compra compulsiva dos universit?rios em Mariana (MG).

No Brasil, o n?mero de fam?lias endividadas aumentou substancialmente nos ?ltimos anos. Isso pode ser explicado, dentre outros fatores, pelo aumento do comportamento de compra compulsiva na sociedade atual. Nesse contexto, o objetivo desta pesquisa foi analisar os antecedentes do comportamento compulsivo de compra de jovens universit?rios de uma Institui??o Federal de Ensino localizada em Mariana (MG). Dentre os v?rios fatores que levam os indiv?duos a comprarem compulsivamente, foram utilizados tr?s como base para este estudo: busca por poder e prest?gio, ansiedade e desconfian?a. Como m?todo de coleta de dados, realizou-se um levantamento de campo. Para an?lise de dados, optou-se pela modelagem de equa??es estruturais, por meio da aplica??o de duas abordagens: an?lise fatorial confirmat?ria e an?lise de caminhos. A partir do referencial te?rico constru?do e da an?lise dos resultados obtidos, foi poss?vel confirmar a ansiedade e a desconfian?a como antecedentes do comportamento de compra compulsivo entre os jovens universit?rios; o primeiro exercendo influ?ncia positiva, e o segundo, negativa.In Brazil, the number of indebted households has increased substantially in recent years, which may be explained, among other factors, by the increase in compulsive buying behavior in society today.In this context, the objective of this research was to analyze the antecedents of compulsive buying behavior of university students of an Education Federal Institution located in Mariana (MG).Among the various factors that lead individuals to buy compulsively, we use three as the basis for this study: search for power and prestige, anxiety and mistrust.As data collection method, we chose to conduct a field survey. For data analysis, we opted for Structural Equation Modeling, through the application of two approaches: Confirmatory Factor Analysis and Path Analysis.From the theoretical framework and analysis of the results, it was possible to confirm the anxiety and distrust as antecedents of compulsive buying behavior among university students, the first exerting positive influence and the second negative

Grain boundary pinning and glassy dynamics in stripe phases

We study numerically and analytically the coarsening of stripe phases in two spatial dimensions, and show that transient configurations do not achieve long ranged orientational order but rather evolve into glassy configurations with very slow dynamics. In the absence of thermal fluctuations, defects such as grain boundaries become pinned in an effective periodic potential that is induced by the underlying periodicity of the stripe pattern itself. Pinning arises without quenched disorder from the non-adiabatic coupling between the slowly varying envelope of the order parameter around a defect, and its fast variation over the stripe wavelength. The characteristic size of ordered domains asymptotes to a finite value $R_g \sim \lambda_0\ \epsilon^{-1/2}\exp(|a|/\sqrt{\epsilon})$, where$\epsilon\ll 1$is the dimensionless distance away from threshold,$\lambda_0$the stripe wavelength, and$a$ a constant of order unity. Random fluctuations allow defect motion to resume until a new characteristic scale is reached, function of the intensity of the fluctuations. We finally discuss the relationship between defect pinning and the coarsening laws obtained in the intermediate time regime.Comment: 17 pages, 8 figures. Corrected version with one new figur

CHD8 Regulates Neurodevelopmental Pathways Associated with Autism Spectrum Disorder in Neural Progenitors

Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10[superscript −8]) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10[superscript −10]). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.Simons FoundationNancy Lurie Marks Family FoundationNational Institutes of Health (U.S.) (Grant MH095867)National Institutes of Health (U.S.) (Grant MH095088)National Institutes of Health (U.S.) (Grant GM061354)March of Dimes Birth Defects FoundationCharles H. Hood FoundationBrain & Behavior Research FoundationAutism Genetic Resource ExchangeAutism Speaks (Organization)Pitt–Hopkins Research Foundatio

Disease Progression Mediated by Egr-1 Associated Signaling in Response to Oxidative Stress

When cellular reducing enzymes fail to shield the cell from increased amounts of reactive oxygen species (ROS), oxidative stress arises. The redox state is misbalanced, DNA and proteins are damaged and cellular transcription networks are activated. This condition can lead to the initiation and/or to the progression of atherosclerosis, tumors or pulmonary hypertension; diseases that are decisively furthered by the presence of oxidizing agents. Redox sensitive genes, like the zinc finger transcription factor early growth response 1 (Egr-1), play a pivotal role in the pathophysiology of these diseases. Apart from inducing apoptosis, signaling partners like the MEK/ERK pathway or the protein kinase C (PKC) can activate salvage programs such as cell proliferation that do not ameliorate, but rather worsen their outcome. Here, we review the currently available data on Egr-1 related signal transduction cascades in response to oxidative stress in the progression of epidemiologically significant diseases. Knowing the molecular pathways behind the pathology will greatly enhance our ability to identify possible targets for the development of new therapeutic strategies

No straight lines – young women’s perceptions of their mental health and wellbeing during and after pregnancy: a systematic review and meta-ethnography

Background: Young mothers face mental health challenges during and after pregnancy including increased rates of depression compared to older mothers. While the prevention of teenage pregnancy in countries such as the United States and the United Kingdom has been a focus for policy and research in recent decades, the need to understand young women’s own experiences has been highlighted. The aim of this meta-ethnography was to examine young women’s perceptions of their mental health and wellbeing during and after pregnancy to provide new understandings of those experiences. Methods: A systematic review and meta-ethnographic synthesis of qualitative research was conducted. Seven databases were systematically searched and forward and backward searching conducted. Papers were included if they were from Organisation for Economic Co-operation and Development countries and explored mental health and wellbeing experiences of young mothers (age under 20 in pregnancy; under 25 at time of research) as a primary research question – or where evidence about mental health and wellbeing from participants was foregrounded. Nineteen papers were identified and the Critical Appraisal Skills Programme checklist for qualitative research used to appraise the evidence. Following the seven-step process of meta-ethnography, key constructs were examined within each study and then translated into one another. Results: Seven translated themes were identified forming a new line of argument wherein mental health and wellbeing was analysed as relating to individual bodily experiences; tied into past and present relationships; underpinned by economic insecurity and entangled with feelings of societal surveillance. There were ‘no straight lines’ in young women’s experiences, which were more complex than dominant narratives around overcoming adversity suggest. Conclusions: The synthesis concludes that health and social care professionals need to reflect on the operation of power and stigma in young women’s lives and its impact on wellbeing. It adds to understanding of young women’s mental health and wellbeing during and after pregnancy as located in physical and structural factors rather than individual capacities alone

Preference for Safe Over Risky Options in Binge Eating.

Binge eating has been usually viewed as a loss of control and an impulsive behavior. But, little is known about the actual behavior of binging patients (prevalently women) in terms of basic decision-making under risk or under uncertainty. In healthy women, stressful cues bias behavior for safer options, raising the question of whether food cues that are perceived as threatening by binging patients may modulate patients' behaviors towards safer options. A cross-sectional study was conducted with binging patients (20 bulimia nervosa (BN) and 23 anorexia nervosa binging (ANB) patients) and two control groups (22 non-binging restrictive (ANR) anorexia nervosa patients and 20 healthy participants), without any concomitant impulsive disorder. We assessed decisions under risk with a gambling task with known probabilities and decisions under uncertainty with the balloon analog risk taking task (BART) with unknown probabilities of winning, in three cued-conditions including neutral, binge food and stressful cues. In the gambling task, binging and ANR patients adopted similar safer attitudes and coherently elicited a higher aversion to losses when primed by food as compared to neutral cues. This held true for BN and ANR patients in the BART. After controlling for anxiety level, these safer attitudes in the food condition were similar to the ones under stress. In the BART, ANB patients exhibited a higher variability in their choices in the food compared to neutral condition. This higher variability was associated with higher difficulties to discard irrelevant information. All these results suggest that decision-making under risk and under uncertainty is not fundamentally altered in all these patients