Saying Hello World with Epsilon - A Solution to the 2011 Instructive Case

Epsilon is an extensible platform of integrated and task-specific languages for model management. With solutions to the 2011 TTC Hello World case, this paper demonstrates some of the key features of the Epsilon Object Language (an extension and reworking of OCL), which is at the core of Epsilon. In addition, the paper introduces several of the task-specific languages provided by Epsilon including the Epsilon Generation Language (for model-to-text transformation), the Epsilon Validation Language (for model validation) and Epsilon Flock (for model migration).Comment: In Proceedings TTC 2011, arXiv:1111.440

Associations of 5-year changes in alcoholic beverage intake with 5-year changes in waist circumference and BMI in the Coronary Artery Risk Development in Young Adults (CARDIA) study

Objective This study aimed to shed light on contradictory associations of alcohol intake with waist circumference (WC) and body mass index (BMI) by examining 5-yr changes in alcohol intake in relation to 5-yr WC and BMI changes. Methods This prospective study included 4,355 participants (1,974 men and 2,381 women) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study at baseline (1985–1986) and followed over 25 years (2010–2011). Longitudinal random effects linear regression models were used to test whether changes in drinking (defined categorically) as starting to drink, increasing, decreasing, stable drinking or stopping drinking (versus stable non-drinking) over a series of 5-yr periods were associated with corresponding 5-yr WC and BMI changes. Associations with 5-yr changes (defined categorically as starting, stable or stopping) in drinking level (i.e., light/moderate and excessive) and 5-yr changes (defined categorically as increasing, no change, or decreasing) by beverage type (i.e., beer, wine and liquor/mixed drinks) were also examined. Results In men, compared to stable non-drinking, decreasing total alcohol intake was associated with lower 5-yr WC (β:-0.62 cm; 95% CI: -1.09, -0.14 cm) and BMI gains (β:-0.20 kg/m2; 95% CI: -0.30, -0.03 kg/m2) and stopping excessive drinking was associated with lower 5-yr WC gains (β:-0.77 cm; 95% CI: -1.51, -0.03 cm). In women, compared to those with stable non-drinking habits, starting light/moderate drinking was associated with lower 5-yr WC (β: -0.78 cm; 95% CI: -1.29, -0.26 cm) and BMI gains (β:-0.42 kg/m2; 95% CI: -0.64, -0.20 kg/ m2). Increasing wine intake was associated with a lower 5-yr BMI gain (β:-0.27 kg/m2; 95% CI: -0.51, -0.03 kg/m2). Decreasing liquor/mixed drink (β:-0.33 kg/m2; 95% CI: -0.56, -0.09 kg/m2) intake was associated with lower 5-yr WC (β:-0.88 cm; 95% CI: -1.43, -0.34 cm) and BMI (β:-0.33 kg/m2; 95% CI: -0.56, -0.09 kg/m2) gains. Conclusions Associations of alcohol intake with obesity measures are complex. In women, wine and liquor/mixed drink intakes had contrasting associations with WC and BMI change. In men, decreasing weekly alcoholic beverage intake with an emphasis on stopping excessive consumption may be beneficial in managing WC and BMI gains

A preliminary examination of gut microbiota, sleep, and cognitive flexibility in healthy older adults

Objectives Inadequate sleep increases the risk for age-related cognitive decline and recent work suggests a possible role of the gut microbiota in this phenomenon. Partial sleep deprivation alters the human gut microbiome, and its composition is associated with cognitive flexibility in animal models. Given these findings, we examined the possible relationship among the gut microbiome, sleep quality, and cognitive flexibility in a sample of healthy older adults. Methods Thirty-seven participants (age 64.59 ± 7.54 years) provided a stool sample for gut microbial sequencing and completed the Pittsburgh Sleep Quality Index and Stroop Color Word Test as part of a larger project. Results Better sleep quality was associated with better Stroop performance and higher proportions of the gut microbial phyla Verrucomicrobia and Lentisphaerae. Stroop Word and Color-Word performance correlated with higher proportions of Verrucomicrobia and Lentisphaerae. Partial correlations suggested that the relationship between Lentisphaerae and Stroop Color-Word performance was better accounted for by sleep quality; sleep quality remained a significant predictor of Color-Word performance, independent of the Lentisphaerae proportion, while the relationship between Lentisphaerae and Stroop performance was non-significant. Verrucomicrobia and sleep quality were not associated with Stroop Word performance independent of one another. Conclusions The current findings suggest a possible relationship among sleep quality, composition of the gut microbiome, and cognitive flexibility in healthy older adults. Prospective and experimental studies are needed to confirm these findings and determine whether improving microbiome health may buffer against sleep-related cognitive decline in older adults

Nucleosynthesis Constraints on a Massive Gravitino in Neutralino Dark Matter Scenarios

The decays of massive gravitinos into neutralino dark matter particles and Standard Model secondaries during or after Big-Bang nucleosynthesis (BBN) may alter the primordial light-element abundances. We present here details of a new suite of codes for evaluating such effects, including a new treatment based on PYTHIA of the evolution of showers induced by hadronic decays of massive, unstable particles such as a gravitino. We also develop an analytical treatment of non-thermal hadron propagation in the early universe, and use this to derive analytical estimates for light-element production and in turn on decaying particle lifetimes and abundances. We then consider specifically the case of an unstable massive gravitino within the constrained minimal supersymmetric extension of the Standard Model (CMSSM). We present upper limits on its possible primordial abundance before decay for different possible gravitino masses, with CMSSM parameters along strips where the lightest neutralino provides all the astrophysical cold dark matter density. We do not find any CMSSM solution to the cosmological Li7 problem for small m_{3/2}. Discounting this, for m_{1/2} ~ 500 GeV and tan beta = 10 the other light-element abundances impose an upper limit m_{3/2} n_{3/2}/n_\gamma < 3 \times 10^{-12} GeV to < 2 \times 10^{-13} GeV for m_{3/2} = 250 GeV to 1 TeV, which is similar in both the coannihilation and focus-point strips and somewhat weaker for tan beta = 50, particularly for larger m_{1/2}. The constraints also weaken in general for larger m_{3/2}, and for m_{3/2} > 3 TeV we find a narrow range of m_{3/2} n_{3/2}/n_\gamma, at values which increase with m_{3/2}, where the Li7 abundance is marginally compatible with the other light-element abundances.Comment: 74 pages, 40 Figure

Genetic loci associated with plasma phospholipid N-3 fatty acids: A Meta-Analysis of Genome-Wide association studies from the charge consortium

Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3×10-64) and lower levels of eicosapentaenoic acid (EPA, p = 5×10-58) and docosapentaenoic acid (DPA, p = 4×10-154). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2×10-12) and DPA (p = 1×10-43) and lower docosahexaenoic acid (DHA, p = 1×10-15). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1×10-8). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries

Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts

Background: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences. Objective: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption. Design: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86, 467) and EPA +DHA (n = 62, 265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts. Results: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities