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[Interpretation of"WHO standard with regard to screening process as well as treatment of cervical pre-cancer wounds pertaining to cervical most cancers reduction, next edition"].
Background Consecutive testing of single nucleotide polymorphisms (SNPs) is usually employed to identify genetic variants associated with complex traits. Ideally one should model all covariates in unison, but most existing analysis methods for genome-wide association studies (GWAS) perform only univariate regression. Results We extend and efficiently implement iterative hard thresholding (IHT) for multiple regression, treating all SNPs simultaneously. Our extensions accommodate generalized linear models, prior information on genetic variants, and grouping of variants. In our simulations, IHT recovers up to 30% more true predictors than SNP-by-SNP association testing and exhibits a 2-3 orders of magnitude decrease in false-positive rates compared with lasso regression. We also test IHT on the UK Biobank hypertension phenotypes and the Northern Finland Birth Cohort of 1966 cardiovascular phenotypes. We find that IHT scales to the large datasets of contemporary human genetics and recovers the plausible genetic variants identified by previous studies. Conclusions Our real data analysis and simulation studies suggest that IHT can (i) recover highly correlated predictors, (ii) avoid over-fitting, (iii) deliver better true-positive and false-positive rates than either marginal testing or lasso regression, (iv) recover unbiased regression coefficients, (v) exploit prior information and group-sparsity, and (vi) be used with biobank-sized datasets. Although these advances are studied for genome-wide association studies inference, our extensions are pertinent to other regression problems with large numbers of predictors.CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumor microenvironment (TME) can dampen their ability to control tumor progression. We describe lipid accumulation in the TME areas of pancreatic ductal adenocarcinoma (PDA) populated by CD8+ T cells infiltrating both murine and human tumors. find more In this lipid-rich but otherwise nutrient-poor TME, access to using lipid metabolism becomes particularly valuable for sustaining cell functions. Here, we found that intrapancreatic CD8+ T cells progressively accumulate specific long-chain fatty acids (LCFAs), which, rather than provide a fuel source, impair their mitochondrial function and trigger major transcriptional reprogramming of pathways involved in lipid metabolism, with the subsequent reduction of fatty acid catabolism. In particular, intrapancreatic CD8+ T cells specifically exhibit down-regulation of the very-long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which exacerbates accumulation of LCFAs and very-long-chain fatty acids (VLCFAs) that mediate lipotoxicity. Metabolic reprogramming of tumor-specific T cells through enforced expression of ACADVL enabled enhanced intratumoral T cell survival and persistence in an engineered mouse model of PDA, overcoming one of the major hurdles to immunotherapy for PDA.Background Priming is a process in which exposure to a stimulus activates relevant mental representations that are given increased weight in subsequent judgment tasks. Affective primes can influence affective evaluations and associations. Such influence has meaningful implications for the promotion of exercise behavior, yet there is scant research on priming effects in exercise settings. Purpose The purpose of the present pair of studies was to examine the efficacy of music (M), music video (MV), and music video with affective primes (PRIME) in modulating psychological responses during and immediately following an exercise bout among two distinct populations. Methods In Study 1, physically active participants completed a brisk walking task on a treadmill under four conditions M, MV, PRIME, and control. Affective valence and rating of perceived exertion (RPE) were assessed during exercise and remembered/forecasted pleasure was measured immediately following each exercise bout. In Study 2, largely inactive and overweight participants completed a brisk walking task on a treadmill under two conditions MV and PRIME. Affective valence was assessed during exercise, while exercise enjoyment and remembered/forecasted pleasure were assessed postexercise. Results In Study 1, PRIME yielded more positively valenced affect, remembered/forecasted pleasure, and lower RPE when compared to the other conditions (MCohen's d for all DVs = 0.91). In Study 2, PRIME elicited more positively valenced affect, greater enjoyment, and enhanced remembered/forecasted pleasure when compared to MV (MCohen's d for all DVs = 0.64). Conclusions Subliminal primes embedded in music video can elicit positive changes in psychological responses during and immediately following exercise.Statistical imputation applied to genome-wide array data is the most cost-effective approach to complete the catalog of genetic variation in a study population. However, imputed genotypes in underrepresented populations incur greater inaccuracies due to ascertainment bias and a lack of representation among reference individuals, further contributing to the obstacles to study these populations. Here we examined the consequences due to the lack of representation by genotyping in a large number of self-reported Native Hawaiians (N = 3693) a functionally important, Polynesian-specific variant in the CREBRF gene, rs373863828. We found the derived allele was significantly associated with several adiposity traits with large effects (e.g. approximately 1.28 kg/m2 per allele in BMI as the most significant; P = 7.5x10-5), consistent with the original findings in Samoans. Due to the current absence of Polynesian representation in publicly accessible reference sequences, rs373863828 or its proxies could not be tested through imputation using these existing resources. Moreover, the association signals at the entire CREBRF locus could not be captured by alternative approaches, such as admixture mapping. In contrast, highly accurate imputation can be achieved even if a small number ( less then 200) of internally constructed Polynesian reference individuals were available; this would increase sample size and improve the statistical evidence of associations. Taken together, our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci such as CREBRF. Yet, they could be easily detected and prioritized with improved representation of diverse populations in sequencing studies.
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