Background: We have used a genetical genomic approach, in conjunction with phenotypic analysis of alcohol consumption, to identify candidate genes that predispose to varying levels of alcohol intake by HXB/BXH recombinant inbred rat strains. In addition, in two populations of humans, we assessed genetic polymorphisms associated with alcohol consumption using a custom genotyping array for 1,350 single nucleotide polymorphisms (SNPs). Our goal was to ascertain whether our approach, which relies on statistical and informatics techniques, and non-human

Transcriptional patterns suggest that drug-tolerant bacilli in sputum are in a slow-growing, metabolically and synthetically downregulated state. Absence of the isoniazid stress signature in drug-tolerant bacilli indicates that physiological state influences drug responsiveness in vivo. These results identify novel drug targets that should aid in development of novel shorter tuberculosis treatment regimens.

Blood transcriptional signatures are promising for tuberculosis (TB) diagnosis but have not been evaluated among U.S. patients. To be used clinically, transcriptional classifiers need reproducible accuracy in diverse populations that vary in genetic composition, disease spectrum and severity, and comorbidities. In a prospective case-control study, we identified novel transcriptional classifiers for active TB among U.S. patients and systematically compared their accuracy to classifiers from published studies. Blood samples from HIV-uninfected U.S. adults with active TB, pneumonia, or latent TB infection underwent whole-transcriptome microarray. We used support vector machines to classify disease state based on transcriptional patterns. We externally validated our classifiers using data from sub-Saharan African cohorts and evaluated previously published transcriptional classifiers in our population.

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Our findings suggest that epigenetic marks may provide an important link between in utero exposure to gestational diabetes and obesity in childhood, and add to the growing body of evidence that DNA methylation is affected by gestational diabetes exposure.

Background: Per- and polyfluoroalkyl substances (PFAS) are environmentally persistent chemicals widely detected in women of reproductive age. Prenatal PFAS exposure is associated with adverse health outcomes in children. We hypothesized that DNA methylation changes may result from prenatal PFAS exposure and may be linked to offspring cardio-metabolic phenotype. Objectives: We estimated associations of prenatal PFAS with DNA methylation in umbilical cord blood. We evaluated associations of methylation at selected sites with neonatal cardio-metabolic indicators. Methods: Among 583 mother–infant pairs in a prospective cohort, five PFAS were quantified in maternal serum (median 27 wk of gestation). Umbilical cord blood DNA methylation was evaluated using the Illumina HumanMethylation450 array. Differentially methylated positions (DMPs) were evaluated at a false discovery rate and differentially methylated regions (DMRs) were identified using comb-p (Šidák-adjusted ). We estimated associations between methylation at candidate DMPs and DMR sites and the following outcomes: newborn weight, adiposity, and cord blood glucose, insulin, lipids, and leptin. Results: Maternal serum PFAS concentrations were below the median for females in the U.S. general population. Moderate to high pairwise correlations were observed between PFAS concentrations ( ). Methylation at one DMP (cg18587484), annotated to the gene TJAP1 , was associated with perfluorooctanoate (PFOA) at . Comb-p detected between 4 and 15 DMRs for each PFAS. Associated genes, some common across multiple PFAS, were implicated in growth ( RPTOR ), lipid homeostasis ( PON1 , PON3 , CIDEB , NR1H2 ), inflammation and immune activity ( RASL11B , RNF39 ), among other functions. There was suggestive evidence that two PFAS-associated loci (cg09093485, cg09637273) were associated with cord blood triglycerides and birth weight, respectively ( ). Discussion: DNA methylation in umbilical cord blood was associated with maternal serum PFAS concentrations during pregnancy, suggesting potential associations with offspring growth, metabolism, and immune function. Future research should explore whether DNA methylation changes mediate associations between prenatal PFAS exposures and child health outcomes. https://doi.org/10.1289/EHP6888

SummaryResearch in aging biology has identified several pathways that are molecularly conserved across species that extend lifespan when mutated. The insulin/insulin‐like signaling (IIS) pathway is one of the most widely studied of these. It has been assumed that extending lifespan also extends healthspan (the period of life with minimal functional loss). However, data supporting this assumption conflict and recent evidence suggest that life extension may, in and of itself, extend the frail period. In this study, we use Caenorhabditis elegans to further probe the link between lifespan and healthspan. Using movement decline as a measure of health, we assessed healthspan across the entire lifespan in nine IIS pathway mutants. In one series of experiments, we studied healthspan in mass cultures, and in another series, we studied individuals longitudinally. We found that long‐lived mutants display prolonged mid‐life movement and do not prolong the frailty period. Lastly, we observed that early‐adulthood movement was not predictive of late‐life movement or survival, within identical phenotypes. Overall, these observations show that extending lifespan does not prolong the period of frailty. Both genotype and a stochastic component modulate aging, and movement late in life is more variable than early‐life movement.

Context Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in developed nations. There are currently no accurate biomarkers of NAFLD risk in youth. Objective Identify sex-specific metabolomics biomarkers of NAFLD in a healthy cohort of youth. Design/setting This prospective study included 395 participants of the EPOCH cohort in Colorado, recruited 2006-2009 (“T1 visit”) and followed for 5 years (“T2 visit”). We entered 767 metabolites measured at T1 into a reduced rank regression model to identify the strongest determinants of hepatic fat fraction (HFF) at T2, separately for boys and girls. We compared the capacity of metabolites vs. conventional risk factors (overweight/obesity, insulin, ALT, AST) to predict NAFLD (HFF≥5%) and high HFF (4th vs. 1st quartile) using area under the receiver operating characteristic curve (AUC). Results Prevalence of NAFLD was 7.9% (8.5% of boys, 7.1% of girls). Mean±SD HFF was 2.5±3.1%. We identified 13 metabolites in girls and 10 metabolites in boys. Metabolites were in lipid, amino acid, and carbohydrate metabolism pathways. At T1, the metabolites outperformed conventional risk factors in prediction of high HFF but not NAFLD. At T2, the metabolites were superior to conventional risk factors as predictors of high HFF (AUC for metabolites vs. conventional risk factors for boys: 0.9565 vs. 0.8851, P=0.02; for girls: 0.9450 vs. 0.8469, P=0.02) with similar trends for NAFLD, though the differences were not significant. Conclusions The metabolite profiles identified herein are superior predictors of high HFF when assessed 5 years prior and concurrently in a general-risk setting.