Hepatic transcript signatures predict atherosclerotic lesion burden prior to a 2-year high cholesterol, high fat diet challenge

The purpose of this study was to identify molecular mechanisms by which the liver influences total lesion burden in a nonhuman primate model (NHP) of cardiovascular disease with acute and chronic feeding of a high cholesterol, high fat (HCHF) diet. Baboons (47 females, 64 males) were fed a HCHF diet for 2 years (y); liver biopsies were collected at baseline, 7 weeks (w) and 2y, and lesions were quantified in aortic arch, descending aorta, and common iliac at 2y. Unbiased weighted gene co-expression network analysis (WGCNA) revealed several modules of hepatic genes correlated with lesions at different time points of dietary challenge. Pathway and network analyses were performed to study the roles of hepatic module genes. More significant pathways were observed in males than females. In males, we found modules enriched for genes in oxidative phosphorylation at baseline, opioid signaling at 7w, and EIF2 signaling and HNF1A and HNF4A networks at baseline and 2y. One module enriched for fatty acid β oxidation pathway genes was found in males and females at 2y. To our knowledge, this is the first study of a large NHP cohort to identify hepatic genes that correlate with lesion burden. Correlations of baseline and 7w module genes with lesions at 2y were observed in males but not in females. Pathway analyses of baseline and 7w module genes indicate EIF2 signaling, oxidative phosphorylation, and μ-opioid signaling are possible mechanisms that predict lesion formation induced by HCHF diet consumption in males. Our findings of coordinated hepatic transcriptional response in male baboons but not female baboons indicate underlying molecular mechanisms differ between female and male primate atherosclerosis

Diet-induced leukocyte telomere shortening in a baboon model for early stage atherosclerosis

Reported associations between leukocyte telomere length (LTL) attrition, diet and cardiovascular disease (CVD) are inconsistent. This study explores effects of prolonged exposure to a high cholesterol high fat (HCHF) diet on LTL in a baboon model of atherosclerosis. We measured LTL by qPCR in pedigreed baboons fed a chow (n = 105) or HCHF (n = 106) diet for 2 years, tested for effects of diet on LTL, and association between CVD risk factors and atherosclerotic lesions with LTL. Though not different at baseline, after 2 years median LTL is shorter in HCHF fed baboons (P \u3c 0.0001). Diet predicts sex- and age-adjusted LTL and LTL attrition (P = 0.0009 and 0.0156, respectively). Serum concentrations of CVD biomarkers are associated with LTL at the 2-year endpoint and LTL accounts approximately 6% of the variance in aortic lesions (P = 0.04). Although heritable at baseline (h2 = 0.27, P = 0.027) and after 2 years (h2 = 0.46, P = 0.0038), baseline LTL does not predict lesion extent after 2 years. Atherogenic diet influences LTL, and LTL is a potential biomarker for early atherosclerosis. Prolonged exposure to an atherogenic diet decreases LTL and increases LTL attrition, and shortened LTL is associated with early-stage atherosclerosis in pedigreed baboons

Next generation sequencing of chromosomal rearrangements in patients with split-hand/split-foot malformation provides evidence for DYNC1I1 exonic enhancers of DLX5/6 expression in humans

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this recordSplit-hand/foot malformation type 1 is an autosomal dominant condition with reduced penetrance and variable expression. We report three individuals from two families with split-hand/split-foot malformation (SHFM) in whom next generation sequencing was performed to investigate the cause of their phenotype.Wellcome Trus

Providing the Missing Link: the Exposure Science Ontology ExO

Environmental health information resources lack exposure data required to translate molecular insights, elucidate environmental contributions to diseases, and assess human health and ecological risks. We report development of an Exposure Ontology, ExO, designed to address this information gap by facilitating centralization and integration of exposure data. Major concepts were defined and the ontology drafted and evaluated by a working group of exposure scientists and other ontology and database experts. The resulting major concepts forming the basis for the ontology are exposure stressor , exposure receptor , exposure event , and exposure outcome . Although design of the first version of ExO focused on human exposure to chemicals, we anticipate expansion by the scientific community to address exposures of human and ecological receptors to the full suite of environmental stressors. Like other widely used ontologies, ExO is intended to link exposure science and diverse environmental health disciplines including toxicology, epidemiology, disease surveillance, and epigenetics

Simplified Symptom Pattern Method for verbal autopsy analysis: multisite validation study using clinical diagnostic gold standards

Background: Verbal autopsy can be a useful tool for generating cause of death data in data-sparse regions around the world. The Symptom Pattern (SP) Method is one promising approach to analyzing verbal autopsy data, but it has not been tested rigorously with gold standard diagnostic criteria. We propose a simplified version of SP and evaluate its performance using verbal autopsy data with accompanying true cause of death.Methods: We investigated specific parameters in SP's Bayesian framework that allow for its optimal performance in both assigning individual cause of death and in determining cause-specific mortality fractions. We evaluated these outcomes of the method separately for adult, child, and neonatal verbal autopsies in 500 different population constructs of verbal autopsy data to analyze its ability in various settings.Results: We determined that a modified, simpler version of Symptom Pattern (termed Simplified Symptom Pattern, or SSP) performs better than the previously-developed approach. Across 500 samples of verbal autopsy testing data, SSP achieves a median cause-specific mortality fraction accuracy of 0.710 for adults, 0.739 for children, and 0.751 for neonates. In individual cause of death assignment in the same testing environment, SSP achieves 45.8% chance-corrected concordance for adults, 51.5% for children, and 32.5% for neonates.Conclusions: The Simplified Symptom Pattern Method for verbal autopsy can yield reliable and reasonably accurate results for both individual cause of death assignment and for determining cause-specific mortality fractions. The method demonstrates that verbal autopsies coupled with SSP can be a useful tool for analyzing mortality patterns and determining individual cause of death from verbal autopsy data

Gender and sexual orientation differences in cognition across adulthood : age is kinder to women than to men regardless of sexual orientation

Despite some evidence of greater age-related deterioration of the brain in males than in females, gender differences in rates of cognitive aging have proved inconsistent. The present study employed web-based methodology to collect data from people aged 20-65 years (109,612 men; 88,509 women). As expected, men outperformed women on tests of mental rotation and line angle judgment, whereas women outperformed men on tests of category fluency and object location memory. Performance on all tests declined with age but significantly more so for men than for women. Heterosexuals of each gender generally outperformed bisexuals and homosexuals on tests where that gender was superior; however, there were no clear interactions between age and sexual orientation for either gender. At least for these particular tests from young adulthood to retirement, age is kinder to women than to men, but treats heterosexuals, bisexuals, and homosexuals just the same

Antigen Identification for Orphan T Cell Receptors Expressed on Tumor-Infiltrating Lymphocytes

The immune system can mount T cell responses against tumors; however, the antigen specificities of tumor-infiltrating lymphocytes (TILs) are not well understood. We used yeast-display libraries of peptide-human leukocyte antigen (pHLA) to screen for antigens of “orphan” T cell receptors (TCRs) expressed on TILs from human colorectal adenocarcinoma. Four TIL-derived TCRs exhibited strong selection for peptides presented in a highly diverse pHLA-A∗02:01 library. Three of the TIL TCRs were specific for non-mutated self-antigens, two of which were present in separate patient tumors, and shared specificity for a non-mutated self-antigen derived from U2AF2. These results show that the exposed recognition surface of MHC-bound peptides accessible to the TCR contains sufficient structural information to enable the reconstruction of sequences of peptide targets for pathogenic TCRs of unknown specificity. This finding underscores the surprising specificity of TCRs for their cognate antigens and enables the facile identification of tumor antigens through unbiased screening