327 research outputs found
Comparison of the Use of a Physiologically Based Pharmacokinetic Model and a Classical Pharmacokinetic Model for Dioxin Exposure Assessments
In epidemiologic studies, exposure assessments of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) assume a fixed elimination rate. Recent data suggest a dose-dependent elimination rate for TCDD. A physiologically based pharmacokinetic (PBPK) model, which uses a body-burden–dependent elimination rate, was developed previously in rodents to describe the pharmacokinetics of TCDD and has been extrapolated to human exposure for this study. Optimizations were performed using data from a random selection of veterans from the Ranch Hand cohort and data from a human volunteer who was exposed to TCDD. Assessment of this PBPK model used additional data from the Ranch Hand cohort and a clinical report of two women exposed to TCDD. This PBPK model suggests that previous exposure assessments may have significantly underestimated peak blood concentrations, resulting in potential exposure misclassifications. Application of a PBPK model that incorporates an inducible elimination of TCDD may improve the exposure assessments in epidemiologic studies of TCDD
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
Rapid assessment of T-cell receptor specificity of the immune repertoire
Accurate assessment of T-cell-receptor (TCR)–antigen specificity across the whole immune repertoire lies at the heart of improved cancer immunotherapy, but predictive models capable of high-throughput assessment of TCR–peptide pairs are lacking. Recent advances in deep sequencing and crystallography have enriched the data available for studying TCR–peptide systems. Here, we introduce RACER, a pairwise energy model capable of rapid assessment of TCR–peptide affinity for entire immune repertoires. RACER applies supervised machine learning to efficiently and accurately resolve strong TCR–peptide binding pairs from weak ones. The trained parameters further enable a physical interpretation of interacting patterns encoded in each TCR–peptide system. When applied to simulate thymic selection of a major-histocompatibility-complex (MHC)-restricted T-cell repertoire, RACER accurately estimates recognition rates for tumor-associated neoantigens and foreign peptides, thus demonstrating its utility in helping address the computational challenge of reliably identifying properties of tumor antigen-specific T-cells at the level of an individual patient’s immune repertoire
High-throughput characterization of HLA-E-presented CD94/NKG2x ligands reveals peptides which modulate NK cell activation
HLA-E is a non-classical class I MHC protein involved in innate and adaptive immune recognition. While recent studies have shown HLA-E can present diverse peptides to NK cells and T cells, the HLA-E repertoire recognized by CD94/NKG2x has remained poorly defined, with only a limited number of peptide ligands identified. Here we screen a yeast-displayed peptide library in the context of HLA-E to identify 500 high-confidence unique peptides that bind both HLA-E and CD94/NKG2A or CD94/NKG2C. Utilizing the sequences identified via yeast display selections, we train prediction algorithms and identify human and cytomegalovirus (CMV) proteome-derived, HLA-E-presented peptides capable of binding and signaling through both CD94/NKG2A and CD94/NKG2C. In addition, we identify peptides which selectively activate NKG2C+ NK cells. Taken together, characterization of the HLA-E-binding peptide repertoire and identification of NK activity-modulating peptides present opportunities for studies of NK cell regulation in health and disease, in addition to vaccine and therapeutic design
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
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