Differential expression of pro-inflammatory and oxidative stress mediators induced by nitrogen dioxide and ozone in primary human bronchial epithelial cells

NO2 and O3 are ubiquitous air toxicants capable of inducing lung damage to the respiratory epithelium. Due to their oxidizing capabilities, these pollutants have been proposed to target specific biological pathways, but few publications have compared the pathways activated

A pleiotropic missense variant in SLC39A8 is associated with Crohn's disease and human gut microbiome composition

Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA)

Direct Particle-to-Cell Deposition of Coarse Ambient Particulate Matter Increases the Production of Inflammatory Mediators from Cultured Human Airway Epithelial Cells

Exposure of cultured cells to particulate matter air pollution is usually accomplished by collecting particles on a solid matrix, extracting the particles from the matrix, suspending them in liquid, and applying the suspension to cells grown on plastic and submerged in medium. The objective of this work was to develop a more physiologically and environmentally relevant model of air pollutant deposition on cultures of human primary airway epithelial cells. We hypothesize that the toxicology of inhaled particulate matter depends strongly on both the particulate dispersion state and the mode of delivery to cells. Our exposure system employs a combination of unipolar charging and electrostatic force to deposit particles directly from the air onto cells grown at an air-liquid interface in a heated, humidified exposure chamber. Normal human bronchial epithelial cells exposed to concentrated, coarse ambient particulate matter in this system expressed increased levels of inflammatory biomarkers at 1 hour following exposure and relative to controls exposed to particle-free air. More importantly, these effects are seen at particulate loadings that are 1-2 orders of magnitude lower than levels applied using traditional in vitro systems

Seasonal Variations in Air Pollution Particle-Induced Inflammatory Mediator Release and Oxidative Stress

Health effects associated with particulate matter (PM) show seasonal variations. We hypothesized that these heterogeneous effects may be attributed partly to the differences in the elemental composition of PM. Normal human bronchial epithelial (NHBE) cells and alveolar macrophages (AMs) were exposed to equal mass of coarse [PM with aerodynamic diameter of 2.5–10 μm (PM(2.5–10))], fine (PM(2.5)), and ultrafine (PM (< 0.1)) ambient PM from Chapel Hill, North Carolina, during October 2001 (fall) and January (winter), April (spring), and July (summer) 2002. Production of interleukin (IL)-8, IL-6, and reactive oxygen species (ROS) was measured. Coarse PM was more potent in inducing cytokines, but not ROSs, than was fine or ultrafine PM. In AMs, the October coarse PM was the most potent stimulator for IL-6 release, whereas the July PM consistently stimulated the highest ROS production measured by dichlorofluorescein acetate and dihydrorhodamine 123 (DHR). In NHBE cells, the January and the October PM were consistently the strongest stimulators for IL-8 and ROS, respectively. The July PM increased only ROS measured by DHR. PM had minimal effects on chemiluminescence. Principal-component analysis on elemental constituents of PM of all size fractions identified two factors, Cr/Al/Si/Ti/Fe/Cu and Zn/As/V/Ni/Pb/Se, with only the first factor correlating with IL-6/IL-8 release. Among the elements in the first factor, Fe and Si correlated with IL-6 release, whereas Cr correlated with IL-8 release. These positive correlations were confirmed in additional experiments with PM from all 12 months. These results indicate that elemental constituents of PM may in part account for the seasonal variations in PM-induced adverse health effects related to lung inflammation

Context-aware experience sampling reveals the scale of variation in affective experience

Emotion research typically searches for consistency and specificity in physiological activity across instances of an emotion category, such as anger or fear, yet studies to date have observed more variation than expected. In the present study, we adopt an alternative approach, searching inductively for structure within variation, both within and across participants. Following a novel, physiologically-triggered experience sampling procedure, participants’ self-reports and peripheral physiological activity were recorded when substantial changes in cardiac activity occurred in the absence of movement. Unsupervised clustering analyses revealed variability in the number and nature of patterns of physiological activity that recurred within individuals, as well as in the affect ratings and emotion labels associated with each pattern. There were also broad patterns that recurred across individuals. These findings support a constructionist account of emotion which, drawing on Darwin, proposes that emotion categories are populations of variable instances tied to situation-specific needs

Determination of quantitative trait loci (QTL) for early maturation in rainbow trout (Oncorhynchus mykiss)

To identify quantitative trait loci (QTL) influencing early maturation (EM) in rainbow trout (Oncorhynchus mykiss), a genome scan was performed using 100 microsatellite loci across 29 linkage groups. Six inter-strain paternal half-sib families using three inter-strain F(1) brothers (approximately 50 progeny in each family) derived from two strains that differ in the propensity for EM were used in the study. Alleles derived from both parental sources were observed to contribute to the expression of EM in the progeny of the brothers. Four genome-wide significant QTL regions (i.e., RT-8, -17, -24, and -30) were observed. EM QTL detected on RT-8 and -24 demonstrated significant and suggestive QTL effects in both male and female progeny. Furthermore, within both male and female full-sib groupings, QTL on RT-8 and -24 were detected in two or more of the five parents used. Significant genome-wide and several strong chromosome-wide QTL for EM localized to different regions in males and females, suggesting some sex-specific control. Namely, QTL detected on RT-13, -15, -21, and -30 were associated with EM only in females, and those on RT-3, -17, and -19 were associated with EM only in males. Within the QTL regions identified, a comparison of syntenic EST markers from the rainbow trout linkage map with the zebrafish (Danio rerio) genome identified several putative candidate genes that may influence EM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10126-008-9098-5) contains supplementary material, which is available to authorized users

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07