Factors governing the solid phase distribution of Cr, Cu and As in contaminated soil after 40 years of ageing

The physico-chemical factors affecting the distribution, behavior and speciation of chromium (Cr), copper (Cu) and arsenic (As) was investigated at a former wood impregnation site (Fredensborg, Denmark). Forty soil samples were collected and extracted using a sequential extraction technique known as the Chemometric Identification of Substrates and Element Distributions (CISED) and a multivariate statistical tool (redundancy analysis) was applied. CISED data was linked to water-extractable Cr, Cu and As and bioavailable Cu as determined by a whole-cell bacterial bioreporter assay. Results showed that soil pH significantly affected the solid phase distribution of all three elements on site. Additionally, elements competing for binding sites, Ca, Mg and Mn in the case of Cu, and P, in the case of As, played a major role in the distribution of these elements in soil. Element-specific distributions were observed amongst the six identified soil phases including residual pore salts, exchangeable, carbonates (tentative designation), Mn-Al oxide, amorphous Fe oxide, and crystalline Fe oxide. While Cr was strongly bound to non-extractable crystalline Fe oxide in the oxic top soil, Cu and notably, As were associated with readily extractable phases, suggesting that Cu and As, and not Cr, constitute the highest risk to environmental and human health. However, bioavailable Cu did not significantly correlate with CISED identified soil phases, suggesting that sequential extraction schemes such as CISED may not be ideally suited for inferring bioavailability to microorganisms in soil and supports the integration of receptor-specific bioavailability tests into risk assessments as a complement to chemical methods

Intestinal fatty acid binding protein is associated with cardiac function and gut dysbiosis in chronic heart failure

BackgroundThe gut microbiota in patients with chronic heart failure (HF) is characterized by low bacterial diversity and reduced ability to synthesize beneficial metabolites. These changes may facilitate leakage of whole bacteria or bacterial products from the gut into the bloodstream, which may activate the innate immune system and contribute to the low-grade inflammation seen in HF. In this exploratory cross-sectional study, we aimed to investigate relationships between gut microbiota diversity, markers of gut barrier dysfunction, inflammatory markers, and cardiac function in chronic HF patients.MethodsIn total, 151 adult patients with stable HF and left ventricular ejection fraction (LVEF) < 40% were enrolled. We measured lipopolysaccharide (LPS), LPS-binding protein (LBP), intestinal fatty acid binding protein (I-FABP), and soluble cluster of differentiation 14 (sCD14) as markers of gut barrier dysfunction. N-terminal pro-B-type natriuretic peptide (NT-proBNP) level above median was used as a marker of severe HF. LVEF was measured by 2D-echocardiography. Stool samples were sequenced using 16S ribosomal RNA gene amplification. Shannon diversity index was used as a measure of microbiota diversity.ResultsPatients with severe HF (NT-proBNP > 895 pg/ml) had increased I-FABP (p < 0.001) and LBP (p = 0.03) levels. ROC analysis for I-FABP yielded an AUC of 0.70 (95% CI 0.61–0.79, p < 0.001) for predicting severe HF. A multivariate logistic regression model showed increasing I-FABP levels across quartiles of NT-proBNP (OR 2.09, 95% CI 1.28−3.41, p = 0.003). I-FABP was negatively correlated with Shannon diversity index (rho = −0.30, p = <0.001), and the bacterial genera Ruminococcus gauvreauii group, Bifidobacterium, Clostridium sensu stricto, and Parasutterella, which were depleted in patients with severe HF.ConclusionsIn patients with HF, I-FABP, a marker of enterocyte damage, is associated with HF severity and low microbial diversity as part of an altered gut microbiota composition. I-FABP may reflect dysbiosis and may be a marker of gut involvement in patients with HF

Molecular and Chemical Characterization of the Biosynthesis of the 6-MSA-Derived Meroterpenoid Yanuthone D in Aspergillus niger.

SummarySecondary metabolites in filamentous fungi constitute a rich source of bioactive molecules. We have deduced the genetic and biosynthetic pathway of the antibiotic yanuthone D from Aspergillus niger. Our analyses show that yanuthone D is a meroterpenoid derived from the polyketide 6-methylsalicylic acid (6-MSA). Yanuthone D formation depends on a cluster composed of ten genes including yanA and yanI, which encode a 6-MSA polyketide synthase and a previously undescribed O-mevalon transferase, respectively. In addition, several branching points in the pathway were discovered, revealing five yanuthones (F, G, H, I, and J). Furthermore, we have identified another compound (yanuthone X1) that defines a class of yanuthones that depend on several enzymatic activities encoded by genes in the yan cluster but that are not derived from 6-MSA

Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci.

A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined)=2.1 × 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb)=1.9 × 10(-6), rs281377; p(comb)=2.1 × 10(-6) and rs601338; p(comb)=2.7 × 10(-6)) is notable due to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC.Norwegian PSC Research Center German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN) Integrated Research and Treatment Center - Transplantation 01EO0802 PopGen biobank NIH DK 8496

Genetic insight into sick sinus syndrome

Aims. The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development. Methods and results. We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1–1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10⁻²⁰), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05). Conclusion. We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 4150 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; PPeer reviewe

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07x10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.Peer reviewe