Einlassbauwerke von Retentionsräumen im Nebenschluss von Fliessgewässern

Aufsatz veröffentlicht in: "Wasserbau-Symposium 2021: Wasserbau in Zeiten von Energiewende, Gewässerschutz und Klimawandel, Zurich, Switzerland, September 15-17, 2021, Band 1" veröffentlicht unter: https://doi.org/10.3929/ethz-b-00049975

Conserved natural IgM antibodies mediate innate and adaptive immunity against the opportunistic fungus Pneumocystis murina

Natural IgM antibodies in diverse species recognize conserved carbohydrates in fungal cell walls and influence early host defense against Pneumocystis in mice

Two New Loci for Body-Weight Regulation Identified in a Joint Analysis of Genome-Wide Association Studies for Early-Onset Extreme Obesity in French and German Study Groups

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85610 x 10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84 x 10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at similar to 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults

Calcium Influx Rescues Adenylate Cyclase-Hemolysin from Rapid Cell Membrane Removal and Enables Phagocyte Permeabilization by Toxin Pores

Bordetella adenylate cyclase toxin-hemolysin (CyaA) penetrates the cytoplasmic membrane of phagocytes and employs two distinct conformers to exert its multiple activities. One conformer forms cation-selective pores that permeabilize phagocyte membrane for efflux of cytosolic potassium. The other conformer conducts extracellular calcium ions across cytoplasmic membrane of cells, relocates into lipid rafts, translocates the adenylate cyclase enzyme (AC) domain into cells and converts cytosolic ATP to cAMP. We show that the calcium-conducting activity of CyaA controls the path and kinetics of endocytic removal of toxin pores from phagocyte membrane. The enzymatically inactive but calcium-conducting CyaA-AC− toxoid was endocytosed via a clathrin-dependent pathway. In contrast, a doubly mutated (E570K+E581P) toxoid, unable to conduct Ca2+ into cells, was rapidly internalized by membrane macropinocytosis, unless rescued by Ca2+ influx promoted in trans by ionomycin or intact toxoid. Moreover, a fully pore-forming CyaA-ΔAC hemolysin failed to permeabilize phagocytes, unless endocytic removal of its pores from cell membrane was decelerated through Ca2+ influx promoted by molecules locked in a Ca2+-conducting conformation by the 3D1 antibody. Inhibition of endocytosis also enabled the native B. pertussis-produced CyaA to induce lysis of J774A.1 macrophages at concentrations starting from 100 ng/ml. Hence, by mediating calcium influx into cells, the translocating conformer of CyaA controls the removal of bystander toxin pores from phagocyte membrane. This triggers a positive feedback loop of exacerbated cell permeabilization, where the efflux of cellular potassium yields further decreased toxin pore removal from cell membrane and this further enhances cell permeabilization and potassium efflux

Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m2 at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Modifying effect of a common polymorphism in the interleukin-6 promoter on the relationship between long-term exposure to traffic-related particulate matter and heart rate variability

Exposure to particulate matter (PM) has been associated with an increase in many inflammatory markers, including interleukin 6 (IL6). Air pollution exposure has also been suggested to induce an imbalance in the autonomic nervous system (ANS), such as a decrease in heart rate variability (HRV). In this study we aimed to investigate the modifying effect of polymorphisms in a major proinflammatory marker gene, interleukin 6 (IL6), on the relationship between long-term exposure to traffic-related PM10 (TPM10) and HRV.; For this cross-sectional study we analysed 1552 participants of the SAPALDIA cohort aged 50 years and older. Included were persons with valid genotype data, who underwent ambulatory 24-hr electrocardiogram monitoring, and reported on medical history and lifestyle. Main effects of annual average TPM10 and IL6 gene variants (rs1800795; rs2069827; rs2069840; rs10242595) on HRV indices and their interaction with average annual exposure to TPM10 were tested, applying a multivariable mixed linear model.; No overall association of TPM10 on HRV was found. Carriers of two proinflammatory G-alleles of the functional IL6 -174 G/C (rs1800795) polymorphism exhibited lower HRV. An inverse association between a 1 µg/m3 increment in yearly averaged TPM10 and HRV was restricted to GG genotypes at this locus with a standard deviation of normal-to-normal intervals (SDNN) (GG-carriers: -1.8%; 95% confidence interval -3.5 to 0.01; pinteraction(additive) = 0.028); and low frequency power (LF) (GG-carriers: -5.7%; 95%CI: -10.4 to -0.8; pinteraction(dominant) = 0.049).; Our results are consistent with the hypothesis that traffic-related air pollution decreases heart rate variability through inflammatory mechanisms

Einlassbauwerke von Retentionsräumen im Nebenschluss von Fliessgewässern

ISSN:0374-005

Opioid prescriptions after knee replacement: a retrospective study of pathways and prognostic factors in the Swiss healthcare setting

Objectives The optimal use of opioids after knee replacement (KR) remains to be determined, given the growing evidence that opioids are no more effective than other analgesics and that their adverse effects can impair quality of life. Therefore, the objective is to examine opioid prescriptions after KR.Design In this retrospective study, we used descriptive statistics and estimated the association of prognostic factors using generalised negative binomial models.Setting The study is based on anonymised claims data of patients with mandatory health insurance at Helsana, a leading Swiss health insurance.Participants Overall, 9122 patients undergoing KR between 2015 and 2018 were identified.Primary and secondary outcome measures Based on reimbursed bills, we calculated the dosage (morphine equivalent dose, MED) and the episode length (acute: &lt;90 days; subacute: ≥90 to &lt;120 days or &lt;10 claims; chronic: ≥90 days and ≥10 claims or ≥120 days). The incidence rate ratios (IRRs) for postoperative opioids were calculated.Results Of all patients, 3445 (37.8%) received opioids in the postoperative year. A large majority had acute episodes (3067, 89.0%), 2211 (65.0%) had peak MED levels above 100 mg/day and most patients received opioids in the first 10 postoperative weeks (2881, 31.6%). Increasing age (66–75 and &gt;75 vs 18–65) was associated with decreased IRR (0.776 (95% CI 0.7 to 0.859); 0.723 (95% CI 0.649 to 0.805)), whereas preoperative non-opioid analgesics and opioids were associated with higher IRR (1.271 (95% CI 1.155 to 1.399); 3.977 (95% CI 4.409 to 3.591)).Conclusion The high opioid demand is unexpected given that current recommendations advise using opioids only when other pain therapies are ineffective. To ensure medication safety, it is important to consider alternative treatment options and ensure that benefits outweigh potential risks

Large-scale field tests on impulse waves

Reservoirs and other hydropower infrastructure in mountainous areas have to deal with various natural hazards. Ice- and rockfalls, landslides as well as rock and snow avalanches may impinge the reservoir, generating impulse waves that may overtop dams. Due to climate change and the rise of the permafrost base, the landslide and rockfall hazard is likely to increase in the future. A reliable risk analysis regarding potential impulse waves is therefore inevitable for the hazard assessment of hydropower infrastructure. The existing computational procedures to calculate wave heights and run-up are mostly based on small-scale model tests and may therefore exhibit scale effects. In addition, the uncertainty of the calculated wave height and run-up is still high. Therefore, new data on impulse wave characteristics were collected using large-scale field tests. A test site was established in a 30 m deep gravel pit. The artificial reservoir was 15 m wide, 55 m long and had a still water depth of 1.5 m. A 40 m long steel ramp along the pit slope (37°) provided a sliding surface. The sliding mass was represented by a steel sledge (3 to 7 tons). The sledge could be released from different ramp positions to vary the impact velocity between 6 and 17 m/s. The resulting wave heights along the wave propagation path and the wave run-up were visually determined using gauge poles. The results help to (1) improve existing computational procedures, (2) determine possible scale effects; and (3) serve as calibration and validation data for numerical modelling of impulse waves