Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

The rough endoplasmatic reticulum is the central site of siRNA-mediated RNA silencing

Despite the rapid advancement of our mechanistic understanding of the RNA interference (RNAi) pathways in the past years, the subcellular sites of RNA silencing still remain under debate. Here we show that a lion’s share of transfected small interfering RNA (siRNA) is cleared quickly and only few siRNA molecules are finally getting loaded into Ago2, with as little as 20 30 siRISC molecules per cell sufficient to promote 50 % mRNA knockdown. While the major RNAi pathway proteins are found in most subcellular compartments, the microRNA (miRNA)- and siRNA loaded Ago2 population as well as the RNAi mediated mRNA cleavage product co-sediment exclusively with the membranes of the rough endoplasmatic reticulum (rER) together with the RISC loading complex (RLC) factors Dicer, TRBP and PACT. Moreover, siRNA-loaded Ago2 associates with the cytosolic side of membranes through TRBP and PACT in an RNA-independent manner, potentially mediated through indirect interaction via Dicer. Our findings demonstrate that the outer membrane of the rER is the central site of RNA silencing, which explains the remarkable thermodynamic and kinetic efficiency of this mechanism

Carbide-Modified Pd on ZrO(2)as Active Phase for CO2-Reforming of Methane-A Model Phase Boundary Approach

Starting from subsurface Zr0-doped “inverse” Pd and bulk-intermetallic Pd0Zr0 model catalyst precursors, we investigated the dry reforming reaction of methane (DRM) using synchrotron-based near ambient pressure in-situ X-ray photoelectron spectroscopy (NAP-XPS), in-situ X-ray diffraction and catalytic testing in an ultrahigh-vacuum-compatible recirculating batch reactor cell. Both intermetallic precursors develop a Pd0–ZrO2 phase boundary under realistic DRM conditions, whereby the oxidative segregation of ZrO2 from bulk intermetallic PdxZry leads to a highly active composite layer of carbide-modified Pd0 metal nanoparticles in contact with tetragonal ZrO2. This active state exhibits reaction rates exceeding those of a conventional supported Pd–ZrO2 reference catalyst and its high activity is unambiguously linked to the fast conversion of the highly reactive carbidic/dissolved C-species inside Pd0 toward CO at the Pd/ZrO2 phase boundary, which serves the role of providing efficient CO2 activation sites. In contrast, the near-surface intermetallic precursor decomposes toward ZrO2 islands at the surface of a quasi-infinite Pd0 metal bulk. Strongly delayed Pd carbide accumulation and thus carbon resegregation under reaction conditions leads to a much less active interfacial ZrO2–Pd0 state