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

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

Phase Behavior of Aqueous Na-K-Mg-Ca-CI-NO3 Mixtures: Isopiestic Measurements and Thermodynamic Modeling

A comprehensive model has been established for calculating thermodynamic properties of multicomponent aqueous systems containing the Na{sup +}, K{sup +}, Mg{sup 2+}, Ca{sup 2+}, Cl{sup -}, and NO{sub 3}{sup -} ions. The thermodynamic framework is based on a previously developed model for mixed-solvent electrolyte solutions. The framework has been designed to reproduce the properties of salt solutions at temperatures ranging from the freezing point to 300 C and concentrations ranging from infinite dilution to the fused salt limit. The model has been parameterized using a combination of an extensive literature database and new isopiestic measurements for thirteen salt mixtures at 140 C. The measurements have been performed using Oak Ridge National Laboratory's (ORNL) previously designed gravimetric isopiestic apparatus, which makes it possible to detect solid phase precipitation. Water activities are reported for mixtures with a fixed ratio of salts as a function of the total apparent salt mole fraction. The isopiestic measurements reported here simultaneously reflect two fundamental properties of the system, i.e., the activity of water as a function of solution concentration and the occurrence of solid-liquid transitions. The thermodynamic model accurately reproduces the new isopiestic data as well as literature data for binary, ternary and higher-order subsystems. Because of its high accuracy in calculating vapor-liquid and solid-liquid equilibria, the model is suitable for studying deliquescence behavior of multicomponent salt systems

Identifi cation of the Tumor Factor of Abnormal Cancer Methylation Enzymes as the Catalytic Subunit of Telomerase

OBJECTIVE The objective was to study the relationship between the tumor factor of cancer MATLT and the catalytic subunit of telomerase. The function of telomerase in the blockade of cell differentiation and in the protection of DNA MT resembles closely the function of the tumor factor of cancer MATLT. Because of this close similarity we made an attempt to examine the possibility that the tumor factor of MATLT might be the catalytic subunit of telomerase. METHODS We used purified MAT isozymes, telomerase antibody, immunoprecipitation, and a selective inhibitor of the tumor factor of MATLT from urine to study the relationship between the tumor factor of MATLT and telomerase.RESULTS We were able to show that the tumor MATLT, but not the liver MATL, was selectively inhibited by the telomerase antibody, and the tumor MATLT, but not the liver MATL, was preferentially immunoprecipitated with the telomerase antibody. The catalytic subunit of telomerase was detectable in the tumor MATLT preparation by immunoblotting, but was undetectable in the liver MATL preparation and the tumor MATL preparation stripped off of the tumor factor. In addition, PP-0.39, which is an effective differentiation inducer purified from urine previously found to selectively antagonize the tumor factor of MATLT, was found in this study to be a potent inhibitor of telomerase. The inhibition of telomerase by PP-0.39 was far more sensitive than the elimination of the tumor factor from MATLT.CONCLUSION All results are consistent with the hypothesis that the tumor factor of MATLT is the catalytic subunit of telomerase. Thus, the blockade of cell diff erentiation by telomerase is mediated through its interaction with MAT to affect methylation enzymes, so that hypomethylation of nucleic acids necessary for the cell to undergo differentiation cannot take place