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

Discrimination between Paralogs using Microarray Analysis: Application to the Yap1p and Yap2p Transcriptional Networks

Ohno [Ohno, S. (1970) in Evolution by Gene Duplication, Springer, New York] proposed that gene duplication with subsequent divergence of paralogs could be a major force in the evolution of new gene functions. In practice the functional differences between closely related homologues produced by duplications can be subtle and difficult to separate experimentally. Here we show that DNA microarrays can distinguish the functions of two closely related homologues from the yeast Saccharomyces cerevisiae, Yap1p and Yap2p. Although Yap1p and Yap2p are both bZIP transcription factors involved in multiple stress responses and are 88% identical in their DNA binding domains, our work shows that these proteins activate nonoverlapping sets of genes. Yap1p controls a set of genes involved in detoxifying the effects of reactive oxygen species, whereas Yap2p controls a set of genes over represented for the function of stabilizing proteins. In addition we show that the binding sites in the promoters of the Yap1p-dependent genes differ from the sites in the promoters of Yap2p-dependent genes and we validate experimentally that these differences are important for regulation by Yap1p. We conclude that while Yap1p and Yap2p may have some overlapping functions they are clearly not redundant and, more generally, that DNA microarray analysis will be an important tool for distinguishing the functions of the large numbers of highly conserved genes found in all eukaryotic genomes

Redução fechada e fixação esquelética externa tipo I para tratamento de fraturas de tibiotarso em pombos domésticos (Columba livia) Closed reduction and type-I external skeletal fixation for treatment of tibiotarsus fractures in domestic pigeons (Columba livia)

Estudaram-se a redução fechada e a fixação esquelética externa tipo I para o tratamento de fraturas de tibiotarso em 10 pombos domésticos (Columba livia) adultos. As aves foram anestesiadas com a associação de xilazina e cetamina e em seguida foi realizada fratura do tibiotarso direito por pressão digital sobre a diáfise do membro. Quatro pinos de Kirschner, dois proximais e dois distais à linha da fratura, foram inseridos percutaneamente através de ambas as corticais ósseas e, após redução fechada da fratura, conectados externamente por uma barra de acrílico autopolimerizável na face lateral do membro. Em três aves foi observado radiograficamente desvio ósseo angular, porém, a função do membro não foi afetada. O tempo médio e o desvio-padrão para a cicatrização óssea foram 23,4± 3,0 dias. Os resultados demonstram que a redução fechada e a aplicação de fixador esquelético externo tipo I é um método efetivo para o tratamento de fraturas de tibiotarso em pombos domésticos (Columba livia).<br>Ten adult domestic pigeons (Columbalivia) were used in order to study closed reduction and type-I external skeletal fixation for tibiotarsus fractures. Anesthesia was induced with xylazine and ketamine hydrochloride and the right tibiotarsus was manually fractured by digital pressure applied at the mid-diaphysis. Kirschner wires were driven percutaneously through the bone, two proximal and two distal to the fracture site, and stabilized by an acrylic bar in the lateral surface of the tibiotarsus after closed reduction of the fracture. Abnormalities in bone angulation were observed radiographically in three birds, however, the function of the limb was not noticeably impaired. The mean &plusmn; standard deviation for fracture healing was 23.4± 3.0 days. The results showed that closed reduction and application of a type-I external skeletal fixation is an effective method of treating tibiotarsus fracture in domestic