Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias

Estratégia de coalimentação na sobrevivência e no crescimento de larvas de Betta splendens durante a transição alimentar

Conduziu-se um experimento com o objetivo de avaliar a influência do período de coalimentação na sobrevivência e no crescimento de larvas de Betta splendens. As larvas foram alimentadas com náuplios de Artemia durante sete dias e, posteriormente, submetidas aos seguintes tratamentos: jejum contínuo; ração contínua; quatro dias de coalimentação + 14 dias de ração; oito dias de coalimentação + 10 dias de ração; 12 dias de coalimentação + seis dias de ração; náuplios de Artemia durante todo o período experimental. Os valores das variáveis de desempenho das larvas do tratamento 12 dias de coalimentação + seis dias de ração e do tratamento náuplios de Artemia foram superiores aos demais tratamentos, exceto para sobrevivência, em que não houve diferença significativa com o tratamento oito dias de coalimentação + 10 dias de ração. Considerando-se apenas o tempo de oferta de Artemia (em dias), obteve-se a equação de regressão para as variáveis analisadas. A sobrevivência e a taxa de crescimento específico (TCE) apresentaram efeito quadrático, e as demais variáveis apresentaram efeito linear. O ponto de máxima para sobrevivência foi de 21,7 dias (88,92%) e para TCE foi de 26,2 dias (23,47% dia-1). O período de co-feeding influencia no crescimento e na sobrevivência de larvas de Betta splendens. Após o período de 19 dias de oferta de alimento vivo, com 12 dias de coalimentação, as larvas estão aptas a aproveitar de maneira eficiente o alimento inerte sem prejuízos ao crescimento e à sobrevivência

Beneficial effects of Ginkgo biloba extract on insulin signaling cascade, dyslipidemia, and body adiposity of diet-induced obese rats

Ginkgo biloba extract (GbE) has been indicated as an efficient medicine for the treatment of diabetes mellitus type 2. It remains unclear if its effects are due to an improvement of the insulin signaling cascade, especially in obese subjects. The aim of the present study was to evaluate the effect of GbE on insulin tolerance, food intake, body adiposity, lipid profile, fasting insulin, and muscle levels of insulin receptor substrate 1 (IRS-1), protein tyrosine phosphatase 1B (PTP-1B), and protein kinase B (Akt), as well as Akt phosphorylation, in diet-induced obese rats. Rats were fed with a high-fat diet (HFD) or a normal fat diet (NFD) for 8 weeks. After that, the HFD group was divided into two groups: rats gavaged with a saline vehicle (HFD+V), and rats gavaged with 500 mg/kg of GbE diluted in the saline vehicle (HFD+Gb). NFD rats were gavaged with the saline vehicle only. At the end of the treatment, the rats were anesthetized, insulin was injected into the portal vein, and after 90s, the gastrocnemius muscle was removed. The quantification of IRS-1, Akt, and Akt phosphorylation was performed using Western blotting. Serum levels of fasting insulin and glucose, triacylglycerols and total cholesterol, and LDL and HDL fractions were measured. An insulin tolerance test was also performed. Ingestion of a hyperlipidic diet promoted loss of insulin sensitivity and also resulted in a significant increase in body adiposity, plasma triacylglycerol, and glucose levels. In addition, GbE treatment significantly reduced food intake and body adiposity while it protected against hyperglycemia and dyslipidemia in diet-induced obesity rats. It also enhanced insulin sensitivity in comparison to HFD+V rats, while it restored insulin-induced Akt phosphorylation, increased IRS-1, and reduced PTP-1B levels in gastrocnemius muscle. The present findings suggest that G. biloba might be efficient in preventing and treating obesity-induced insulin signaling impairment