No abstract

Chronic CO exposure promotes a pathological phenotype of cardiomyocytes in the absence of underlying cardiomyopathy. The less severe phenotype in vivo suggests a role for compensatory mechanisms. Arrhythmia propensity may derive from intracellular Ca(2+) overload.

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.

No abstract

Objective: Nitrate (NO3-)-rich beetroot juice (BR) is recognized as an ergogenic supplementation that improves exercise tolerance during submaximal to maximal intensity exercise in recreational and competitive athletes. A recent study has investigated the effectiveness of BR on exercise performance during supramaximal intensity intermittent exercise (SIE) in Olympic-level track cyclists, but studies conducted in elite endurance athletes are scarce. The present study aimed to determine whether BR supplementation enhances the tolerance to SIE in elite endurance athletes. Methods: Eleven elite endurance athletes (age: 21.7±3.7 years, maximal oxygen uptake (V̇O %&'(): 71.1±5.2 mL•kg-1 •min-1) performed a SIE test until exhaustion following either a 3-day BR supplementation (340 mg/day) or a placebo (PL) supplementation (<2,5 mg/day) in a randomized, single blind, placebo-controlled and crossover study. The exercise test consisted of 15-s cycling exercise bouts at 170% of the maximal aerobic power interspersed with 30-s passive recovery periods. Gas exchange was measured during SIE tests as local muscle O2 delivery and extraction were assessed by near infrared spectroscopy. Results: The number of repetitions completed was not significantly different between BR (13.9±4.0 reps) and PL conditions (14.2±4.5 reps). BR supplementation did not affect oxygen uptake (V̇O %) during SIE tests (BR: 3378.5±681.8 mL•min-1 , PL: 3466.1±505.3 mL•min-1). No significant change in the areas under curves was found for local muscle total hemoglobin 3 (BR: 6816.9±1463.1 arbitrary units (a.u.), PL: 6771.5±3004.5 a.u.) and deoxygenated hemoglobin (BR: 6619.7±875.8 a.u., PL: 6332.7±1336.8 a.u.) during time-matched work+recovery periods from SIE tests following BR supplementation. Conclusion: BR supplementation does not enhance the tolerance to supramaximal intensity intermittent exercise in elite endurance athletes and does affect neither V̇O % nor local muscle O2 delivery and extraction.