Novel small molecules potentiate premature termination codon readthrough by aminoglycosides

International audienceNonsense mutations introduce premature termination codons and underlie 11% of genetic disease cases. High concentrations of aminoglycosides can restore gene function by eliciting premature termination codon readthrough but with low efficiency. Using a high-throughput screen, we identified compounds that potentiate readthrough by aminoglyco-sides at multiple nonsense alleles in yeast. Chemical optimization generated phthalimide derivative CDX5-1 with activity in human cells. Alone, CDX5-1 did not induce readthrough or increase TP53 mRNA levels in HDQ-P1 cancer cells with a homozygous TP53 nonsense mutation. However, in combination with aminoglycoside G418, it enhanced readthrough up to 180-fold over G418 alone. The combination also increased readthrough at all three nonsense codons in cancer cells with other TP53 nonsense mutations, as well as in cells from rare genetic disease patients with nonsense mutations in the CLN2, SMARCAL1 and DMD genes. These findings open up the possibility of treating patients across a spectrum of genetic diseases caused by nonsense mutations

Citrus juices technology

Citrus fruits are widely grown throughout the world and contain various bioactive compounds with antioxidant activities including vitamin C, carotenoids, and phenolic compounds. These components are very important for human health and provide protection against harmful free radicals. Citrus fruits are mostly consumed as fresh fruits or fruit juices. To obtain high quality and safe citrus juice, certain critical points (oil extraction from peel, juice extraction, pulp removing, pasteurization, evaporation, and aseptic filling) need to be taken into consideration during citrus juice processing. Firstly, oil extraction from the peel is a necessary step to limit the level of peel oil components in the juice. Secondly, selected juice extraction techniques and process conditions are very important for the yield and total quality of the juice. Thirdly, the pulp removal is an important step to remove most of pectinmethylesterase (PME) and its heat resistance isoenzymes. Further inactivation of remaining PME enzymes and pathogenic or spoilage microorganisms is also obtained with the pasteurization step. Finally, equipment used for the juice production and the concentration conditions have various effects on the sensory properties of the citrus juices. As a result, minimal processing would be applied to citrus juices if the processing steps detailed above are optimized. Obtaining clarified citrus juices from the citruses which have lower carotenoid content including lemon and lime juice is a new trend these days. It is needed to be focused on enzymation (depectinization), clarification assistance agents, and filtration conditions during the clarified juices production. Citrus peel (flavedo) and layer of albedo are the main byproducts of the citrus juice industry. Citrus peel oil is obtained from flavedo layer which has a significant commercial value. Recently, promising nonthermal food preservation technologies were developed including pulsed electric fields (PEF), high pressure processing (HPP), and ultrasonication process (US). These technologies are highly appreciated for their ability to extend the shelf life of food products without the application of heat, thus also preserving the quality attributes such as sensory quality and nutritional value, as well as controlling the microbiological safety of food products. © 2014, Springer Science+Business Media New York

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

International audienceSignificance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population