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

Background: We 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 ~ 80% of cases. Methods: We 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. Results: No 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 = 1.1 × 10−4) 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 = 2.1 × 10−4). 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 = 3.4 × 10−3), 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 = 7.7 × 10−8). 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 = 1.68 × 10−5). Conclusions: Rare 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

Les multiples visages des orbitales moléculaires

Les orbitales moléculaires sont devenues un outil d’analyse incontournable dans les programmes universitaires et de classes préparatoires. Pourtant, leur définition et leur signification ne sont pas aussi univoques que leur omniprésence pédagogique le suggère. Il s’agit au contraire d’une notion protéiforme dont il importe, sans en remettre en cause l’utilité, de délimiter les contours et les limites d’application

Les multiples visages des orbitales moléculaires

Les orbitales moléculaires sont devenues un outil d’analyse incontournable dans les programmes universitaires et de classes préparatoires. Pourtant, leur définition et leur signification ne sont pas aussi univoques que leur omniprésence pédagogique le suggère. Il s’agit au contraire d’une notion protéiforme dont il importe, sans en remettre en cause l’utilité, de délimiter les contours et les limites d’application

Fonctions de Fukui : un outil pour l'étude de la réactivité chimique

La compréhension de la réactivité chimique des espèces est un enjeu majeur en chimie. Dans cet article, l'utilisation directe de la densité électronique par le biais des fonctions de Fukui est abordée afin de montrer le caractère intuitif de cette approche. Une comparaison des avantages et des inconvénients de cette méthode par rapport à l'utilisation de l'approximation des orbitales frontières est présentée pour montrer que, dès lors que l'utilisation des orbitales moléculaires nécessite le recours à un outil informatique, il est conceptuellement plus simple et chimiquement plus exact d'utiliser les fonctions de Fukui

A quantum chemistry evaluation of the stereochemical activity of the lone pair in PbII complexes with sequestering ligands

International audienceThe stereochemical activity of the lone pair on PbII complexes is assessed using several theoretical methods, including structural analyses, computations of Fukui functions, natural bond orbitals, electron localization function, investigation of the electron density and of its laplacian. The attention is focused on four octadentate N-carbamoylmethyl-substituted tetraazamacrocycles of various ring sizes ranging from 8 to 14 atoms associated with the PbII cation. The theoretical study illustrates the geometrical constraints imposed by the ring structure which limits the spatial development of the lone pair but without fully preventing it. For a given coordination number, the lone pair activity is strongly correlated to the geometry of the ligand and in particular to the size of the cage that the ligand forms around the PbII cation. Some limitations of the theoretical tools used are also evidenced, among them the necessity to sample around a critical point instead of just analyzing its nature. In the case of the laplacian of the electron density, a visualization method is introduced to moderate the results based only on the nature of a critical point. These limitations should also be related to the difficulty to extend the lone pair concept for the heaviest atoms of the classification

Complexation of some divalent cations with morin: a spectroscopic and theoretical study

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Emergence of high aqueous solubility for some flavone glycosides by disruption of molecular planarity

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The photo-degradation of mesotrione, a triketone herbicide, in the presence of Cu^II ions

The study focuses first on the complexation of CuII ions with mesotrione. Experimental absorption spectra combined with quantum chemical calculations highlight that CuII ions bind to the molecule in bidentate mode between O1 and O7 atoms. The calculated electronic transitions of the complex show that three of them are mostly ligand-to-ligand electron transfer while the lowest-energy one involves a ligand-to-metal charge transfer (LMCT). The second aim of this work is to explore the effect of CuII complexation on the photo-degradation of mesotrione. The kinetics and mechanisms of the reactions are proposed on the basis of the experimental results. The effect of different parameters such as the irradiation wavelength, the oxygen concentration and the pH of the mixture and also the production of reactive species such as hydroxyl radicals is investigated. The photochemical degradation of mesotrione in water arises from the triplet excited state of the molecule and results in a photo-hydrolysis process. For the complex, by exciting mainly in its LMCT absorption band, an electron transfer between copper and mesotrione probably occurs and the mechanism of mesotrione-CuII photo-degradation differs: in addition to the photo-hydrolysis route, a photo-cyclisation process takes place and the oxidation of the ligand is accompanied by the reduction of CuII ions