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

Solubilisation of biological active substances inside supramolecular assemblies based on amphiphilic cyclodextrins

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Synthesis of carbohydrate functionalised n-propoxy-calix[4]arenes

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Interfacial interactions between amphiphilic cyclodextrins and physiologically relevant cations.

International audienceThe compression isotherms of a series of amphiphilic cyclodextrins, formed (a) by acylation at the secondary hydroxyl face and (b) by acylation accompanied by varying degrees of sulfatation (DS) at the primary hydroxyl face (DS=0, 4, and 7), have been studied on subphases of pure water and of water containing NaCl, KCl, MgCl(2), and CaCl(2) at inter- and extracellular concentrations. The formation of solid lipid nanoparticles (SLNs) by two of the molecules has been observed, while these do not aggregate at concentrations of monovalent salts up to 150 mM for the sulfated derivative. In the presence of divalent salts one of these with a DS=0 for sulfatation degree flocculates at divalent salt concentrations below 0.1 mM while the other with a DS=4 flocculates at Mg(2+) concentration above 5 mM and a Ca(2+) concentration above 3 mM. AFM noncontact mode imaging has been carried out, in air, for the SLNs deposited on mica.The compression isotherms of a series of amphiphilic cyclodextrins, formed (a) by acylation at the secondary hydroxyl face and (b) by acylation accompanied by varying degrees of sulfatation (DS) at the primary hydroxyl face (DS=0, 4, and 7), have been studied on subphases of pure water and of water containing NaCl, KCl, MgCl(2), and CaCl(2) at inter- and extracellular concentrations. The formation of solid lipid nanoparticles (SLNs) by two of the molecules has been observed, while these do not aggregate at concentrations of monovalent salts up to 150 mM for the sulfated derivative. In the presence of divalent salts one of these with a DS=0 for sulfatation degree flocculates at divalent salt concentrations below 0.1 mM while the other with a DS=4 flocculates at Mg(2+) concentration above 5 mM and a Ca(2+) concentration above 3 mM. AFM noncontact mode imaging has been carried out, in air, for the SLNs deposited on mica

Novel amphiphilic fluorophilic beta-cyclodextrins: Synthesis, self-organisation in water and application to the transport of drugs

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Nanoparticles of amphiphilic cyclodextrins

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PANI pseudopolyrotaxanes as new conducting materials

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Formulation de molécules antifongiques par inclusion dans des cyclodextrines

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Polyaniline soluble dans l'eau par formation de complexes d'inclusion de type polyrotaxane

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