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

The scattering and transmission of elastic waves in quasi-two-dimensional planar waveguides with linear defect boundaries

The influence of linear defect boundaries on the transmission and scattering of elastic waves in quasi-two-dimensional wave-guides is studied using the matching method. A linear defect boundary separating two wave-guide crystalline lattice domains is characterised here by a linear chain of defect masses and by modified elastic constants in the boundary, different from their values in the bulk of the domains. In particular a square lattice is considered to model the domains of the two-dimensional planar wave-guide containing the linear defect. The reflection and transmission probabilities, and the total transmission probabilities are calculated numerically and presented for the scattering processes in a variety of cases. We show that the interaction between the localised modes introduced by the defect boundary and the propagating modes of the system leads to Fano resonances. These resonances shift to higher (lower) frequencies for smaller (larger) defect masses, and for the same mass as function of the angle of the incident wave. Other spectral features shown to exist are due to interference effects especially at oblique incidence and when modifying the boundary elastic constants

Phonons heat transport at an atomic well boundary in ultrathin solid films

A model calculation is presented for the heat transport across an extended atomic well boundary separating two ultrathin solid films, due to the phonons coherent elastic scattering at the boundary. Using the matching method, the transmission spectra are calculated for the phonons coherent scattering, for all propagating frequencies, and incident angles from inside the films, and for different boundary elastic conditions. The group velocities of the phonon branches in the ultrathin material films are explicitly calculated as a function of frequency and incidence angle. The model is applied to a corresponding gold material system, where the individual thermal conductivities for the phonon branches of this system are numerically evaluated for different boundary conditions. The results show that the heat transport at the boundary may be reduced or enhanced by controlling its elastic properties. Copyright EDP Sciences, SIF, Springer-Verlag Berlin Heidelberg 2011