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

Molecular mechanisms of mosaic aneuploidy in Leishmania : characterization of the nuclear pore complex in trypanosomatids

Chez les trypanosomatidés, on observe un double cycle cellulaire : karyokinèse et cytodiérèse sont synchronisées mais indépendantes. La membrane nucléaire persiste au cours de la mitose dite fermée. Les modalités de réplication de l'ADN et de sa régulation, de même que plusieurs étapes de la ségrégation des chromosomes, restent non élucidées : le kinétochore est composé de protéines très atypiques (KKTs), et il existe un déficit du nombre de kinétochores par rapport au nombre de chromosomes. D'autre part, la constitution des pôles du fuseau mitotique associés à la membrane nucléaire est totalement inconnue. Les nucléoporines sont des protéines conservées au cours de l'évolution, principalement impliquées dans la constitution des pores nucléaires et le trafic entre le noyau et le cytoplasme, mais également de plus en plus considérées comme des acteurs importants de la dynamique chromatinienne. En utilisant des vecteurs d'expression protéique sous forme fusionnée à la GFP, nous avons déterminé la localisation subcellulaire de 15 nucléoporines chez Leishmania major. Si la plupart de ces nucléoporines se localisent à la membrane nucléaire, plusieurs d'entre elles ont des localisations secondaires qui peuvent être prédominantes. Ainsi la nucléoporine Mlp2 est préférentiellement localisée au niveau du kinétochore et, en fin de mitose, à l'extrémité du fuseau mitotique chez les deux parasites Leishmania major et Trypanosoma brucei. En accord avec la localisation de TbMlp2 au kinétochore chez T. brucei, où les centromères sont identifiés, nous avons fréquemment détecté TbMlp2 à proximité des séquences centromériques, elles-mêmes détectées par FISH en périphérie du nucléole. Egalement grâce à la technique de FISH, nous montrons que l'inhibition de l'expression de TbMlp2 par ARN-interférence perturbe la distribution des chromosomes au cours de la mitose, conduisant à une aneuploïdie. Paradoxalement, cette inhibition n'a aucun effet sur la croissance des cellules. Nous présentons également le cas singulier de Mlp1, dont la localisation chez T. brucei dépend du site d'intégration choisi. Cette localisation sera discutée à la lumière des phénotypes observés lors de l'inhibition de son expression.Trypanosomatid parasites exhibit two independent though coordinated (nuclear and mitochondrial) cell cycles, and a closed mitosis, of which many constituents and processes are unknown. In particular, most steps of the chromosome segregation remain elusive: the kinetochore is composed of atypical proteins called KKT and the number of kinetochores is deficient in relation to the number of chromosomes. Moreover, the constitution of the nuclear membrane-associated mitotic spindle poles is unknown. Nucleoporins are evolutionary conserved proteins mainly involved in the constitution of the nuclear pores and trafficking between the nucleus and cytoplasm, but are also increasingly viewed as main actors in chromatin dynamics. Using GFP-fused proteins, we determined the cellular localization of the 15 nucleoporins in Leishmania major. If most of these nucleoporins localized at the nuclear membrane, some of them exhibited secondary locations which are predominant in a few cases. Thus, the nucleoporin Mlp2 localized preferentially at the kinetochore and, at the end of mitosis, at the mitotic spindle poles in both parasites Leishmania major and Trypanosoma brucei. Consistent with the localisation of TbMlp2 to the kinetochore in T. brucei, where centromeres are identified, TbMlp2 was frequently detected in the vicinity of the centromeric sequences in the periphery of the nucleolus. The use of FISH allowed us to show that RNAi knockdowns of TbMlp2 disturbed the distribution of chromosomes during mitosis, leading to aneuploidy. Paradoxically RNAi knockdowns of TbMlp2 had no effect on cell growth. We will also present the singular case of Mlp1 whose location is dependent on the integration site in T. brucei. This location will be discussed in the light of the phenotypes observed after inhibition of its expression

Diagnostic moléculaire de la toxoplasmose (étude comparative d'un kit commercial et de deux méthodes "maison")

MONTPELLIER-BU Pharmacie (341722105) / SudocSudocFranceF

2-Dimensional Optical CDMA system performances with Parallel Interference Cancellation

International audienceIn this paper, we investigate the feasibility of a 2-Dimensional Optical Code Division Multiple Access (2D-OCDMA) system, with electronic coding and decoding functions. We develop a modified construction method of Multi-Wavelength Optical Orthogonal Codes (MWOOC) that permits high flexibility in the code parameters choice. The 2D code performance is calculated for a Conventional Correlation Receiver (CCR) and a more complex one, named Parallel Interference Cancellation (PIC) receiver. For example, for a Bit Error Rate (BER) =<10^-^9, and 30 simultaneous users, we show that contrary to the CCR, the use of a PIC receiver leads to workable 2D electric coding solutions

Optimal code design for multi wavelength OOC optical CDMA systems

International audienceThe objective of this work is to design optimal codes for a 2 Dimensional Optical Code Division Multiple Access system (2D-OCDMA), and to test their robustness to noise perturbation. 2D coding is performed by Multi-Wavelength Optical Orthogonal Codes (MWOOC). They are obtained with our new construction method which permits to choose the code parameters with high flexibility. Different receiver structures are studied: a Conventional Correlation Receiver (CCR), and a Parallel Interference Cancellation receiver (PIC). For each structure, the optimal code parameters are evaluated, in order to obtain a Bit Error Rate (BER) 10-9, for 30 active users, with a minimal temporal code length, and a minimal number of wavelengths. Finally, we show that, compared to the CCR, the PIC receiver permits to reduce the temporal code length and the number of wavelength, and that it also permits to reduce the required SNR for noisy signal

2-Dimensionnal code design for an optical CDMA system with parallel interference cancellation receiver

International audienceThe objective of this paper is to design a two-Dimensional Optical Code Division Multiple Access system (2D-OCDMA) for application in access networks, with coding and decoding functions performed by electronic devices. We present a new construction method of Multi-Wavelength Optical Orthogonal Codes (MWOOC), which permits a high flexibility in the code parameters choice. This work evaluates in the noiseless case, the MWOOC potentialities for two receiver structures: a Conventional Correlation Receiver (CCR) and a Parallel Interference Cancellation receiver (PIC). We show that with a PIC receiver, it is possible to design two-Dimensional codes that respect the access specification

Environmental controls on the brGDGT and brGMGT distributions across the Seine River basin (NW France): Implications for bacterial tetraethers as a proxy for riverine runoff

Branched glycerol dialkyl glycerol tetraethers (brGDGTs) are bacterial lipids that have been largely used as environmental proxies in continental paleorecords. Another group of related lipids, branched glycerol monoalkyl glycerol tetraethers (brGMGTs), has recently been proposed as a potential paleotemperature proxy. Nevertheless, the sources and environmental dependencies of both brGDGTs and brGMGTs along the river-sea continuum are still poorly understood, complicating their application as paleoenvironmental proxies in aquatic settings. In this study, the sources of brGDGTs and brGMGTs and the potential factors controlling their distributions are explored across the Seine River basin (NW France), which encompasses the freshwater to seawater continuum. To this aim, brGDGTs and brGMGTs were analyzed in soils, Suspended Particulate Matter (SPM) and sediments (n=237) collected all along this basin, from land to sea. Both types of compounds are shown to be produced in situ, in freshwater as well as saltwater. Redundancy analysis further shows that both salinity and nitrogen loadings dominantly control the brGDGT distributions. Furthermore, the relative abundance of 6-methyl vs. 5-methyl brGDGTs (IR6Me ratio), Total Nitrogen (TN), δ15N and chlorophyll a concentration co-vary in the upstream area, suggesting that 6-methyl brGDGTs are preferentially produced under low-salinity and high-productivity conditions. In contrast with brGDGTs, brGMGT distribution appear to be primarily regulated by salinity, with a distinct influence on the individual homologues. Salinity is positively correlated with homologues H1020a and H1020b, and negatively correlated with compounds H1020c, H1034b, and H1034c. This suggests that bacteria thriving in freshwater preferentially produce compounds H1020c, H1034b, and H1034c, whereas bacteria primarily growing in saltwater appear to be predominantly responsible for the production of homologues H1020a and H1020b. Based on the abundance ratio of the freshwater-derived compounds (H1020c, H1034b, and H1034c) vs. saltwater-derived homologues (H1020a and H1020b), a novel proxy, Riverine Index (RIX) is proposed to trace riverine organic matter inputs, with high values (>0.5) indicating higher riverine contribution. As RIX relies on compounds that are specifically produced in certain settings (freshwater or saltwater), this index has potential to serve as a powerful proxy for riverine runoff in modern samples as well as in paleorecords

Constitutive mosaic aneuploidy is a unique genetic feature widespread in the Leishmania genus

International audienceUsing fluorescence in situ hybridization, we determined the ploidy off our species of Leishmania: L.infantum, L.donovani, L.tropicaand and L.amazonensis. We found that each cell in a strain possesses a combination of mono-, di- and trisomies for all chromosomes; ploidy patterns were different among all strains/species. These results extend those we previously described in L. major, demonstrating that mosaic aneuploidy is a genetic feature widespread to the Leishmania genus. In addition to the genetic consequences induced by this mosaicism, the apparent absence of alternation between haploid/diploid stages questions the modality of genetic exchange in Leishmania sp