Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis

The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease. Regions on chr3q29 (MUC4/MUC20; P=3.3 × 10−11), chr5p15.3 (SLC9A3; P=6.8 × 10−12), chr6p21.3 (HLA Class II; P=1.2 × 10−8) and chrXq22-q23 (AGTR2/SLC6A14; P=1.8 × 10−9) contain genes of high biological relevance to CF pathophysiology. The fifth locus, on chr11p12-p13 (EHF/APIP; P=1.9 × 10−10), was previously shown to be associated with lung disease. These results provide new insights into potential targets for modulating lung disease severity in CF

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

Rôle des "toll-like receptor" (TLR) 3 et TLR4 dans l'immunité innée de la muqueuse pulmonaire

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Host signaling and proteolytic pathways in the resolution or the exacerbation of coronavirus (CoV-2) infection in COVID-19 disease: what therapeutic targets?

COVID-19 is caused by the Severe Acute Respiratory Syndrome (SARS) coronavirus (Cov)-2, an enveloped virus with a positive single-stranded RNA genome. Pandemic initial outbreak began in December 2019 and is threatening the health of the global community. In common with previous pandemics (Influenza H1N1, SARS-CoV-1) and the epidemics of Middle east respiratory syndrome (MERS)-CoV, CoVs target bronchial and alveolar epithelial cells. Virus proteins ligands (eg haemagglutinin or spike protein for Influenza and CoV, respectively) interact with cellular receptors such as (depending on the virus), either sialic acids, Dipeptidyl peptidase 4 (DPP4), or angiotensin-converting enzyme 2 (ACE2). Host proteases, eg cathepsins, furin, or members of the type II transmembrane serine proteases (TTSP) family such as Transmembrane protease serine 2 (TMPRSS2) are involved in virus entry by proteolytically activating virus ligands. Also involved are Toll Like Receptor (TLR) familly members which up-regulate anti-viral and pro-inflammatory mediators (interleukin (IL)-6 and IL-8...), through the activation of Nuclear Factor (NF)-kB. When these events (virus cellular entry and innate immune responses) are uncontrolled, a deleterious systemic response is sometimes encountered in infected patients, leading to the well described ‘cytokine storm’ and an ensuing multiple organ failure, promoted by a down-regulation of dendritic cells, macrophage and T cell function. We aim to describe how the lung and systemic host innate immune responses affect survival either positively, through down-regulating initial viral load, or negatively, by triggering uncontrolled inflammation. An emphasis will be put on host cellular signaling pathways and proteases involved, with a view on tackling these therapeutically

SLC6A14, UN GENE MODIFICATEUR DANS LA MUCOVISCIDOSE

International audienceAlthough cystic fibrosis is a monogenic disease, a considerable clinical phenotypic variability is observed in patients with the same CFTR mutations. Thanks to the development of new and powerful tools for carrying out genetic studies, several genes called “modifier genes” have been identified as being associated with the severity of the lung function disorder in cystic fibrosis patients. Among these genes, SLC6A14 may modulate the anti-infective response and epithelial integrity of the airways, thus providing a potential therapeutic target to improve the patient's lung function.Bien que la mucoviscidose soit une maladie monogénique, une diversité phénotypique considérable est observée chez des patients portant les mêmes mutations de CFTR. Grâce au développement d’outils nouveaux et puissants pour la réalisation d’études génétiques, de nombreux gènes appelés « gènes modificateurs » ont été découverts comme étant associés à la sévérité de l’atteinte pulmonaire chez les patients atteints de mucoviscidose. Parmi ces gènes, le gène SLC6A14 pourrait moduler la réponse anti-infectieuse et l’intégrité de l’épithélium des voies aériennes, constituant ainsi une cible thérapeutique potentielle pour améliorer la fonction respiratoire des patients

Non-triangular self-synchronizing stream ciphers

International audienceIn this paper, we propose an instantiation, called \textsf{Stanislas}, of a dedicated Self-Synchronizing Stream Cipher (SSSC) involving an automaton with finite input memory using non-triangular state transition functions. Previous existing SSSC are based on automata with shifts or triangular functions (T-functions) as state transition functions. Our algorithm Stanislas admits a matrix representation deduced from a general and systematic methodology called Linear Parameter Varying (LPV). This particular representation comes from the automatic theory and from a special property of dynamical systems called flatness

Design and tensile properties of a bcc Ti-rich high-entropy alloy with transformation-induced plasticity

International audienc

Design and tensile properties of a bcc Ti-rich high-entropy alloy with transformation-induced plasticity

International audienc

Ferromagnetic L 10 phase formation in the Mn–Al–C alloys induced by high-pressure spark plasma sintering

International audienceStructural and magnetic characterization of Mn-Al-C permanent magnets obtained by spark plasma sintering (SPS) is reported. The transformation from the parent-phase to the ferromagnetic τ-phase occurs simultaneously with the process of sintering. The use of a tungsten carbide crucible enabled us to decrease the sintering temperature, which hampered the precipitation of secondary phases. As a result, the sintered samples show higher coercivity as compared to the annealed powder. However, the finely milled powder, ensuring better densification, turned out to be more prone to phase decomposition during sintering. The phase constitution of the samples was determined by X-ray diffraction, magnetic hysteresis loops were recorded using a vibrating sample magnetometer. Scanning electron microscopy and electron backscatter diffraction were employed to study the microstructure and orientation distribution of grains after SPS. The dependence of coercivity and magnetization on the preparation conditions and sintering temperature is analyzed. To combine good magnetic properties with proper density, further optimization of the production parameters is necessary