Étude de l'expression génique des molécules reliées à l'apoptose durant la maturation des cellules dendritiques : rôle pro-apoptotique de fas

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal

Generalised Methodology for Sizing of Air Vehicles with Hybrid-Electric Propulsion

In the context of increasing attention given to aircraft propulsive system electrification by the aeronautical community, Department of Aerodynamics, Energetics and Propulsion at ISAE-SUPAERO is undertaking an effort to develop a preliminary sizing tool for aeroplanes with propulsive architectures ranging between conventional gas turbine and different hybrid-electric solutions. The baseline used to initiate this work is semi-empirical handbook sizing method by Jan Roskam. The method is firstly extended by introducing a generic propulsive power architecture space, described parametrically by an array of power hybridisation parameters. Furthermore, a proposal of modified Breguet range equation is given for fuel weight iterations including batteries. With these upgrades, a trial sizing run was performed on a Pilatus PC-12 test case to verify the functioning of the developed tool. A more comprehensive study of an equivalent aeroplane powered with various hybrid-electric solutions is then presented, along with an associated parametric study. Mission performance results of all the hybrid architectures are inferior to the ones for the fuel-based baseline, with the most promising solutions indicated by the results being series and parallel hybrid architectures. While the tool produces qualitatively coherent results, the quantitative validity thereof is yet to be ascertained. Notably, the hybrid range equation needs to be further placed under scrutiny and its applicability for mission sizing of all the hybrid architectures of interest is to be validated. In the long run, the work will look into other current limitations such as lack of possibility to consider battery recharge in the mission calculations or lack of capability to perform sensitivity studies

Cytotoxic CD8⁺ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons.

Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4 <sup>+</sup> T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8 <sup>+</sup> T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8 <sup>+</sup> T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8 <sup>+</sup> T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1) <sup>G93A</sup> mutant decreased spinal motoneuron loss. Using motoneuron-CD8 <sup>+</sup> T cell coculture systems, we found that mutant SOD1-expressing CD8 <sup>+</sup> T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron and SOD1 <sup> G93A </sup> CD8 <sup>+</sup> T cells. Activated mutant SOD1 CD8 <sup>+</sup> T cells produce interferon-γ, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8 <sup>+</sup> T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS

IL-27 promotes T cell–dependent colitis through multiple mechanisms

T cells lacking the IL-27 receptor generate less severe colitis in mice, and more readily up-regulate Foxp3 expression

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity

Numerical Low-Fidelity Method for Improved Analysis of Breakthrough Aero-Propulsive Systems

This work presents an approach to evaluating the impact of Boundary Layer Ingestion (BLI) propulsion on airplane aerodynamic performance by accounting for the propulsive system environment. To that end, Reynolds-Averaged Navier-Stokes (RANS) simulations are performed on an aero-propulsive assembly, with Body Force Modeling (BFM) used to simulate the fan stage. The configuration consists of a wing section with a ducted propulsor mounted on its suction side. The aero-propulsive performance of the assembly is analyzed for different fan rotor rotational speeds, as well as different angles of attack of the upstream flow. The distortion due to BLI is found to be still visible at the fan stage exit, creating a lateral loading. The presented numerical approach fully accounts for the aero-propulsive coupling between the airframe and the propulsor and is associated with a low CPU cost, which makes it well suited for preliminary design space explorations

How Degeneration of Cells Surrounding Motoneurons Contributes to Amyotrophic Lateral Sclerosis

International audienceAmyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by the progressive degeneration of upper and lower motoneurons. Despite motoneuron death being recognized as the cardinal event of the disease, the loss of glial cells and interneurons in the brain and spinal cord accompanies and even precedes motoneuron elimination. In this review, we provide striking evidence that the degeneration of astrocytes and oligodendrocytes, in addition to inhibitory and modulatory interneurons, disrupt the functionally coherent environment of motoneurons. We discuss the extent to which the degeneration of glial cells and interneurons also contributes to the decline of the motor system. This pathogenic cellular network therefore represents a novel strategic field of therapeutic investigation

Les cellules dendritiques transfectées avec de l’ARN messager

Les cellules dendritiques, sentinelles du systèmeimmunitaire, sont des cellules spécialisées dans la capture, l’apprêtement et la présentation d’antigènes. Ces cellules ont un rôle central dans la réponse immunitaire car ce sont les seules capables d’activer les lymphocytes T naïfs et de déclencher une réponse immune primaire. La possibilité de les différencier et de les manipuler génétiquement ex vivo en fait un outil de choix pour stimuler des réponses immunitaires contre des antigènes d’intérêt. C’est pourquoi les cellules dendritiques sont largement utilisées en immunothérapie anti-tumorale et anti-infectieuse.Récemment, plusieurs études ont montré que des cellules dendritiques transfectées avec des ARNm autologues tumoraux ou viraux sont capables d’induire une réponse immunitaire spécifique et efficace associée à une réponse cliniquebénéfique. Cette stratégie de vaccination très prometteuse offre une approche thérapeutique applicable à de nombreuses pathologies et, de plus, adaptée à chaque patient. Cet article fait le point sur les progrès actuels réalisés en immunothérapie anti-tumorale et anti-VIH(virus de l’immunodéficience humaine)