Characterizing the impact of the mutational landscape of SARS-CoV-2 on epitope presentation and CTL

La pandémie actuelle de COVID-19, causée par le coronavirus 2 du syndrome respiratoire aigu sévère (SRAS-CoV-2), a entraîné plus de 6 millions de décès et près de 680 millions de cas confirmés dans le monde. Depuis l'émergence du virus en décembre 2019, beaucoup d’efforts de recherche mondiaux ont visé à étudier la relation entre le SRAS-CoV-2 et l'immunité adaptative à médiation cellulaire. La caractérisation des réponses immunitaires à base de lymphocytes T CD4+ et CD8+ contre le SRAS-CoV-2 dans le contexte de mutations virales est d'une pertinence immédiate pour l’approfondissement de nos connaissances concernant l'immunité adaptative envers un virus en évolution, ainsi que l'amélioration de vaccins. Dans cette thèse, je passerai en revue les découvertes actuelles concernant la biologie du SRAS-CoV-2 et sa relation avec le système immunitaire adaptatif humain. Je discuterai ensuite les divers mécanismes par lesquels le SRAS-CoV-2, ainsi que d'autres virus, se sont avérés échapper l’immunité adaptative humoral et cellulaire. Enfin, je présenterai mes contributions à la compréhension du paysage mutationnel global du SRAS-CoV-2 et de sa capacité à échapper à la reconnaissance par les lymphocytes T CD8+. Dans ce travail, j'ai observé que le paysage mutationnel global du SRAS-CoV-2 était régi par des biais de mutation au cours de la première année de la pandémie, le plus répandu d’entre eux conduisant à la suppression de la proline. Il a ensuite été prédit que cette élimination globale de la proline conduirait à la perte d’épitopes reconnues par les cellules T CD8+ d'une manière dépendante sur les super-types HLA, avec la perte d'épitopes survenant préférentiellement dans le contexte du super-type HLA-B7. Le modèle développé dans ce travail propose un lien entre les biais mutationnels globaux du SRAS-CoV-2, les allèles HLA et l'évasion des lymphocytes T. Ce travail crée un cadre pour anticiper l'impact des variantes existantes et émergentes du SRAS-CoV- 2 envers la réponse immunitaire à base de lymphocytes T CD8+.The current COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has led to upwards of 6 million deaths and nearly 680 million confirmed cases worldwide. Since the emergence of the virus in December 2019, astounding global research efforts have been aimed at investigating the relationship between SARS-CoV-2 and cell-mediated adaptive immunity. Characterizing CD4+ and CD8+ T Lymphocyte responses to SARS-CoV-2 in the context of viral mutations is of immediate relevance to understanding the breadth of a population’s adaptive immunity to an evolving virus and is central to the improving existing vaccines. In this thesis, I will review all present findings pertaining to the biology of SARS-CoV-2 and its relationship with the human adaptive immune system. I will then discuss the various mechanisms by which SARS-CoV-2, along with other viruses, have been found to evade the various arms of the adaptive immune system. Finally, I will present my contributions to the understanding of the global mutational landscape of SARS-CoV-2 and its ability to evade recognition by CD8+ T lymphocytes. By investigating over 300,000 SARS-CoV-2 genomic sequences, I observed that the mutational landscape of SARS-CoV-2 was governed by mutation biases during the first year of the pandemic, with the most prevalent bias leading to the removal of proline. The observed global removal of Proline was predicted to lead to the loss of CD8+ T cell epitopes in an HLA-supertype-dependent manner, with the loss of epitopes occurring preferentially in the context of the HLA-B7 supertype. The model developed proposes a link between SARS-CoV-2 global mutational biases, HLA alleles and T cell evasion. This work creates a framework to anticipate the population-specific impact of existing and emerging SARS-CoV-2 variants on CD8+ T cell-based immunity

Tangui Perron (dir.), L’Écran rouge. Syndicalisme et cinéma de Gabin à Belmondo

L’initiative de la parution de ce livre salutaire, tant pour l’histoire du cinéma que pour celle du syndicalisme, nous la devons à Tangui Perron qui est loin d’être novice sur le sujet. Chargé du patrimoine audiovisuel au sein de l’association Périphérie et membre du conseil scientifique de l’Institut d’histoire sociale de la CGT, Tangui Perron interroge sous différentes formes, depuis un peu moins de trente ans, les relations complexes entre le cinéma et le mouvement social, en particulier l..

O trzech różnorodnych, ale zapomnianych dramatach K.H. Rostworowskiego

Numer wydany w 2017 r.This artice presents three dramas by Karol Hubert Rostworowski (1877-1938). The text concerns the problem of variety his dramas and values in: Judasz z Kariothu (1913), Miłosierdzie (1920) and Niespodzianka (1929). Talented Rostworowski was also an psychologist of the people

Assessing Wind Impact on Semi-Autonomous Drone Landings for In-Contact Power Line Inspection

In recent years, the use of inspection drones has become increasingly popular for high-voltage electric cable inspections due to their efficiency, cost-effectiveness, and ability to access hard-to-reach areas. However, safely landing drones on power lines, especially under windy conditions, remains a significant challenge. This study introduces a semi-autonomous control scheme for landing on an electrical line with the NADILE drone (an experimental drone based on original LineDrone key features for inspection of power lines) and assesses the operating envelope under various wind conditions. A Monte Carlo method is employed to analyze the success probability of landing given initial drone states. The performance of the system is evaluated for two landing strategies, variously controllers parameters and four level of wind intensities. The results show that a two-stage landing strategies offers higher probabilities of landing success and give insight regarding the best controller parameters and the maximum wind level for which the system is robust. Lastly, an experimental demonstration of the system landing autonomously on a power line is presented

Rhythmogenic neuronal networks, pacemakers, and k-cores

Neuronal networks are controlled by a combination of the dynamics of individual neurons and the connectivity of the network that links them together. We study a minimal model of the preBotzinger complex, a small neuronal network that controls the breathing rhythm of mammals through periodic firing bursts. We show that the properties of a such a randomly connected network of identical excitatory neurons are fundamentally different from those of uniformly connected neuronal networks as described by mean-field theory. We show that (i) the connectivity properties of the networks determines the location of emergent pacemakers that trigger the firing bursts and (ii) that the collective desensitization that terminates the firing bursts is determined again by the network connectivity, through k-core clusters of neurons.Comment: 4+ pages, 4 figures, submitted to Phys. Rev. Let

Sr-Nd-Pb-Hf isotope results from ODP Leg 187: Evidence for mantle dynamics of the Australian-Antarctic Discordance and origin of the Indian MORB source

New high precision PIMMS Hf and Pb isotope data for 14–28 Ma basalts recovered during ODP Leg 187 are compared with zero-age dredge samples from the Australian-Antarctic Discordance (AAD). These new data show that combined Nd-Hf isotope systematics can be used as an effective discriminant between Indian and Pacific MORB source mantle domains. In particular, Indian mantle is displaced to lower εNd and higher εHf ratios compared to Pacific mantle. As with Pb isotope plots, there is almost no overlap between the two mantle types in Nd-Hf isotope space. On the basis of our new Nd-Hf isotope data, we demonstrate that Pacific MORB-source mantle was present near the eastern margin of the AAD from as early as 28 Ma, its boundary with Indian MORB-source mantle coinciding with the eastern edge of a basin-wide arcuate depth anomaly that is centered on the AAD. This observation rules out models requiring rapid migration of Pacific MORB mantle into the Indian Ocean basin since separation of Australia from Antarctica. Although temporal variations in isotopic composition can be discerned relative to the fracture zone boundary of the modern AAD at 127°E, the distribution of different compositional groups appears to have remained much the same relative to the position of the residual depth anomaly for the past 30 m.y. Thus significant lateral flow of mantle along the ridge axis toward the interface appears unlikely. Instead, the dynamics that maintain both the residual depth anomaly and the isotopic boundary between Indian and Pacific mantle are due to eastward migration of the Australian and Antarctic plates over a stagnated, but slowly upwelling, slab oriented roughly orthogonal to the ridge axis. Temporal and spatial variations in the compositions of Indian MORB basalts within the AAD can be explained by progressive displacement of shallower Indian MORB-source mantle by deeper mantle having a higher εHf composition ascending ahead of the upwelling slab. Models for the origin of the distinctive composition of the Indian MORB-source based on recycling of a heterogeneous enriched component that consist of ancient altered ocean crust plus<10% pelagic sediment are inconsistent with Nd-Hf isotope systematics. Instead, the data can be explained by a model in which Indian mantle includes a significant proportion of material that was processed in the mantle wedge above a subduction zone and was subsequently mixed back into unprocessed upper mantle

Unraveling the temperature dependence of the yield strength in single-crystal tungsten using atomistically-informed crystal plasticity calculations

We use a physically-based crystal plasticity model to predict the yield strength of body-centered cubic (bcc) tungsten single crystals subjected to uniaxial loading. Our model captures the thermally-activated character of screw dislocation motion and full non-Schmid effects, both of which are known to play a critical role in bcc plasticity. The model uses atomistic calculations as the sole source of constitutive information, with no parameter fitting of any kind to experimental data. Our results are in excellent agreement with experimental measurements of the yield stress as a function of temperature for a number of loading orientations. The validated methodology is then employed to calculate the temperature and strain-rate dependence of the yield strength for 231 crystallographic orientations within the standard stereographic triangle. We extract the strain-rate sensitivity of W crystals at different temperatures, and finish with the calculation of yield surfaces under biaxial loading conditions that can be used to define effective yield criteria for engineering design models