L'écosystème de la production audiovisuelle est structuré par la réglementation issue de la libéralisation de la télévision d'État (1984-86). Celle-ci accorde aux chaînes des fréquences hertziennes en échange d'obligations de financement et de diffusion. Il en résulte un système administré dont les règles ont très peu évolué en trente ans. Cette organisation industrielle s'essouffle: la part de marché des films français en salle stagne, tandis que le public vieillit. La rentabilité des chaînes de télévision s'effrite et les fictions qu'elles financent s'exportent mal. L'entrée des plateformes étrangères telles que Netflix fragmente encore l'audience. L'objectif de ce travail est d'étudier l'évolution de l'industrie audiovisuelle française et de sa régulation, depuis la libéralisation de la télévision d'État, ainsi que d'analyser l'effet de l'entrée des diffuseurs "over-the-top" sur l'écosystème historique. / The French ecosystem of audiovisual production has been structured by the liberalization of state television (1984-1986). Radio frequencies were granted to broadcasters in exchange for a commitment to invest a percentage of their turnover into French production. The result is a heavily regulated system whose rules have changed very little in thirty years. This industrial organization is showing its limits: the market share of French films in theaters is stagnant, while the audience is aging. The profitability of TV-channels crumbles and series they finance don't sell. The entry of foreign platforms such as Netflix fragments the audience even more. The purpose of this thesis is to study the creation of the industrial ecosystem of the French Television, its evolution and the impact of the entry of international players on the incumbents' strategies and on regulation.

En combinant des techniques de microscopie et de spectroscopie, il est possible de réaliser des images résolues spectralement. Ces images apportent des réponses à de nombreux problèmes en chimie, biologie, et médecine. La diffusion Raman cohérente (CRS) s'est révélée capable de surpasser la diffusion Raman spontanée dans l'analyse chimique d'échantillons, en offrant une meilleure résolution spatiale et un temps d'acquisition plus faible. La vitesse d'acquisition de l'information spectrale demeure toutefois un facteur limitant en imagerie CRS, et de nombreuses recherches se concentrent sur le développement de nouvelles méthodes d'acquisition. Le présent travail s'inscrit dans cette démarche. En combinant la diffusion Raman stimulée (une branche de la CRS), la focalisation spectrale d'impulsions optiques, ainsi qu'une ligne à délai acousto-optique, nous réalisons les premières mesures à de telles vitesses d'acquisition. Le cadre théorique, technologique, ainsi que l’ingénierie nécessaire pour parvenir à ce résultat sont détaillés. Cette technique d'acquisition rapide est illustrée par le suivi de réaction chimique, le contrôle qualité pharmaceutique, en biologie, et en histologie / Combining microscopy and spectroscopy, one can achieve spectrally resolved imaging, and provide a solution to various chemical, biological, or medical challenges. Coherent Raman scattering (CRS) has proven extremely valuable in providing chemical information, with a higher resolution and shorter acquisition time than spontaneous Raman scattering. The acquisition rate of the spectral information from a sample remains the limiting factor of CRS imaging, and several experimental schemes are being investigated to push the technology toward higher imaging frame rates. This work develops one such scheme. Combining stimulated Raman scattering (a CRS technique), spectral focusing with chirped pulses, and a fast acousto-optic delay line, we achieved unprecedented spectral acquisition rates. The theoretical, technological, and engineering frameworks enabling such acquisition are described in details. The application to pharmaceutical quality control, time resolved chemical transformations, biology, and histology are demonstrated

Sur la base des travaux antérieurs du laboratoire, nous avons développé une nouvelle approche synthétique énantiosélective, en deux étapes, pour l’accès à des glutarimides fonctionnalisés à partir de cyclobutanones facilement accessibles, selon deux directions: une stratégie impliquant une extension de cycle à deux atomes et une stratégie basée sur une contraction de cycle à deux atomes. En parallèle, nous avons démontré que les arynes porteurs de la chiralité axiale en position ortho de la triple liaison réactive peuvent être générés à partir des précurseurs iodo/triflate de type Suzuki et réagissent in situ avec divers substrats. Leur stabilité configurationnelle et leur grande réactivité nous ont permis de proposer une nouvelle méthode de synthèse pour introduire un fragment biaryle à chiralité axiale au sein de pratiquement toutes molécules organiques réactives vis-à-vis des arynes / Based on the previous work in our laboratory, we have developed a new enantioselective two-step synthetic approach to access functionalized glutarimide derivatives using readily available cyclobutanones following two directions: a two-atom ring expansion strategy and a two-atom ring contraction strategy. Meanwhile, we have demonstrated that arynes bearing axial chirality ortho to their reactive triple bond can be generated from the corresponding iodo/triflate Suzuki-type precursors and trapped in situ by various substrates. Their configurational stability and high reactivity allow us to propose a new synthetic method for the facile introduction of an axially chiral biaryl unit onto virtually any organic molecule reacting with arynes

Les arbovirus (dont le virus chikungunya, CHIKV) sont responsables de millions d'infections chaque année ; aucun vaccin n'est encore approuvé, et les traitements disponibles restent limités. De part leur circulation constante entre le moustique et l'humain, leur adaptation rapide à différents hôtes est un facteur clé pour leur pathogenèse. Le taux d'erreur particulièrement élevé de leur polymérase ARN permet une rapide diversification génique qui conduit à la génération d'un nuages de mutants, appelée quasi espèce. Les quasi espèces contiennent non seulement des génomes mutés, mais aussi des ARN recombinés à partir de deux génomes d'origine différente, ainsi que des génomes avec de grandes délétions, incapables de se répliquer sans l'aide d'un autre virion qui doit infection la même cellule, nommés génomes viraux défectifs (GVD). Une régulation étroite de la taille du nuage de mutants est clé pour une pathogenèse efficace : si trop petit, le potentiel adaptatif du virus sera impacté ; au contraire, une quasi-espèce trop grande peut mener à l'accumulation rapide de mutations délétères pour le virus. Alors que la régulation du paysage mutationnel est atteinte grâce à un taux d'erreur de la polymérase viral finement contrôlé, la recombinaison et la réplication des génomes défectifs sont influencés par le potentiel de co-infection des cellules cibles. Dans ce contexte, l'exclusion de la surinfection (ESI), un processus par lequel l'infection par un premier virus inhibe l'infection par un second virus, peut influer le dynamique de la quasi-espèce. Bien que décrite dans la plupart des familles virales, les mécanismes à l'origine de l'ESI restent mal caractérisés. Dans ce travail, je montre que CHIKV exclut une infection future par CHIKV, mais aussi par le virus Sindbis et le virus de la grippe A, mais non par le virus du Nil occidental. Je démontre que l'exclusion de CHIKV se situe au niveau de la pénétration du génome viral dans le cytoplasme, puis de sa réplication, mais n'influence ni l'attachement du virion ni la traduction de son génome. Je montre également que l'ESI est indépendant de l'action des interférons de type I, et qu'elle n'est médiée ni par la transcription cellulaire, ni par un facteur soluble. De plus, l'exclusion n'est pas due à une unique protéine virale, suggérant un potentiel rôle de la réponse cellulaire à l'infection.Déterminer l'influence des pressions immunologiques dans l'établissement de la quasi-espèce peut aider à une meilleure compréhension de l'interaction entre évolution virale et réponse immunitaire. Bien que la caractérisation non biaisée des mutations ponctuelles fût le fruit de nombreux travaux, les GVD restent peu caractérisées, en particulier chez les alphavirus. Dans la deuxième partie de ce travail, je développe des outils bio-informatiques pour isoler rapidement les GVD de données de séquençage à haut débit, et analyse les avantages et les inconvénients d'un ajout d'une étape de pré-amplification pour détecter et quantifier les GVD. À l'aide de ces outils, je fournis ensuite la première description complète des GVD produits par des passages séquentiels de CHIKV en culture cellulaire. En particulier, je montre que le type de GVD générés est très dépendants du type cellulaire, avec des motifs de séquences et des cadres de lecture ouverts différents lorsque les cellules hôtes sont des cellules de mammifère ou d'insecte. Ces résultats soulignent le role de l'environnement cellulaire dans le modelage de la quasi-espèce, et des GVD en particulier. Des travaux futurs aideront à dévoiler les mécanismes sous-jacents à cette interaction et pourraient permettre la conception de nouvelles stratégies thérapeutiques ciblant les dynamiques des quasi-espèces. / Arboviruses such as chikungunya virus (CHIKV) are responsible for millions of yearly infections, with no approved vaccines and limited treatments. Because they circulate between mosquitoes and humans, their fast adaptation potential to different hosts is key to pathogenesis. To achieve genome diversification, they rely on the error-prone nature of their self-encoded RNA-dependent RNA polymerase, which quickly generates a cloud of mutants, termed quasispecies. Quasispecies contain not only mutated genomes, but also shuffled genomes of different parental origin (through a process known as recombination), as well as genomes with large deletions, unable to replicate without the co-infection with a full-length helper genome, and thus termed defective viral genomes (DVGs). A tight regulation of the mutant cloud size is key to pathogenesis: if too small, it will limit the adaptation potential of the virus, whilst too big a quasispecies may lead to the fast accumulation of deleterious mutations. While regulation of the mutational landscape is achieved through the finely tuned error rate of the viral polymerase, recombination and DVG replication are influenced by the co-infection potential of the target cells.In this context, superinfection exclusion (SIE), a process by which infection by a first virus prevents infection by a second, closely related virus, can regulate quasispecies dynamics. While described in most viral families, mechanisms underlying SIE remain poorly characterised. Here, I show that CHIKV infection excludes subsequent infection by CHIKV, Sindbis virus and influenza A virus, but not West Nile virus. I demonstrate that CHIKV exclusion occurs at two steps, impacting independently viral penetration and replication, but does not directly influence binding, nor viral protein translation. I further show that SIE is interferon independent, and does not rely on host cell transcription nor on soluble cellular factors. Moreover, exclusion is not mediated by the action of a single CHIKV protein, suggesting that a cellular response may be at play. Assessing how different immunological pressures can shape quasispecies landscape may prove useful to a more thorough understanding of the interplay between viral evolution and the immune response. Although the unbiased study of point mutations has received much attention, less is known about the characteristics of DVGs, especially in alphaviruses. In the second part of this work, I develop bioinformatics tools to quickly isolate DVGs from next-generation sequencing data, and assess the advantages and drawbacks of pre-amplification steps to detect and quantify DVGs. Using these tools, I provide the first unbiased description of the DVG landscape generated through serial passaging of CHIKV in cell culture. In particular, I show that the DVG landscape is highly dependent on the cell type, with sequence patterns and open reading frames differing between DVGs generated in mammalian and insect cells. These results highlight the role of the cellular environment in shaping quasispecies, and DVGs in particular. Future work will help uncover the mechanisms underlying this crosstalk and may prove useful for the design of treatments targeting quasispecies dynamics.

Les travaux menés dans cette thèse de doctorat s’inscrivent dans le cadre d’un effort pluslarge d’automatisation des systèmes de simulation industriels. Dans l’industrie aéronautique,et plus particulièrement au sein d’Airbus, l’application historique de la simulation est laformation des pilotes. Il existe aussi des utilisations plus récentes dans la conception desystèmes, ainsi que dans l’intégration de ces systèmes. Ces dernières utilisations exigent untrès haut degré de représentativité, là où historiquement le plus important était le ressenti dupilote. Les systèmes sont aujourd’hui divisés en plusieurs sous-systèmes qui sont conçus, implémentéset validés indépendamment, afin de maintenir leur contrôle malgré l’augmentationde leurs complexités et la réduction des temps de mise sur le marché. Airbus maîtrise déjà lasimulation de ces sous-systèmes, ainsi que leurs intégrations en simulation. Cettemaîtriseest empirique, les spécialistes de la simulation reprennent l’ordonnancement d’intégrationsprécédentes, et l’adaptent à une nouvelle intégration. C’est un processus qui peut parfois êtrechronophage, et qui peut introduire des erreurs. Les tendances actuelles de l’industrie sont à la flexibilité des moyens de production, àl’intégration d’outils logistiques permettant le suivi, à l’utilisation d’outils de simulation enproduction, et à l’optimisation des ressources. Les produits sont de plus en plus souvent desitérations d’anciens produits améliorés, et les tests et simulations intégrés à leurs cycles de vie.Travailler de manière empirique dans une industrie qui nécessite de la flexibilité estune contrainte, et il est aujourd’hui important de facilement modifier des simulations. Laproblématique est donc de mettre en place des méthodes et outils permettant a priori degénérer des ordonnancements de simulations représentatifs.Afin de répondre à ce problème, nous avons mis en place une méthode permettant de décrireles composants d’une simulation, la manière dont cette simulation pourra être exécutée,ainsi que des fonctions permettant de générer des ordonnancements. Par la suite, nous avonsimplémenté un outil afin d’automatiser la recherche d’ordonnancement, en se basant sur desheuristiques. Enfin nous avons testé et vérifié notre méthode et outils sur des cas d’étudesacadémiques et industriels. / The work carried out in this Ph.D. thesis is part of a broader effort to automate industrialsimulation systems. In the aeronautics industry, and more especially within Airbus, thehistorical application of simulation is pilot training. There are also more recent uses in thedesign of systems, as well as in the integration of these systems. These latter applicationsrequire a very high degree of representativeness, where historically the most important factorhas been the pilot’s feeling. Systems are now divided into several subsystems that are designed, implemented andvalidated independently, in order tomaintain their control despite the increase in their complexity,and the reduction in time-to-market. Airbus already has expertise in the simulationof these subsystems, as well as their integration into a simulation. This expertise is empirical;simulation specialists use the previous integrations schedulings and adapt it to a newintegration. This is a process that can sometimes be time-consuming and can introduce errors.The current trends in the industry are towards flexible production methods, integrationof logistics tools for tracking, use of simulation tools in production, as well as resourcesoptimization. Products are increasingly iterations of older, improved products, and tests andsimulations are increasingly integrated into their life cycles. Working empirically in an industry that requires flexibility is a constraint, and nowadays itis essential to facilitate the modification of simulations. The problem is, therefore, to set upmethods and tools allowing a priori to generate representative simulation schedules.In order to solve this problem, we have developed a method to describe the elementsof a simulation, as well as how this simulation can be executed, and functions to generateschedules. Subsequently, we implemented a tool to automate the scheduling search, based onheuristics. Finally, we tested and verified our method and tools in academic and industrialcase studies.

Murine leukemia virus (MLV), classified as a gammaretrovirus, has been studied extensively to enhance our understanding of the biology and replication of retroviral infection. Typically referred to as a simple retrovirus, its usefulness as a model is highlighted owing to its minimal genome. The genetic material for MLV was thought to only code the basic and essential defining features of a retrovirus. Through the understanding developed from the use of simple retroviruses, the clinical and research communities were immeasurably more prepared to combat the more complex and decidedly infamous human immunodeficiency virus (HIV). Interestingly, a scenario of convergent evolution has directed MLV to encode an accessory protein, termed Glycosylated Gag (gGag), that shares functionality reminiscent of several HIV proteins. Herein, I present a dissection of a novel function of this enigmatic protein, paired with an improved understanding of the biology of MLV that was revealed by the development of small particle flow cytometry performed on viruses, also known as flow virometry. Initially, we elucidated that gGag is responsible for the resistance of MLV towards the restriction factor murine APOBEC3 (mA3). I showed that even endogenous mA3 from primary cells exhibited an enhanced enzymatic activity towards MLV with mutant gGag proteins which have lost glycosylation sites. In our following study, I illustrated that these mutants displayed a reduced viral core stability, the severity of which was correlated directly with susceptibility to mA3. These results are in line with the hypothesis that viral core stability and APOBEC3-susceptibility are directly linked. Furthermore, I showed for the first time that unprocessed gGag was associated with viral particles released from producer cells in the orientation of a type I membrane protein, with the structural regions directed within the viral core. This may be the direct evidence of how gGag improves capsid stability, a mechanism which is still unresolved. On the flip side, gGag as a type II membrane protein was observed exclusively on virus-like particles devoid of detectable envelope glycoprotein (Env). This marks a potential new function for gGag in the context of infection. Given the ubiquitous necessity of an optimized core stability for any virus, combined with the overlapping function of gGag with HIV accessory proteins, continuation of this work represents an as of yet clinically unexplored avenue for the development of HIV therapeutics. At the same time, in order to characterize individual viral particles, I played an instrumental role in developing the technique of flow virometry within our core facility. I illustrated that the Env of MLV does not significantly accumulate on extracellular vesicles (EVs) and acts as an effective marker for viral particles. With this evidence in hand, the enumeration of MLV virions was made possible. By correlating this information with an absolute viral genome determination, I was able to estimate the packaging efficiency for MLV in a quantitative manner. This information suggests that roughly 80-85% of MLV particles are missing their essential genetic information. These findings may implicate the disease progression of MLV infection may be enhanced by the use of defective-interfering particles, a theory that has been suggested for HIV. This work highlighted the fact that flow virometry is uniquely capable to discriminate viral particles from other cell-derived membraned vesicles in a highly sensitive manner. Overall, my work has unveiled new complexities of a simple retrovirus, while laying the groundwork towards both diagnostics and therapeutics for the ongoing battle with HIV.

The purpose of this qualitative thesis research was to explore the state of distance education in Saudi universities. The research focused on teaching and learning from the perspectives of the universities’ instructors as well as expert designers from the Ministry of Education working in distance education. By using a multiple case studies approach, this study aimed to understand the opportunities and challenges faced in the development of online learning environments at Saudi universities from an ethical and cultural perspectives. Data collection methods consisted of 28 in-depth, one-on-one interviews as well a thematic analysis of 152 supporting documents related to the universities’ strategies to deliver online learning. The advanced findings revealed how the recent integration of a blended learning model has helped to contribute to a shift in the Saudi distance education system, as it moves from a teacher-centered approach to a learner-centered approach. Furthermore, drawing on Hofstede’s Cultural Dimensions and Social Construction of Technology (SCOT), the study uncovers complex interactions between the Saudi learning culture, technology integration, and ethical issues. This research contributes unique knowledge about the state of online learning development in Saudi higher education to help enhance distance education development in Saudi Arabia, as well as in other areas of the world where similar distance education development initiatives are underway.

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This thesis describes optimization of die temperature in high pressure die-casting (HPDC) of A380 alloy by experimental observation and numerical simulation with the use of statistical tools. The goal of this research is to determine the optimum die temperature to minimize incidence of these defects and thus maximize production of parts without defects.   In HPDC, molten metal is injected into the die at high speed (40-60 m/s for aluminum alloys). Die temperature plays an important role on the rate of rejected parts. Therefore, flow patterns of molten metal in HPDC of an automotive component with very complex geometry (the ladder frame from the EF7 motor) were examined to determine the optimal die temperature. Defects in the production process fall into three categories, including surface, internal and dimensional defects. Samples produced in the experiments were classified according to any present defects. Another important parameter that influences casting defects is the cooling rate. Die temperatures were measured at the initial step and final filling positions. Experiments were performed with die temperatures ranging from 150 °C to 250 °C. The results show that the melt temperature difference in the die between the initial step and the final filling position was between 20 and 25 °C. Statistical tools such as regressions, relationships, max, min, correlations, ANOVA, T-test, Principal Component Analysis (PCA) and descriptive statistics were used to facilitate interpretation of data from the die-cast experiments. Perform some case studies in order to study the process behavior, take a better knowledge of effective parameters, and measure the required parameters. The collected data are utilized to: Set the model Validate/ verify the model ProCast software was used to simulate the fluid flow and solidification step, and the results were verified by experimental measurements. The optimal die temperature for this alloy was found to be above 200 oC. Statistical analysis of the experimental results found that defects were minimized and confirmed parts were maximized in HPDC of the ladder frame within a die temperature range of 210° C to 215° C.