Le récepteur à la transferrine (TfR1) est un récepteur très bien conservé au cours de l’évolution qui permet l’entrée du fer (Fe) lié à la transferrine (Fe-Tf) dans les cellules. Une fois internalisé, le fer se détache de la Tf et est exporté dans le cytoplasme tandis que le complexe Tf/TfR1 est recyclé à la membrane plasmique. Le TfR1 est internalisé par un mécanisme clathrine dépendant et peut être soit recyclé à la membrane plasmique par la voie rapide, soit être dirigé vers le compartiment endosomal de recyclage (ERC). Une fois dans l’ERC, le TfR1 peut être soit recyclé à la membrane plasmique par la voie lente, soit être dirigé vers les lysosomes. De nombreuses protéines régulent le routage des protéines internalisées comme les protéines Rab. Il s’agit de petites GTPases impliquées dans les échanges moléculaires entre les différents compartiments cellulaires.Etant la principale voie d’entrée du fer dans la cellule,le TfR1 est exprimé par la plupart des cellules et est surexprimé par les cellules hautement prolifératives dont certaines cellules cancéreuses. Le TfR1 est très étudié comme cible thérapeutique dans le développement de nouvelles stratégies anti-cancéreuses. A24 est un anticorps murin anti-TfR1 dont l’action anti-proliférative et pro-apoptotique ont été démontrées dans plusieurs hémopathies malignes.Nous nous sommes demandés comment la fixation de A24 sur le TfR1 peut produire des effets différents de la fixation de la Fe-Tf. En générant un fragment Fab, nous avons d’abord démontré que le routage du TfR1 dépend de la valence de son ligand. Nous avons ensuite démontré que la fixation monovalente du TfR1 par la Fe-Tf et le Fab induisent son recyclage sans passer par l’ERC. Nous avons également démontré que la fixation divalente du TfR1 par A24 induit son routage depuis l’ERC vers les lysosomes par une voie dépendante de Rab12. / The transferrin receptor (TfR1) is a highly conserved receptor that allows the entry of iron (Fe) linked to transferrin (Fe-Tf) into cells. Once internalized, Fe separates from the Tf and is exported in the cytoplasm whereas the complex Tf/TfR1 is recycled to the cell membrane. TfR1 is internalized by a clathrin mediated endocytosis and can be either recycled to the cell membrane through the rapid pathway or be routed towards the endosomal recycling compartment (ERC). Once in the ERC, the TfR1 can be either recycled to the cell membrane through the slow pathway or be routed towards lysosomes. Many proteins regulates the routing of internalized proteins such as Rab proteins. They are small GTPases involved in molecular exchanges between the different cellular compartments.Being the main mode of entry of iron into cells, TfR1is expressed by almost every cells and is overexpressed by highly proliferative cells including some cancer cells. TfR1 is extensively studied as a therapeutic target for the development of new anti-cancer strategies. A24 is a murine anti-TfR1 whose anti-proliferative and pro-apoptotic roles were demonstrated in several hematological malignancies.We wondered how A24 binding on TfR1 can produce different effects from Fe-Tf binding. By the manufacturing of a Fab fragment, we first demonstrated that TfR1 fate depends on its ligand’s valency. We then demonstrated that the monovalent binding of TfR1 with Fe-Tf or the Fab leads to its recycling without going through the ERC. We also showed that the divalent binding of the TfR1 by A24 leads to its routing from the ERC to lysosomes through a Rab12 dependent pathway.

This research approaches independent film producer-distributor company A24 as a neoliberalentity in the context of the contemporary indie film industry. A24’s deliberate construction ofa public image as the ‘cool’ outsider positions them on the borders of independentcinema—in Indiewood. By means of a critical discourse analysis on A24’s indieness, framedby theories of paratextuality and neoliberalism, this research examines the essence of indieoppositionality as performed by A24. The respective indieness and neoliberal character ofindustry trendsetter A24 assist in reflecting on the general trend of independent cinema sincethe digital media wave of the mid-2010s, and suggest a trend towards a neoliberalmainstream-alternative middle ground.

The primary purpose of this dissertation is to investigate the stability of reticulated domes under multiple static and dynamic loads. Two elastic geometrically nonlinear structural models of a reticulated dome with 21 and 39 degrees of freedom are considered. The nonlinear response of the system to static loads is obtained using nonlinear programming and discrete perturbation techniques. The nonlinear programming technique is used to obtain a starting solution for the discrete perturbation technique and to optimize the choice of the perturbation parameter. Convergence criteria and error estimates to limit errors in a perturbation scheme are developed. A method for selecting a "suitable" perturbation parameter for imperfection sensitive systems is proposed. The investigation of stability of equilibrium of the system subjected to finite disturbances is based on the concept of "degree of stability" and the associated sufficient stability condition. The stability condition is derived from a theorem on extent of asymptotic stability of Liapunov's direct method of the theory of stability of motion. Its application requires the determination of the nonlinear fundamental path and the "nearest" unstable post-buckling path. This is obtained via static analysis. The perturbed motion of the system under a given set of perturbations is obtained by numerically integrating the nonlinear equations of motion. The dynamic stability tests confirm the sufficiency of the dynamic stability condition. However, they also indicate that there is a dynamic disturbance with a specific spatial distribution for which the sufficient condition of stability is also a necessary condition for each equilibrium state tested. Since in practice, the spatial distribution of the disturbances cannot be controlled, the sufficient dynamic stability condition employed is practical for the design of reticulated domes. The stability boundaries corresponding to two independent loads on the models are presented. Limit points lie on a boundary which is convex towards the region of stability. Bifurcation points lie on a continuous but piecewise differentiable boundary. Each piece of the boundary containing bifurcation points appears to be convex towards the region of stability. / Ph. D.