L’interaction d’un ligand avec un récepteur à sept domaines transmembranaires (7TMR) couplé aux protéines G, mène à l’adoption de différentes conformations par le récepteur. Ces diverses conformations pourraient expliquer l’activation différentielle des voies de signalisation. Or, le lien entre la conformation et l’activité du récepteur n’est pas tout à fait claire. Selon les modèles classiques pharmacologiques, comme le modèle du complexe ternaire, il n’existe qu’un nombre limité de conformations qu’un récepteur peut adopter. Afin d’établir un lien entre la structure et la fonction des récepteurs, nous avons choisi dans un premier temps, le récepteur de chimiokine CXCR4 comme récepteur modèle. Ce dernier, est une cible thérapeutique prometteuse, impliqué dans l’entrée du VIH-1 dans les cellules cibles et dans la dissémination de métastases cancéreuses. Grâce au transfert d’énergie par résonance de bioluminescence (BRET) nous pouvons détecter les changements conformationnels des homodimères constitutifs de CXCR4 dans les cellules vivantes. En conséquence, nous avons mesuré les conformations de mutants de CXCR4 dont les mutations affecteraient sa fonction. Nous montrons que la capacité des mutants à activer la protéine Galphai est altérée suite au traitement avec l’agoniste SDF-1. Notamment, ces mutations altèrent la conformation du récepteur à l’état basal ainsi que la réponse conformationnelle induite suite au traitement avec l’agoniste SDF-1, l’agoniste partiel AMD3100 ou l’agoniste inverse TC14012. Ainsi, différentes conformations de CXCR4 peuvent donner lieu à une activation similaire de la protéine G, ce qui implique une flexibilité des récepteurs actifs qui ne peut pas être expliquée par le modèle du complexe ternaire (Berchiche et al. 2007). Également, nous nous sommes intéressés au récepteur de chimiokine CCR2, exprimé à la surface des cellules immunitaires. Il joue un rôle important dans l’inflammation et dans des pathologies inflammatoires telles que l’asthme. CCR2 forme des homodimères constitutifs et possède différents ligands naturels dont la redondance fonctionnelle a été suggérée. Nous avons étudié le lien entre les conformations et les activations d’effecteurs (fonctions) de CCR2. Notre hypothèse est que les différents ligands naturels induisent différentes conformations du récepteur menant à différentes fonctions. Nous montrons que les réponses de CCR2 aux différents ligands ne sont pas redondantes au niveau pharmacologique et que les chimiokines CCL8, CCL7 et CCL13 (MCP-2 à MCP-4) sont des agonistes partiels de CCR2, du moins dans les systèmes que nous avons étudiés. Ainsi, l’absence de redondance fonctionnelle parmi les chimiokines liant le même récepteur, ne résulterait pas de mécanismes complexes de régulation in vivo, mais ferait partie de leurs propriétés pharmacologiques intrinsèques (Berchiche et al. 2011). Enfin, nous nous sommes intéressés au récepteur de chimiokine CXCR7. Récemment identifié, CXCR7 est le deuxième récepteur cible de la chimiokine SDF-1. Cette chimiokine a été considérée comme étant capable d’interagir uniquement avec le récepteur CXCR4. Notamment, CXCR4 et CXCR7 possèdent un patron d’expression semblable dans les tissus. Nous avons évalué l’effet de l’AMD3100, ligand synthétique de CXCR4, sur la conformation et la signalisation de CXCR7. Nos résultats montrent qu’AMD3100, tout comme SDF-1, lie CXCR7 et augmente la liaison de SDF-1 à CXCR7. Grâce au BRET, nous montrons aussi qu’AMD3100 seul est un agoniste de CXCR7 et qu’il est un modulateur allostérique positif de la liaison de SDF-1 à CXCR7. Aussi, nous montrons pour la première fois le recrutement de la beta-arrestine 2 à CXCR7 en réponse à un agoniste. L’AMD3100 est un ligand de CXCR4 et de CXCR7 avec des effets opposés, ce qui appelle à la prudence lors de l’utilisation de cette molécule pour l’étude des voies de signalisation impliquant SDF-1 (Kalatskaya et al. 2009). En conclusion, nos travaux amènent des évidences qu’il existe plusieurs conformations actives des récepteurs et appuient les modèles de structure-activité des récepteurs qui prennent en considération leur flexibilité conformationnelle. / Ligand binding to 7TMRs is thought to induce conformational changes within the receptor that translate into activation of downstream effectors. The link between receptor conformation and activity is still poorly understood, as current models of receptor activation fail to take an increasing amount of experimental data into account. Classical pharmacological models such as the ternary complex model are based on the concept that receptors can only adopt a limited number of conformations. To clarify structure-function relationships in 7TMRs, first we studied chemokine receptor CXCR4. This receptor is an important drug target, involved in HIV-1 entry and cancer metastasis. Bioluminescence Resonance Energy Transfer (BRET) allows us to directly probe conformational changes within pre-formed CXCR4 homodimers in live cells. Using BRET, we measured the conformation of CXCR4 mutants and we also monitored their function by measuring their ability to induce Galphai activation. The analyzed mutants had substitutions in locations which are pivotal molecular switches for receptor conformation and activation. We show that agonist induced Gi activation is altered for most mutants. These mutations also alter CXCR4’s conformation at basal conditions (in absence of ligand) and in the presence of the agonist, SDF-1, the partial agonist, AMD3100 and the inverse agonist, TC14012. Moreover, different conformations of active receptors were detected in the presence of SDF-1, suggesting that different receptor conformations are able to trigger Galphai activity. These data provide biophysical evidence for different active receptor conformations, that cannot be explained by classical models of receptor function (Berchiche et al. 2007). Furthermore, the second part of our work focused on chemokine receptor CCR2. Mainly expressed on immune cells, CCR2 is involved in many inflammatory and vascular diseases. This receptor binds seven natural ligands that have been referred to as redundant. We set out to explore whether the different chemokine ligands of CCR2 receptor induce different conformational changes leading to different functional consequences. Our results show that the different natural ligands of CCR2 are not pharmacologically redundant. Moreover, chemokines CCL8, CCL7 and CCL13 (MCP-2 to MCP-4) are partial agonists of CCR2, at least in the systems we used. Our results support the validity of models for receptor-ligand interactions in which different ligands stabilize different receptor conformations also for endogenous receptor ligands, demonstrating that these natural ligands are not pharmacologically and functionally redundant (Berchiche et al. 2011). As the third part of this work, we studied chemokine receptor CXCR7, the alternative receptor for SDF-1. Until recently, CXCR4 was the only receptor known to bind SDF-1. Moreover, the expression patterns are similar for receptors CXCR4 and CXCR7. Therefore, we investigated the conformational and functional consequences of the synthetic inhibitor of CXCR4, AMD3100, on CXCR7. We show that AMD3100 also binds the alternative SDF-1 receptor, CXCR7. SDF-1 or AMD3100 alone trigger beta-arrestin recruitment to CXCR7, which we identify as a previously unreported signalling pathway of CXCR7. In addition, AMD3100 has positive allosteric effects on SDF-1 binding to CXCR7, on SDF-1-induced conformational rearrangements in the receptor dimer as measured by BRET, and on SDF-1-induced beta-arrestin recruitment to CXCR7. The finding that AMD3100 not only binds CXCR4, but also to CXCR7, with opposite effects on the two receptors, call for caution in the use of this compound as a tool to dissect SDF-1 effects on the respective receptors in vitro and in vivo. Finally, these data provide biophysical evidence for different active receptor conformations, and support models of 7TMR structure-activity relationships that take conformational heterogeneity into account.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

This thesis argues that consumerism and the mass media wield an unparalleled influence over contemporary North American society, and that these forces constitute the primary means through which identity is constituted. The historical and theoretical developments that have led to the foregrounding of these forces are outlined in the introduction - developments, it is argued, that are intrinsically connected to the social upheava1 that characterized America in the late 1960's and early 1970's, while their presence in and effects on the fiction of four contemporary North American writers - Thomas Pynchon, Don DeLillo, Bret Easton Ellis and Douglas Coupland - are examined in the main body of the thesis. Chapter I focuses on Pynchon whose novels, it is argued, are the product of a uniquely post-1960's America, which mourns the sacrifice of traditional ideals to the corporate mindset which has been prevalent since ths 1980's Pynchon's dominant metaphor for the direction in which he believes American society to be moving is the thermodynamic concept of entropy, which stipulates that all prqress is towards death. His novels abound with characters who disintegrate due to the information overload fostered by their media-based world. However, he retains his faith that a return to historical values and traditions will stem and even reverse the entropic tide DeLillo, a close contemporary of Pynchon's, draws on a different aspect of the legacy of the 1960's, for his writing is overshadowed by the 1963 assassination of President Kennedy and the years of turbulence that ensued. His novels are ultimately more pessimistic because his characters do not succeed in escaping from the repressive narratives of consumerism and the mass media in order to reassert their own personalities. One reason for this failure, it is argued, is that DeLillo's characters represent a metaphorical dramatization of the dichotomy between the modernist desire for structure and the postmodernist embrace of fluidity and uncertainty. The fictional characters of the younger authors, Ellis and Coupland, inhabit this postmodern world where all experience has been rendered depthless and traditional ontological and epistemological certainties have been collapsed Ellis' characters fluctuate between the extremes of apathy and violence as they search for a way of preventing their psyches from disintegrating amidst the surrounding chaos. Neither one of these options brings - any relief. Coupland is more optimistic about the ability of his characters to survive and even prosper in the contemporary world. He arms them with the linguistic and technological skills necessary to adapt to the rapid social and technological changes. Most importantly of all, he draws on the sense of objectivity fostered by his own background as a Canadian in order to provide them with an alternative and a sense of escape from the media-saturated environment of the American West Coast. What is perhaps most remarkable about these four authors as a group is that in spite of their obvious insight into the nature of the contemporary postmodern world, they are unwilling - or perhaps even unable - to fully relinquish their hold on a number of traditional metanarratives, most notably the ideal of the stable, supportive family unit. This implies a degree of uncertainty and perhaps even of fear on their parts about fully committing to the fluidity of contemporary culture.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

This dissertation studies a group of contemporary Anglo-American novelists who contribute to the development of a new humanism after the postmodern critique of Euro-American culture. As such, these writers respond to positions in twentieth-century philosophy that converge in a call for silence which has an ontological as well as ethical valence: as a way of rigorously thinking the ‘outside’ to language, it avoids charges of metaphysical inauthenticity; as an ethical stance in the wake of the Shoah, it eschews a complicity with the reifications of modern culture. How to reconcile this post-metaphysical promise with the politico-aesthetic inadequacy of speechlessness is the central question for this nexus of novelists—David Markson, Bret Easton Ellis, David Foster Wallace, and Zadie Smith—at the center of which the study locates Wallace as a key figure of contemporary literature. By reconstructing the conversation among these authors, this dissertation argues that the nexus writers turn to indirect means of representation that do justice to the demand for silence in matters of metaphysics, but also gesture past it in the development of a neo-romantic aesthetics that invites the humanist category of the self back onto the scene after its dismissal by late postmodernism. The key to such indirection lies in an aporetic method that inspires explorations of metaphysical assumptions by seducing readers to an ambiguous site of aesthetic wonder; in conversation with a range of contemporary philosophers, the dissertation defines this affective site as a place of proximity, rather than absorption or detachment, which balances out the need for metaphysical distance with the productive desire for a fullness of experience. Such proximate aesthetic experiences continue the work of ‘doing metaphysics’ in post-metaphysical times by engaging our habitual responsiveness to the categories involved. Hence the novels discussed here stage limit cases of reason such as the unknowable world, the unreachable other, the absence of the self, and the unstable hierarchy between irony and sincerity: Markson’s Wittgenstein’s Mistress imagines skepticism as literal abandonment and reminds us of our metaphysical indebtedness to a desired object/world; Ellis’s American Psycho shows the breakdown of communication due to a similarly skeptical vision of human interaction and presents a violence that tries to force a response from the desired subject/person; Wallace’s Infinite Jest creates a large canvas on which episodes of metaphysical and literal ‘stuckness’ afford possibilities for becoming human; Smith’s The Autograph Man, finally, pays attention to gestural language at the breaking point of materialism and theology, nature and culture, tragedy and comedy. / Graduate / 2020-08-01

No description available.

“American Impotence” investigates a continuity between literary representations of masculinity and considerations of national identity in the works of five postwar novelists. In particular, I illustrate the manner in which Ralph Ellison’s Invisible Man, John Updike’s Couples, Robert Coover’s The Public Burning, Joan Didion’s Democracy and The Last Thing He Wanted, and Bret Easton Ellis’s American Psycho challenge the patterns of daily life through which a single figure is imagined to be the essential agent of American polity: namely, the self-made individualist, characterized by manly virtues like dominance, aggression, ambition, mastery, vitality, and virility. More specifically, this project examines the manner in which the iconicity of men helps sustain a narrative of “imperilled masculinity” that at once privileges an impossible identity, situated in the representative nucleus of postwar democracy, and forecloses other modalities of political life. Observing the full meaning of the word “potency,” I elucidate the interrelationships between narrative forms, masculine norms, and democratic practice. Ellison’s work ties the maturation of African American boys to the impossibility of full participation in civic life, for instance, while in Updike’s Couples the contradictions of virile manhood manifest in the form of a fatalism that threatens to undo the carefully cultivated social boundaries of early sixties bohemianism; in a variety of ways, The Public Burning and American Psycho represent the iconic nature of masculinity as a psychic threat to those men closest to it, while Didion’s female protagonists find themselves flirting with the promises of a secret agency linked to imperial adventures in Southeast Asia and Central America. In the cultural context of the Cold War, these novelists demonstrate how intensified participation in national fantasies of potency and virility is inevitably disempowering; as an alternative, this dissertation seeks to consider impotence as dissensus detached from the mandates of hegemonic masculinity.

“American Impotence” investigates a continuity between literary representations of masculinity and considerations of national identity in the works of five postwar novelists. In particular, I illustrate the manner in which Ralph Ellison’s Invisible Man, John Updike’s Couples, Robert Coover’s The Public Burning, Joan Didion’s Democracy and The Last Thing He Wanted, and Bret Easton Ellis’s American Psycho challenge the patterns of daily life through which a single figure is imagined to be the essential agent of American polity: namely, the self-made individualist, characterized by manly virtues like dominance, aggression, ambition, mastery, vitality, and virility. More specifically, this project examines the manner in which the iconicity of men helps sustain a narrative of “imperilled masculinity” that at once privileges an impossible identity, situated in the representative nucleus of postwar democracy, and forecloses other modalities of political life. Observing the full meaning of the word “potency,” I elucidate the interrelationships between narrative forms, masculine norms, and democratic practice. Ellison’s work ties the maturation of African American boys to the impossibility of full participation in civic life, for instance, while in Updike’s Couples the contradictions of virile manhood manifest in the form of a fatalism that threatens to undo the carefully cultivated social boundaries of early sixties bohemianism; in a variety of ways, The Public Burning and American Psycho represent the iconic nature of masculinity as a psychic threat to those men closest to it, while Didion’s female protagonists find themselves flirting with the promises of a secret agency linked to imperial adventures in Southeast Asia and Central America. In the cultural context of the Cold War, these novelists demonstrate how intensified participation in national fantasies of potency and virility is inevitably disempowering; as an alternative, this dissertation seeks to consider impotence as dissensus detached from the mandates of hegemonic masculinity.

Thesis (MA)--University of Stellenbosch, 2007. / Bibliography. Also available via the Internet.

My thesis discusses male identity in contemporary culture in relation to work by Bret Easton Ellis and Chuck Palahniuk. Such work reflects the problems, anxieties, and dilemmas of the masculine subject in American culture. The characters in my six selected texts, namely, Ellis' Less Than Zero, American Psycho, and Glamorama, and Palahniuk's Fight Club, Survivor, and Choke, symbolize a generation with no discernible future. Each male protagonist finds himself in a place of no time and no meaning because image and illusion have supplanted essence. These characters combat culture-prevalent emptiness in the sense that each ironically re-asserts his so-called individuality against the dogmas of the establishment. Each, furthermore, is aware that his existence is not subject to a higher order or preset goal: traditional morality thereby has no meaning. My selected texts feature masculine subjects struggling with their own contingencies once stripped of given privileges (gender, class, race, and otherwise). To examine the notion of masculinity, I emphasize the role of power relations in gender construction. Bret Easton Ellis characterizes a world of appearance defined by particular styles. Chuck Palahniuk's males are empty--they do not have any definitive meaning. Judith Butler challenges the proposition of a fixed identity, or an essential permanent masculinity or femininity as structured and reified by social norms. Therefore, we should not view masculinity as a cohesive and homogeneous category. Following Foucault, I examine the relationship between masculine subjects and social practices. At stake here, is how the performative articulation of proper masculinity disempowers and imprisons the masculine subject in a material form over which he has no control. The body becomes the object of desire and thus the vehicle/preserve of the sense of powerlessness that the masculine subject experiences daily within a hegemonic culture. Power is exercised through a dominant presence. This presence structures as a binary classification serving to underscore differences and ensure particular privileged social positioning. The proposition of a fixed identity, or an essential permanent masculinity or femininity, is structured and reified by social norms. Masculinity as a cohesive and homogeneous category is historically represented as an unstable center from which all other identities are defined.