This thesis explores the archetypal theme of initiation in selected texts by Joseph Conrad. The Introduction first surveys critical attention to initiatory motifs in Conrad with the objective of demonstrating the need for an approach to the topic informed by a more formal and theorized understanding of initiation. It then offers a prima facie case for the centrality of the idea of initiation in Conrad's oeuvre, based on references culled from a range of the author's writings. Chapter One seeks to contextualise initiation by providing a history of anthropological research into and theorisations of the rite, proceeding to a description of its typical structure and functions. A detailed account is given of the most widely accepted model of initiation, Arnold van Gennep's tripartite schema. Moving on to Conrad's writing, Chapter Two draws on both his fiction and more personal writings in order to provide a provisional account of the writer's own understanding of initiation and its importance, and to offer some explanation of why Conrad should have been prompted to accord the motif such prominence in his work. Conrad's presentation and (impliedly) his understanding of initiation was never entirely consistent and underwent some change in the course of his writing career. The critical assessment of "Typhoon" in Chapter Three depicts Conrad's more optimistic conception of initiation as a rite benefitting both society, by promoting solidarity, and the individual, by advancing self-knowledge. Chapter Four introduces, via analyses of the novellas "Youth" and "The Shadow Line", that variation on the motif of initiation which is more typical of its manifestation in Conrad: the failure of individuals to complete their cycles of initiation. Chapter Five identifies those characteristics of initiation which appear to be determinative in the representations of incomplete initiation in Conrad's work. Initiation seems to play out approximately seven paradoxes; the impact of some of these is examined through analysis of the initiatory ordeals of the main protagonists in The Secret Agent. Integral to this discussion is an attempt to demonstrate the vital role which initiation plays in the healthy maintenance not only of social order but also of faith and life itself. The Conclusion summarises the more important findings of the study and indicates some directions for further, related research.

La mélanomagenèse est un processus complexe sous-tendu par des mécanismes cellulaires et moléculaires variés. L’ensemble de ces mécanismes moléculaires est impliqué dans les réseaux moléculaires permettant une signalisation coordonnée au sein de la cellule. De nombreuses publications montrent que les voies de signalisation MAPK et PI3K/AKT ont un rôle important dans la mélanomagenèse. NRAS et BRAF sont des oncogènes de la voie MAPK mutés respectivement dans 20% et 50% des mélanomes. PTEN est un gène suppresseur de tumeur inhibant la voie PI3K/AKT, dont la perte est souvent associée aux mutations de BRAF. Le traitement récent des mélanomes métastatiques avec les inhibiteurs spécifiques de BRAFV600E donne des résultats exceptionnels, mais ces résultats sont limités aux patients dont le mélanome est porteur de la mutation BRAFV600E, et il existe naturellement des échappements thérapeutiques, parfois lié à l’apparition de mutations NRAS. Nous avons choisi d’étudier le rôle de NRAS et de PTEN, qui sont des protéines majeures des voies MAPK et PI3K. Le but de ce travail est d’évaluer la coopération de NRAS et PTEN au cours de la mélanomagenèse. L’expression de PTEN est fréquemment altérée au cours du mélanome, mais le rôle de PTEN est mal connu. Au cours de ce travail, nous décrivons pour la première fois une mutation de NRAS concomitante à une perte de PTEN dans des prélèvements humains de mélanome et dans des lignées cellulaires humaines. Afin de comprendre l’effet de cette double mutation sur la mélanomagenèse, nous avons étudié des souris transgéniques avec expression d’une forme oncogénique de NRAS et/ou inactivation de PTEN dans le lignage mélanocytaire. L’inactivation isolée de PTEN n’a aucun effet sur la mélanomagénèse. En revanche, en association avec la mutation oncogénique de NRAS, la perte de PTEN accélère le développement des mélanomes, en réduisant le temps de latence et en provoquant l’apparition de métastases plus nombreuses en comparaison aux mélanomes présentant uniquement la mutation oncogénique de NRAS. Nous avons également démontré que la perte de PTEN induit un échappement au phénomène de sénescence. En conclusion, l’inactivation de PTEN coopère avec les mutations de NRAS pour l’initiation et la progression des mélanomes. / Melanomagenesis is a multistep process involving various cellular and molecular changes. The phospho-inositide-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways have important roles in melanoma development. Treatment with BRAF inhibitors can be highly effective against metastatic melanomas, but the effects are limited to BRAFV600E patients, and resistance often develops. PTEN and NRAS, both major components of the PI3K and MAPK pathways, are potential alternative targets for melanoma therapy. The aim of this study was to evaluate the cooperation between NRAS and PTEN during melanomagenesis. PTEN expression is frequently altered in melanoma, but the role of PTEN is not yet fully understood. We found concomitant NRAS mutation and loss of PTEN in human melanoma samples and cell lines. Then, we studied transgenic mice with inactivation of PTEN and/or expression of an oncogenic form of NRAS in the melanocyte lineage. PTEN inactivation alone had no discernible effect on melanomagenesis. However, in melanomas initiated by oncogenic NRAS, inactivation of PTEN caused more rapid melanoma development and higher metastatic rate. We demonstrate that PTEN loss induces a senescence bypass. Thus, PTEN inactivation cooperated with oncogenic NRAS to promote melanoma initiation and progression

Magister Legum - LLM / This thesis used female genital mutilation as a lens through which the effectiveness of the current laws aimed at protecting women and girls can be explored. / South Africa

Les glioblastomes (GB) sont des tumeurs cérébrales extrêmement agressives, très hypoxiques qui récidivent dans les champs d'irradiation malgré un traitement bien conduit qui associe radio et chimiothérapie. L'hypoxie tumorale et les facteurs de transcription inductibles par l'hypoxie (HIF-1alpha et HIF-2alpha) sont des facteurs importants de résistance aux thérapeutiques anti-cancéreuses, en particulier dans les glioblastomes. Récemment, un nouveau partenaire de HIF-2alpha a été identifié. Il s'agit de la protéine Int6 également connue sous le nom d'eIF3e, sous-unité " e " du facteur d'initiation de la traduction eIF3. De façon intéressante, des études ont montré que les niveaux d'expression d'eIF3e étaient associés à l'état d'avancement tumoral, dans les cancers du sein et du colon. Ces données de la littérature suggèrent que le facteur Int6/eIF3e pourrait être une cible particulièrement intéressante dans les cellules de glioblastome. Au cours de ma thèse et dans l'optique de vérifier cette hypothèse, j'ai démontré sur un plan fonctionnel que l'inhibition d'Int6/eIF3e dans différentes lignées de GB diminue la prolifération en provoquant un arrêt du cycle cellulaire en phase G1 et en augmentant la mort cellulaire, notamment par apoptose et par une augmentation des processus autophagiques. Sur un plan moléculaire j'ai mis en évidence que cette diminution de la survie des cellules de glioblastome en réponse à l'inhibition d'Int6/eIF3e est en partie causée par une réduction de l'expression des HIFs. De plus, l'étude de la biosynthèse protéique et en particulier de la traduction, via l'analyse des ARNm associés aux polysomes combinée à une analyse microarray, a permis de mettre en évidence une modulation de la traduction d'ARNm spécifiques permettant d'expliquer les phénotypes observés. Dans une perspective thérapeutique, j'ai pu démontrer que l'association de l'inhibition d'Int6/eIF3e avec les radiations ionisantes potentialise les effets de l'irradiation sur ces cellules de GB. Enfin sur un plan clinique j'ai mis en évidence une corrélation entre la perte d'expression d'Int6/eIF3e et une augmentation de la survie des patients atteints de GB. En conclusion, mes travaux de thèse ont permis de valider Int6/eIF3e comme une nouvelle cible essentielle pour la survie des cellules de glioblastome en régulant la traduction d'ARNm spécifiques. / Glioblastomas (GB) are very aggressive and malignant brain tumors, with frequent relapses despite an appropriate treatment combining surgery, chemotherapy and radiotherapy. In GB, hypoxia is a characteristic feature and activation of the Hypoxia Inducible Factors (HIF-1a and HIF-2a) has been associated with resistance to anti-cancer therapeutics. Int6, also named eIF3e, is the "e" subunit of the translation initiation factor eIF3, and was identified as novel regulator of HIF-2a. Interestingly, studies led in colon and breast cancers showed that high expression of eIF3e was correlated with a bad prognosis. These data suggest that Int6/eIF3e could become an interesting target in cancer cells and particularly in glioblastoma. During my graduate work and to assess this hypothesis, I first demonstrated at a functional level that Int6/eIF3e inhibition leads to a decreased GB cell proliferation induced by a cell cycle arrest in G1 phase and an increased cell death, especially apoptotic and autophagic processes in various GB cell lines. At the molecular level, I showed that this decreased GB cell survival in response to Int6/eIF3e inhibition was partly due to a reduction in HIFs expression. Moreover, the study of protein synthesis mechanisms, and particularly translation, via polysome-bound mRNA and microarray analyses revealed a modulation in the translation of specific subsets of mRNA, which could potentially explain our phenotypes. From a therapeutic prospect, I demonstrated that combination of Int6/eIF3e inhibition with ionizing radiations potentiates radiation effects on GB cells. Finally, immunohistochemistry studies showed that low expression of Int6/eIF3e is correlated with a longer survival for patients with GB, suggesting a potential relevance for Int6/eIF3e as a prognostic marker. In conclusion, my doctoral work allowed us to identify Int6/eIf3e as a new target essential for glioblastoma cell survival through the regulation of translation of specific mRNA subsets.

Children diagnosed with autism show marked impairments in social and communicative behaviors. According to social motivation and social orienting models of autism, decreased social interest leads to less social input and fewer social learning opportunities (Chevallier et al., 2012; Mundy & Neal, 2001). These models suggest that the ability to initiate and participate in social interactions are important factors in language development. Research in this area has focused on the role of joint attention in language development however; the current study takes a broad view of social interest and posits that not only joint attention, but all socially mediated behaviors are important in language development. The aim of the current study was (1) to evaluate a novel behavioral-coding scheme of social approach behaviors and (2) evaluate the relationship between social approach behaviors and language development. The social approach coding scheme used frequency counts of seven social behaviors emitted during an administration of the ADOS. These behaviors were coded as being either initiated by the child or occurring in response to the parent or examiner, however, no distinction was made on the basis of on the function of the behavior. Social approach rates gleaned using this novel coding scheme were correlated with existing measures of social motivation suggesting that social approach coding is capturing a similar construct as those of existing measures. Social approach rates were also used to evaluate the relationship between social behaviors and language development. The results indicated that both social initiations and social responses are important in language development. Overall, children with higher rates of both social initiations and social responses showed increased scores on language measures. The coding scheme presented provides an alternative way to quantify behaviors on the ADOS that may be used in treatment development and assessment. Given the relationship between social approach rates and language development, using this coding scheme may provide a way to determine those behaviors that are most challenging for a child so that they can be targeted in intervention to facilitate not only their social development but also language acquisition.

The prevalence of waterpipe smoking exceeds that of cigarettes among adolescents in the Middle East where waterpipe is believed as less harmful, less addictive and can be a safer alternative to cigarettes. This dissertation tested the gateway hypothesis that waterpipe can provide a bridge to initiate cigarette smoking, identified the predictors of cigarette smoking progression, and identified predictors of waterpipe smoking progression among a school-based sample of Jordanian adolescents (mean age ± SD) (12.7 ±0.61) years at baseline. Data for this research have been drawn from Irbid Longitudinal Study of smoking behavior, Jordan (2008-2011). The grouped-time survival analysis showed that waterpipe smoking was associated with a higher risk of cigarette smoking initiation compared to never smokers (P < 0.001) and this association was dose dependent (P < 0.001). Predictors of cigarette smoking progression were peer smoking and attending public schools for boys, siblings’ smoking for girls, and the urge to smoke for both genders. Predictors of waterpipe smoking progression were enrollment in public schools, frequent physical activity, and low refusal self-efficacy for boys, ever smoking cigarettes, friends’ and siblings’ waterpipe smoking for girls. Awareness of harms of waterpipe among boys and seeing warning labels on the tobacco packs by girls were protective against waterpipe smoking progression. In Conclusion, waterpipe can serve as a gateway to cigarette smoking initiation among adolescents. Waterpipe and cigarette smoking progressions among initiators were solely family-related among girls, and mainly peer-related among boys. The unique gender differences for both cigarette and waterpipe smoking among Jordanian adolescents in Irbid call for cultural and gender-specific smoking prevention interventions to prevent the progression of smoking among initiators.

Internal ribosome entry site (IRES)-mediated translation is critical for the cell’s ability to respond to stress. Understanding how RNA binding proteins (IRES trans-acting factors; ITAFs) regulate IRESes is crucial to elucidating the mechanism of alternative translation initiation. Furthermore, determining how these ITAFs are regulated is central to understanding their functions in diseased states. I have identified the tumour suppressor programmed cell death 4 (PDCD4) as a novel ITAF of the XIAP and Bcl-xL IRES elements. I demonstrate that under normal conditions, PDCD4 acts to inhibit translation from these IRES elements by preventing formation of the 48S translation initiation complex. Furthermore, I show that in response to treatment with the pro-survival fibroblast growthfactor-2 (FGF-2), S6 kinase 2 (S6K2) phosphorylates PDCD4 leading to its degradation and the subsequent de-repression of XIAP and Bcl-xL translation. Importantly, I demonstrate the clinical significance of this regulation in glioblastoma multiforme (GBM) tumours where the loss of PDCD4 expression correlates with an increase in Bcl-xL protein and poor patient outcome. Additionally, re-expression of PDCD4 down-regulates Bcl-xL and decreases cell viability, and direct inhibition of Bcl-xL by a small molecule antagonist ABT-737 sensitizes GBM cells to the chemotherapeutic doxorubicin. Finally, I demonstrate that PDCD4 can be regulated at multiple levels. Importantly, I identify the RNA binding protein HuR as a regulator of microRNA (miR) -21 induced silencing of PDCD4. I show that HuR can bind the PDCD4 3'UTR and prevent miR-21 binding, and that a loss of PDCD4 expression following H2O2 treatment is mediated via miR-21. These results provide novel insight into the role of PDCD4 as a tumour suppressor and highlight the importance of ITAFs in cancer progression.

The ability to stop ongoing movements or prevent unwanted movements is fundamental to behavioural control. This thesis addresses the neural processes underlying inhibitory control and how initiation and stop processes interact to control behaviour. We conducted four studies, employing various behavioural tasks that require humans to prepare to initiate a response with the possibility that it may have to be prevented or stopped from being initiated. In the first experiment we sought to determine whether the increase in reaction time (RT) during the performance of traditional stop-signal task was due to a decreased the amount of go-related preparatory activation. We used a startling acoustic stimulus (SAS) to determine whether the go-response could be triggered involuntarily, and investigated whether the latency of SAS responses were delayed when participants were instructed that they might have to stop their response compared to when they knew they would never stop (i.e., simple RT task). We found that the go-response was prepared in advance during the stop-signal task, but to a lesser degree as indicated by the slower SAS response latency, compared to when go trials were completed in the simple RT task. Thus, even the possibility of having to stop a response reduces the level of preparatory go-activation. The second experiment tested the hypothesis that behavioural control during a stop-signal task is determined by an independent race between go- and stop-processes. In this experiment we used a SAS to manipulate initiation and inhibition by probing the go- and stop-response prior to and after the stop-signal respectively in a stop-signal task. We found that the go-response could be triggered by the SAS even 200 ms following the stop-signal suggesting that behavioural control during a stop-signal task is not determined by an independent race between go- and stop-activations, but rather by an interaction between go-activation and stop processes. The third experiment investigated the effect of advance preparation on the ability to proactively and selectively inhibit a single limb in a bimanual response that had been cued to maybe stop. TMS was used to measure the excitability of the limb that was cued to maybe stop in comparison to the limb that was to continue with its response. In addition, a SAS was used to probe the preparatory state of the go-response in each limb. We found that increased preparatory go-activation of responses in both limbs overshadowed the neurophysiological evidence of proactive selective inhibition, while processes related to the selective stopping task appeared to suppress subcortical motor structures and the ability of the SAS to involuntarily trigger the prepared responses. The fourth experiment sought to determine the role of the right inferior frontal gyrus (rIFG) and the pre-supplementary motor area (preSMA) in the inhibition of response initiation during a go/no-go task. We temporarily deactivated rIFG or preSMA using continuous theta burst stimulation (cTBS) and examined changes in inhibition, voluntary initiation, and the ability of a SAS to involuntary trigger the initiation of the response. We found that stimulation to both cortical sites impaired participant’s ability to withhold movements during no-go trials. Notably, deactivating rIFG and preSMA did not affect voluntary initiation and did not enable the SAS to involuntarily trigger the response. These findings implicate the rIFG and the preSMA in the ability to inhibit responses during a go/no-go task, and suggests that preparation and initiation of the go-response occurs in response to the imperative stimulus, with inhibition only applied once the stimulus is identified as a no-go signal. Taken together, these studies show that i) modulation of preparatory go-activation contributes to the ability to inhibit a motor response, ii) motor response inhibition is achieved by initiation activation being prevented from reaching threshold, iii) preparatory go-activation overshadows proactive inhibition, iv) inhibitory control depends on the integrity and recruitment of top-down inhibitory control to suppress initiation activation once a no-go stimulus is identified. This research speaks to the interaction between initiation and inhibition processes and provides novel insight and evidence in support of an interactive model of inhibitory control.

Cette étude vise à comprendre de quelle manière Cormac McCarthy caractérise le cow-boy novice dans le contexte contemporain de l'Ouest américain, théâtre de la première tragédie américaine: la fermeture de la frontier. John Grady et Billy, les deux protagonistes de cette Border Trilogy, s'embarquent dans des quêtes initiatiques afin de mieux comprendre leur statut d'héros américain moderne, tiraillé entre l'héritage du mythe et de la frontier, et la modernité d'un monde qui leur échappe. Par leurs méditations, leurs cheminements, les rituels qu'ils tentent de pratiquer à mi-chemin entre mythe et réalité, les jeunes novices définissent une éthique de l'apprentissage qui justifie la violence McCarthienne, un sujet intarissable d'étude critique sur l'auteur. En s'intéressant au problème de l'initiation, cette thèse espère apporter un éclairage nouveau sur ce débat, et propose comme pistes de réflexions les problèmes d'apprentissage et de rites inachevés, la solitude du héros et sa finitude ainsi que la "finitude" narrative d'un livre qui s'achève et la finitude "artistique" du narrateur qui s'interroge sur sa responsabilité sur l'(H)istoire. / This dissertation undertakes the study of Cormac McCarthy's characterization of the cowboy hero,from his early state of innocence in the modern American West to his understanding of the first greatAmerican tragedy, the closing of the frontier. John Grady and Billy, the two main protagonists of thisBorder Trilogy, try to follow in the old pioneers' footsteps, attempting to achieve heroic status throughpublic display of bravery in a modern world that ignores them. Through their meditation, theirinitiatory journeys, and attempts to perform rites they define an ethics of experience making whichhelps justify the violence at the core of McCarthy's novels, a topic very popular in McCarthian studies.This dissertation hopes to shed light on the bond that ties initiation to violence and offers to discussproblems of experimentation and unfulfilled rituals, the hero's solitude and finitude, as well as thenarrative finitude of the book that always ends and the artistic finitude of the storyteller who also seeksanswers on his responsibility in the (hi)story.

Esta pesquisa teve como objetivo compreender o processo da Iniciação Científica (IC) enquanto um dispositivo de formação do pesquisador na graduação, analisando especificamente o modo como os textos produzidos ao longo da IC podem revelar o desenvolvimento do aluno-pesquisador. Dentre as pesquisas já realizadas sobre a IC, observamos que elas não mostraram a relação entre o pensamento a linguagem nesse percurso formativo. Por isso, tivemos, como objetivos específicos, verificar quais as marcas textuais que nos permitem compreender essa prática científica e de formação por meio da relação entre a linguagem e o pensamento. Para tanto, partimos da teoria do Interacionismo Social (VIGOTSKI, 2001, 2007, 2009) e de estudos contemporâneos acerca da teoria vigotskiana (FRIEDRICH, 2012), sobretudo da noção de funções psicológicas superiores linguagem e pensamento e sua relação na formação dos conceitos científicos. Em seguida, baseamo-nos na corrente do Interacionismo sociodiscursivo (BRONCKART, 1999, 2006, 2008a, 2008b, 2008c, 2009, 2011), que é uma atualização contemporânea do Interacionismo social e que tem entre seus objetivos estudar o papel da linguagem no desenvolvimento humano e na construção de saberes, com base emVigotski e outros autores. Como dados de pesquisa coletamos os textos que, obrigatoriamente, os estudantes devem produzir no contexto da IC, na Faculdade de Filosofia, Letras e Ciências Humanas da Universidade de São Paulo. Assim, foram coletados projetos de pesquisa, relatórios finais, apresentações orais de pesquisa com os respectivos resumos de três estudantes do curso de Letras, na habilitação de Português/Francês. Esses dados foram analisados por meio dos níveis de análise textual e discursiva proposta por Bronckart (1999) e os resultados foram discutidos por meio dos sistemas linguageiros, assim como abordados por Bronckart (2008b) e Bota (2011), pelos quais toda produção linguageira sofre três tipos de restrições: social (incluem-se aqui os mecanismos enunciativos como as vozes e as modalizações), psicológica (restrições impostas pelo uso dos tipos de discurso) e lingüística (restrições impostas pelo uso dos conectores e da coesão verbal e nominal). Como resultado da pesquisa, encontramos uma dinâmica específica entre os tipos de discurso e o gênero textual produzido, pois, a cada etapa da pesquisa, os gêneros determinavam a escolha de determinado tipo de discurso. Também verificamos que a coesão nominal pode nos fornecer resultados importantes para a análise do posicionamento do autor empírico no texto, ou seja, a emergência de um posicionamento de pesquisador. Ademais, encontramos dois tipos de vozes no decorrer da Iniciação Científica: a voz do estudante e a voz do pesquisador. A primeira, identificada nos projetos de pesquisa, tem a função de organizar a pesquisa segundo uma ideia central advinda da experiência das estudantes enquanto graduandas em Letras, na habilitação de Português/Francês. A segunda voz, delimitada nos textos finais das pesquisas, o relatório final e a apresentação oral, é a voz do pesquisador, a qual busca a regularidade nos resultados das pesquisas e os nomeia, dando-lhes um contorno conceitual por meio de uma generalização. / This research aimed to understand the process of Scientific Initiation as an educational device in the undergraduate courses, analyzing specifically how the texts produced over the Scientific Initiation can reveal the development of student-researcher. Among the research already conducted on the Scientific Initiation, we found that they did not show the relationship between language and thought. So we had, as specific objectives, to check which textual markers allow us to understand this scientific educational practice through the relationship between language and thought. The theories that underlie our study are the Social Interactionism (VIGOTSKI, 2001, 2007, 2009) and the contemporary studies of Vigotskian theory (FRIEDRICH, 2012), especially the notion of higher mental functions \"language\" and \"thought\" and their relationship in the development of scientific concepts. We also rely on the Socio-Discursive Interactionism (BRONCKART, 1999, 2006, 2008a, 2008b, 2008c, 2009, 2011), which is a contemporary branch of social interactionism and which has among its objectives to study the role of language in human development and in the construction of knowledge, based on Vigotski and other authors. As research data,we collected texts that students must produce in the context of Scientific Initiation at the Faculty of Philosophy, Letters and Human Sciences, at the University of São Paulo. So we collected research projects, final reports and oral presentations with their abstracts of three students of Letters, students of Portuguese/French languages. These data were analyzed by levels of textual and discourse analysis proposed by Bronckart (1999) and the results were discussed through the language systems concept conceived by Bronckart (2008b) and Bota (2011), by which all language production suffers three types of constraints: social (they include the enunciative mechanisms such as voices and modalizations), psychological (restrictions imposed by use of the types of discourse) and linguistic (restrictions imposed by use of connectors and verbal and nominal cohesion). As a result of the research, we found a specific dynamic between the types of discourse and the produced genre, because in every stage of the research, the genres determined the choice of a particular type of discourse. We also found that the nominal cohesion can provide us with important results for the analysis of the empirical author positions in the text, so the emergence of a researcher position. Furthermore, we find two types of voices during the scientific initiation: the voice of the students and the voice of the researcher. The first, identified in the projects, is used toto organize the research according to a central idea arising from the experience of students in the Undergraduate courses in Letters (Portuguese/ French). The second voice, found on the final texts of the research, the final report and the oral presentation, is the voice of the researcher, which seeks regularities in search results and names them, giving them a conceptual outline through a generalization.