Orientador: Peter James Harris / Banca: Lauro Maia Amorim / Banca: João Luís Cardoso Tápias Ceccantini / Resumo: Publicada em 1865 e considerada obra nonsense, Alice's Adventures in Wonderland é o livro mais conhecido de Lewis Carroll (pseudônimo de Charles Lutwidge Dodgson). Escrito e publicado no período vitoriano, Alice apresenta um cenário repleto de fantasia onde a protagonista vive suas aventuras, que são vistas por muitos leitores como algo meramente fantasioso e desprovido de lógica. A partir de leituras relacionadas à sociedade vitoriana e ao discurso histórico, percebe-se que os acontecimentos e experiências experimentados pela garota são permeados por traços irônicos relativos à sociedade em que Alice vivia. A presente dissertação propõe, com base no estudo da narrativa histórica realizado por Hayden White, particularmente a questão do tropo da ironia, o entendimento de como o discurso no Alice é relacionado a implicações da ideologia da época. No âmbito da História da época e das técnicas discursivas utilizadas pelo autor o presente trabalho resgata alguns dos aspectos históricos ironizados por Carroll, utilizando não somente os estudos relacionados à linguagem e aos modos de elaboração de enredo de Hayden White (1994, 1995), mas também a história dos princípios educacionais da Inglaterra vitoriana, de Morais (2004) / Abstract: Published in 1865 and considered a work nonsense, Alice's Adventures in Wonderland is the best-known book by Lewis Carroll (pen-name of Charles Lutwidge Dodgson). Written and published in the Victorian period, Alice is set in a fantastic scenario where the protagonist's adventures take place, and the book is seen by many readers as something merely fanciful and illogical. From readings related to Victorian society and historical discourse, it is clear that the events and experiences lived by the girl are permeated by ironic traces related to the society of Alice's day. The present dissertation, based on Hayden White's study of historical narrative, particularly the question of the trope of irony, proposes an understanding of how Carroll's discourse in Alice is related to implications of the prevailing ideology. In the context of the history of the period and of the discursive techniques used by the author the present study examines some of the historical aspects satirised by Carroll, utilising not only Hayden White's studies of language and modes of plot development (1994, 1995), but also Morais's history of the principles of Victorian education, Morais (2004) / Mestre

Parmi les couples avec un projet parental, le facteur masculin d’infertilité est responsable d’environ 20%. Malgré de longues années d’activités d’assistance médicale à la procréation, un nombre important de cas reste idiopathiques. Considérant le nombre élevé des gènes potentiellement impliqués dans la gamétogenèse, il est fort probable que la majorité des formes ‘idiopathiques’ sont d’origine génétique. Dans l'étude présente, nous avons d’identifier deux nouveaux gènes impliqués dans une infertilité masculine. Nos données suggèrent que la mutation dans TEX15 puisse corréler avec une diminution du nombre de spermatozoïdes au fil du temps. Un test diagnostique identifiant la mutation chez un patient pourrait fournir une indication d’organiser au plus tôt une cryopréservation du sperme. On a aussi identifié MAGEB4 liées à l’X comme un nouveau gène impliqué dans une infertilité masculine héritée. Cette étude fournit le premier indice sur la fonction physiologique d'une protéine MAGE. / Among couples with a desire for a child, male factor is responsible approximately 20%. Despite long years of assisted reproductive activities, a significant number of cases remain idiopathic. Considering the high predicted number of genes involved in male gametogenesis, it is likely that most ‘idiopathic’ forms may have a genetic origin. In the present study, we have defined two new genes implicated in male infertility. Our data suggested that a nonsense mutation in TEX15 correlates with a decrease in sperm count over time. A diagnostic test identifying the mutation in man could provide an indication of spermatogenic failure and prompt patients to undertake sperm cryopreservation at an early age. We also identified MAGEB4 as a new X-linked gene involved in an inherited male infertility. This study provides the first clue on the physiological function of a MAGE protein.

No description available.

Entre 10% et 30% des maladies humaines sont liées à l'apparition d'une mutation non-sens (PTC). La synthèse protéique est alors arrêté prématurément. Cet arrêt peut être inhibé par des molécules inductrices de translecture qui permettent l’incorporation d’un ARNt suppresseur naturel au niveau du PTC (translecture). Le ribosome peut alors franchir le PTC et restaurer l’expression de la protéine.Au cours de ma thèse, je me suis intéressé à la suppression des codons stop en caractérisant de nouvelles molécules inductrices de translecture et en analysant les mécanismes de la fidélité de la traduction.J’ai tout d’abord mis au point un système de criblage innovant avec lequel j’ai testé plus de 17 000 molécules et identifié la molécule TLN468. J’ai pu mettre en évidence que cette molécule est capable d’induire la réexpression d’une protéine p53 active.J'ai aussi caractérisé de nouveaux composés dérivés d’aminoglycosides. J’ai pu montré que le NB124 est capable d’induire l’apoptose de cellules tumorales via la réexpression de la protéine p53 tout ayant une toxicité bien plus faible que la gentamicine.En parallèle, j’ai développé une approche en molécule unique permettant d’étudier les erreurs programmées du ribosome (recodage). J’ai ainsi pu analyser la cinétique d’élongation des ribosomes eucaryotes et montré que l’initiation de la traduction sur un site d’entrée interne (IRES) ralentit le ribosome lors des premiers cycles d’élongation. / Nonsense mutations, also known as premature termination codons (PTCs) are responsible for 10% to 30% of all human genetic diseases. Nonsense translation suppression can be induced by readthrough inducers. The presence of such PTC leads to premature translation termination. These stop therapeutic strategies have emerged which attempt to use molecules that facilitate tRNA incorporation at the PTC (readthrough). The, translation continue in the same reading frame until the next stop codon. I first developed an innovative screening system I used to test more than 17,000 molecules and have identified one hit, TLN468 molecule. I have shown that this molecule is able to induce re-expression of an active p53 protein.I also characterized new compounds derived from aminoglycosides. I have shown that the NB124 induces apoptosis of tumor cells by re-expressing p53 protein while having a much lower toxicity than gentamicin.I developed a single molecule approach for studying the ribosome programmed errors (recoding). I was able to analyze the kinetics of elongation eukaryotic ribosomes and showed that the initiation of translation at an internal entry site (IRES) slows the ribosome during the first elongation cycle.

Dbp2p, a member of the large family of DEAD-box proteins and a yeast homolog of human p68, was shown to interact with Upf1p, an essential component of the nonsense-mediated mRNA decay pathway. Dbp2p:Upf1p interaction occurs within a large conserved region in the middle of Upf1p that is largely distinct from its Nmd2p and Sup35/45p interaction domains. Deletion of DBP2, or point mutations within its highly conserved DEAD-box motifs, increased the abundance of nonsense-containing transcripts, leading us to conclude that Dbp2p also functions in the nonsense-mediated mRNA decay pathway. Dbp2p, like Upf1p, acts before or at decapping, is predominantly cytoplasmic, and associates with polyribosomes. Interestingly, Dbp2p also plays an important role in rRNA processing. In dbp2Δ cells, polyribosome profiles are deficient in free 60S subunits and the mature 25S rRNA is greatly reduced. The ribosome biogenesis phenotype, but not the mRNA decay function, of dbp2Δ cells can be complemented by the human p68 gene. We propose a unifying model in which Dbp2p affects both nonsense-mediated mRNA decay and rRNA processing by altering rRNA structure, allowing specific processing events in one instance and facilitating dissociation of the translation termination complex in the other.

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

L’errance est thématiquement présente dans le théâtre irlandais du début du XXe siècle. Le personnage errant est tout d’abord un moyen pour le dramaturge d’explorer et de dénoncer la perte ressentie par le peuple irlandais. Les vagabonds mis en scène expriment également le questionnement métaphysique de l’homme sur terre. Dans la Seconde moitié du siècle, l’errance infiltre la structure de la pièce, qu’il s’agisse de pièces irlandaises ou anglaises. Elle demeure, à travers le siècle, un thème de prédilection pour explorer les traumatismes, qu’ils soient économiques, politiques ou éthiques. La crise de valeurs du XXe siècle trouve écho sur des scènes théâtrales qui n’ont de cesse de questionner les certitudes, et qui mettent au jour la « déroute » du sens. L’ampleur et l’évolution de l’errance, à la fois thématique et structurelle, à travers des œuvres dramatiques étalées sur tout le XXe siècle, permettent de confirmer l’existence d’une dramaturgie de l’errance. Forte d’un siècle de remise en cause des certitudes, celle-ci se dessine à travers de nombreux exemples tirés des scènes anglaises et irlandaises du XXe siècle. / Thematically speaking, wandering and erring are particularly noticeable in early XXth century Irish drama. Playwrights stage vagrants, tramps, and Tinkers as a means to explore the loss felt by a large part of the Irish population throughout history. These characters also express metaphysical questions which will be echoed in the second half of the century. From being rather important themes, wandering and errancy gradually invade the very structure of the plays, be they Irish or British. Wandering has remained a major way of exploring trauma-related situations, be they economical, political or ethical. As the stage keeps questioning certainties, directions and sense are played with. The thematical and structural roles of wandering onstage highlight the widespread existence of a skeptical dramaturgy debunking trust and conviction.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron death and subsequent muscle atrophy. Approximately 15% of ALS cases are inheritable, and mutations in the Fused in Sarcoma (FUS) gene contribute to approximately 5% of these cases, as well as about 2% of sporadic cases. FUS performs a diverse set of cellular functions, including being a major regulator of RNA metabolism. FUS undergoes liquid- liquid phase transition in vitro, allowing for its participation in stress granules and RNA transport granules. Phase transition also contributes to the formation of cytoplasmic inclusions found in the cell bodies of FUS ALS patients motor neurons. The nature of these inclusions has remained elusive, as the proteins localized to them have not been identified. Additionally, the functional consequence of the accumulation of cytoplasmic FUS inclusions has not been established, nor is it understood how they contribute to selective motor neuron death. We carried out two related, but independent studies to characterize the proteins that may be included in FUS-positive inclusions. In this first study, we utilized immunoprecipitation of wild-type and mutant FUS in the presence and absence of RNase, followed by LC MS/MS. The identified proteins represent those that directly or indirectly interact with FUS, with relatively high affinity that can be pulled down with immunoprecipitation. A wide variety of interacting proteins were identified and they are involved in a multitude of pathways including: chromosomal organization, transcription, RNA splicing, RNA transport, localized translation, and stress response. Their interaction with FUS varied greatly in their requirements for RNA. Most notably, FUS interacted with hnRNPA1 and Matrin-3, proteins also known to cause familial ALS. Immunofluorescent staining of proteins interacting with mutant FUS were localized to cytoplasmic inclusions. We concluded that mis-localization of these proteins potentially lead to their dysregulation or loss of function, thus contributing to FUS pathogenesis. In the second study, we developed a protocol to isolate dynamic FUS inclusions and employed LC MS/MS to identify all proteins associated with FUS inclusions. We identified a cohort of proteins involved in translation, splicing, and RNA export to be associated with the FUS inclusions. Further pathway and disease association analysis suggested that proteins associated with translation and RNA quality control pathways may be the most significant. Protein translation assays using both N2A and ALS patient fibroblasts demonstrated suppression of protein biosynthesis in mutant FUS expressing cells. However, translation initiation was not impaired. To understand how protein synthesis is suppressed by mutant FUS mediated defects in RNA metabolism, we examined changes in a well conserved RNA turnover pathway namely: nonsense mediated decay (NMD). We found that NMD is hyperactivated in cells expressing mutant FUS, likely due to chronic suppression of protein translation shifting the pathways autoregulatory circuit to allow for hyperactivation. We concluded that mutant FUS suppresses protein biosynthesis and disrupts NMD regulation. These defects together likely contribute to motor neuron death.

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

Conselho Nacional de Desenvolvimento Científico e Tecnológico / The goal of this dissertation is to examine the claim of the penultimate aphorism of the Tractatus Logico-Philosophicus, according to which the propositions of the book elucidate if the reader understands the author and acknowledge that they do not make sense, because they are absurd. Thus, the work tries to put into relief some of the central issues of dispute between the interpretive trends, observing the problematic aspects of each line of interpretation, as well as the way in which his supporters articulate their ideas against the prospects of his opponents. To do so, we analyze the two interpretations of the aphorism 6:54. For the standard reading, Wittgenstein discusses issues that the work itself says are ineffable, but there is a substratum of truth which subsists claim of nonsensity. If the standard reading is correct, after the process elucidating the reader reaches a logically correct view of the world, and is in possession of some truths that only show up on the legitimate use of language. As for the revisionist reading, there is no hidden meaning in the work, but only and solely nonsense, do not say anything. The process of elucidating it is a philosophical exercisetherapy. If correct, the revisionist interpretation suggests that the goal of the work is a change in the mode of being of the reader in his relationship with nonsense. Accordingly, from the revisionist reading of Michael Kremer holds up nonsensity an acceptance of the work in line with a positive understanding for contrassensos book. The recognition of the tractarian nonsense as such is the purpose of the work, and this recognition has the ethical purpose. The purpose of the Tractatus is ethical philosophical attitude change front to ultimate foundations for either language, either for ethics. If Kremer is correct, it leads to an alternative nondestructive to the tractarian nonsense, showing that despite their nonsensity, the tractarian absurdities may be useful therapeutically. Thus, it is possible to reconcile tractarian nonsense with his elucidation process and understand how a book composed of absurdities can be useful philosophically. / O objetivo da presente dissertação é analisar a reivindicação do penúltimo aforismo do Tractatus Logico-Philosophicus, segundo a qual as proposições do livro elucidam, caso o leitor entenda o seu autor e reconheça que elas não fazem sentido, pois são absurdas. Assim, o trabalho tenta colocar em relevo algumas das questões centrais da disputa entre as correntes interpretativas, observando os aspectos problemáticos de cada linha de interpretação, bem como o modo segundo o qual seus partidários articulam suas ideias contra as perspectivas de seus adversários. Para tanto, analisa-se as duas interpretações do aforismo 6.54. Para a leitura padrão, Wittgenstein aborda assuntos que a própria obra afirma serem inefáveis, mas há um substrato de verdades que subsiste a reivindicação de contrassensualidade. Se a leitura padrão é correta, ao cabo do processo elucidativo o leitor alcança uma perspectiva logicamente correta do mundo, e fica de posse de algumas verdades que somente se mostram no uso legítimo da linguagem. Já para a leitura revisionista, não há nenhum sentido oculto sob a obra, mas apenas e tão somente contrassensos, que não dizem nada. O processo de elucidação se constitui um exercício filosófico-terapêutico. Se correta, a interpretação revisionista propõe que o objetivo da obra é uma mudança no modo de ser do leitor em sua relação com contrassensos. Nesse sentido, a partir da leitura revisionista de Michael Kremer sustenta-se uma aceitação da contrassensualidade da obra em consonância com uma compreensão positiva para os contrassensos do livro. O reconhecimento dos absurdos tractarianos enquanto tais é o objetivo da obra, e esse reconhecimento tem finalidade ética. A finalidade ética do Tractatus é mudar atitude filosófica frente a fundamentações ultimas, quer para a linguagem, quer para ética. Se Kremer está correto, ele conduz a uma alternativa não autodestrutiva para os absurdos tractarianos, mostrando que não obstante sua contrassensualidade, os absurdos tractarianos podem ser terapeuticamente úteis. Dessa forma, é possível conciliar a contrassensualidade tractariana com seu processo de elucidação e entender como um livro composto de absurdos pode ser de utilidade filosófica.