RA is a chronic and disabling disease with no known cure. The disease has a strong genetic component and modern genetic studies have successfully identified over 100 loci associated with the onset of RA. Despite the number of associations identified, the full genetic component of RA is not known, and for the majority of the loci the causal variant remains unknown. The overall aim of this study was to utilise well-powered genetic data, in order to identify novel loci, refine genetic associations, and generate robust evidence for the causal SNP and causal gene at a selected RA locus. An initial analysis was undertaken utilising 3870 RA cases and 8430 controls from the UK-ImmunoChip, a study designed for comprehensive fine-mapping of confirmed RA susceptibility loci. Analysis of the UK-ImmunoChip data identified a novel finding with the TYK2 locus, and proved informative to refining association signals, illustrating the utility of fine-mapping and implicated SNPs with putative regulatory function. The UK-ImmunoChip was subsequently expanded to incorporate samples from five additional cohorts in a study led by Dr. Stephen Eyre. In additional to novel loci discovery, this study provided evidence for SNPs putatively associated with RA (P smaller or equal to5E-05 < 5E-08). In a combined meta-analysis of 17,581 cases and 20,160 controls, convincing evidence was obtained for two novel RA loci, BACH2 and RAD51B.The newly identified genes implicate two novel pathways in RA (B-cell differentiation and DNA repair) and add to the growing number of loci associated with multiple AIDs. These findings are important to aid comprehensive pathway analysis and add to the knowledge of RA risk genes. The third most associated RA locus in both serological subtypes of disease, with an uncharacterised protein, ANKRD55, was subsequently selected for in-depth characterisation. Utilising genetic and haplotypic analysis the association at this locus was refined to a single signal, with four SNPs in strong LD (r2 > 0.8). Through bioinformatic analysis, two SNPs rs6859219 and rs10065637 showed evidence for functional activity, with evidence of being located in an enhancer element, supported by histone marks, DNAse hypersensitivity, evidence of transcription factor binding and eQTL. The use of RNA and ChIP experiments have established a testable hypothesis that the presence of the putative causal variants rs6859219 and rs10065637, act to weaken the strength of the enhancer element in which they are located, (evidenced by diminished H3k4me1 modification), which in turn down-regulates the transcriptional output of the target gene ANKRD55 (evidenced by eQTL in both whole blood and CD4+ T cells).In summary this study has led to the identification of three novel loci, highlighted the importance of fine-mapping and developed a successful systemic strategy for the characterisation of the 5q11 risk locus associated with RA.

Cette étude se propose de cerner le statut particulier du roman de Rousseau dans l'ensemble de son œuvre, et pas seulement du point de vue du genre littéraire. Rousseau envisage deux sortes de croyances : d'une part celle qui relève spécifiquement de la religion ; d'autre part celles qui ressortissent aux valeurs purement mondaines (avoir, pouvoir et gloire). Dans son œuvre philosophique, validant la première, Rousseau condamne radicalement les secondes. La présente étude vise à montrer que le roman, en accord avec l'œuvre philosophique sur la religion, se trouve dans une position infiniment plus ambiguë quant aux valeurs mondaines (en particulier le pouvoir et la gloire). / Rousseau aims at defining the particular status of Rousseau's novel in his whole work, as regards his literary genre but also others perspectives. Rousseau considers two sorts of beliefs : one pertaining to religion specifically and the other having to do with purely mundane values (possession, power and glory). In his philosophical work, he approves the former and absolutely condemns the latter. This study aims to show that the novel, which matches the philosophical works regarding religion, has a much more amiguous position as far as mundane values are concerned (particularly power and glory).

The aim of the diploma thesis The Picture of a Journalist in the 20th century British novel is to map the space dedicated to characters of journalists in literature, the 20th century British novels in particular. Depiction of the journalistic characters is based on fifteen selected literary works within three different novel types - comic novel, detective novel and social-critical novel. Using a detailed analysis of a sum of both the narrative and the extra-literary elements the thesis compares various characters of male and female journalists appearing in the selected novels. It tries to compare the differences as well as the similarities within portrayals of journalists in different novel types. As a conclusion the thesis evaluates the overall picture of journalists in these works and attempts to trace any similarities or recurring trends in depiction of journalists in literature.

A teoria semiótica de linha francesa, em seu início, tinha como preocupação maior as questões do inteligível, quando Greimas propôs um percurso gerativo do sentido capaz de dar conta dos diversos sistemas de significação. Entretanto, com o passar do tempo, as questões da ordem do sensível e do afeto se colocaram como um desafio para os analistas e pediram espaço na teoria trazendo textos em que a narrativa não era central. Claude Zilberberg, em especial, é um dos autores que caminha na direção de propor a primazia do sensível em relação ao inteligível com os recursos do que veio a se chamar semiótica tensiva. Acompanhando o movimento feito tanto pela teoria quanto pela literatura, nossa dissertação tem como objeto um romance experimental, Catatau, de Paulo Leminski, que se apresenta como uma obra de difícil acesso devido à sua pouca linearidade narrativa. Nosso intuito é abordar a obra pelo viés da teoria tensiva tentando apontar caminhos possíveis de leitura a partir de estratégias e procedimentos recorrentes no texto. Assim como Zilberberg encontra no modelo saussuriano da silabação um sistema rítmico passível de ser expandido a todos os domínios semióticos, podemos encontrar em um romance como o Catatau células ou elementos que se repetem em determinados intervalos criando uma lei, uma orientação, enfim, um ritmo. É curioso notar, no entanto, que no caso da obra analisada, tal ritmo se mostra mais como um desorganizador da linguagem que como um organizador. Queremos com isso dizer que é a alternância da célula rítmica que provoca no leitor o efeito ininteligibilidade. Evidentemente que há diversos outros recursos, principalmente de nível discursivo, que também reforçam esse efeito, como mostramos ao longo do trabalho. Enxergamos então o romance de Leminski menos como uma narrativa diluída que como o produto de uma vivência, sendo que tal vivência só é possível por meio de um sujeito sensível, afetado pelo que está à sua volta. É nessa linha de abordagem que encontramos os meios para explicitar a construção do sentido do texto, objetivo por excelência da teoria semiótica / In its beginnings, the French semiotic theory had as its major concern the issues of the intelligible, when Greimas proposed a generative path of meaning capable to comprise many systems of meaning. In the course of time, though, the analysts were defied by issues related to sensibility and affection, which claimed for a place in theory, through texts in which narrative was not central. Claude Zilberberg, in particular, is one of the authors who defends the primacy of the sensibility over intelligibility through the features of which came to be called tensive semiotics. Following this movement both through theory and literature, this dissertation chooses as its subject an experimental novel, Paulo Leminskis Catatau, almost considered an unintelligible work due to its non-linear narrative patterns. We aim to approach this novel through the tensive semiotics theory, proposing some ways for its reading based on the texts iterant strategies and procedures. As Zilberberg finds in Saussures syllabic model a rhythmic system which can be expanded to all semiotic domains, we can find in a novel like Catatau cells or elements which repeat in certain intervals, creating a rule, an orientation, a rhythm at least. In Catatau, this rhythm seems much more to disorganize than to organize the language. It means that its the rhythmic cell interchange that leads the reader to that effect of unintelligibility. Of course that there are more features that reinforce this effect within the novel, as we show along our work. That means that we see Leminskis novel less as a diluted narrative and more as the offspring of some experience only made possible if built upon some persons sensibility, affected by his/her surroundings. On this specific approach we find our means to make explicit the building of the text meaning, which is considered the semiotic theory main goal.

O estudo da literatura e de objetos artísticos, por um viés da teoria Semiótica greimasiana, prevê que todo sentido é gerado a partir de articulações semióticas que arquitetam um discurso presente em todo e qualquer texto. Desse modo, o presente trabalho propõe uma análise semiótica da autobiografia em quadrinhos de Alison Bechdel, Fun Home:Uma tragicomédia em família. Por meio da metodologia da Semiótica francesa, a presente análise descreve os artifícios discursivos de persuasão do gênero autobiográfico utilizados pela quadrinista norte-americana para convencer o leitor de que está diante de uma história real. Tais artifícios apontam para uma aproximação da realidade por meio de efeitos de sentido predominantemente referenciais. No entanto, Bechdel (2007b) complexifica tal aproximação, ficcionalizando seus personagens por meio da literatura, não só pela própria natureza do enunciado, mas também como artifício discursivo no interior do texto. Além do gênero autobiográfico, analisa-se a estrutura dos quadrinhos e os efeitos de sentido produzidos pelo sincretismo inerente ao gênero, isto é, a relação entre texto verbal e texto visual. Também é analisada a temática lésbica que permeia todo o enunciado e a rede discursiva polêmica que problematiza. Na obra de Bechdel encontram-se, portanto, as relações entre o gênero autobiográfico, a sua textualização por meio do sistema dos quadrinhos e a pertinência entre eles para a literatura que abrange a temática lésbica. / The study of literature and art objects from the standpoint of the Greimasian Semiotic Theory indicates that all meaning is generated from semiotic articulations that construct a discourse in any given text. Thus, this study proposes a semiotic analysis of Alison Bechdels graphic autobiography Fun Home: A Family Tragicomic. Through the methodology of French semiotics, this analysis describes the discursive devices of persuasion of the autobiographical genre used by the North American cartoonist to convince the reader that they are faced with a real story. Such devices point to an approximation of reality through predominantly referential meaning effects. However, Bechdel (2007b) complicates such an approximation, fictionalizing her characters through literature, not only due to the nature of the utterance, but also as a discursive device within the text. Besides the autobiographical genre, we analyze the structure of comics and the meaning effects produced by the syncretism inherent in the genre, that is, the relationship between verbal text and visual text. Also analyzed are the lesbian issues that permeate the whole utterance and the controversial discursive network that it examine. The proposal is to open a dialogue between language studies, sexuality studies and gender studies. In Bechdel\'s work there is, therefore, the relationship between the autobiographical genre, its textualization through the system of comics and their relevance for a literature encompassing lesbian issues.

A presente dissertação propõe um estudo do espaço literário no romance A House for Mr. Biswas (1961), do escritor indo-caribenho V. S. Naipaul. Num primeiro momento, pautamos nossa leitura na relação constituída entre o espaço e o sujeito por meio do estudo dos cronotopos, de Bakhtin, verificando a presença de dois principais temas espaciais: o da clausura, sobre como o espaço influi na constituição da subjetividade dos personagens e o de transição, sobre o deslocamento do protagonista, Mr. Biswas, do espaço rural para o urbano, despertando nele um vislumbre de agência. Realizamos uma análise detalhada do jornal e da educação colonial e, em seguida, enfocamos a casa e seus constituintes estruturais, bem como as possessões que o protagonista acumula ao longo de sua vida. Concluímos que A House for Mr. Biswas é um romance metaficcional que utiliza a metáfora da escrita e da construção da casa para representar o processo de sua própria construção. A metaficção se manifesta por meio da paródia do gênero do romance de formação, já incorporado pela literatura inglesa dos séculos XVIII e XIX, resultando na criação de um novo romance que almeja pertencer à tradição literária estabelecida, mas que, ao mesmo tempo, encontra-se em dívida em relação a ela. / This dissertation examines the concept of literary space in the novel A House for Mr. Biswas (1961), by the Indo-Caribbean writer V. S. Naipaul. We have based our reading upon the relationship between space and subject by means of Bakhtins chronotopes, verifying the presence of two major themes: that of closure, related to the way in which space affects the constitution of the subjectivity of the characters, and that of transition, about the displacement of the protagonist, Mr. Biswas, from a rural to an urban space, awakening in him a glimpse of agency. We have conducted a detailed analysis of the newspaper and of colonial education, and then the focus shifts to the house and its structural components, as well as to the possessions which the protagonist accumulates throughout his life. We conclude that A House for Mr. Biswas is a metafictional novel that uses the metaphor of writing and that of the building of the house in order to represent the process of constructing the novel itself. Metafiction is disclosed through the parody of the formation novel, already incorporated by English literature of the 18th and 19th centuries, resulting in the creation of a new novel, which aspires to become part of the established literary tradition, but that is still, at the same time, is indebted to it.

La littérature gabonaise, forte de son dynamisme, voit davantage d’écrivains faire le choix de décrire les réalités sociales dans une langue française réappropriée. Ce qui consiste pour eux à réinventer le français, à l’image de leur société, et à en faire leur propre langue d’écriture. Notre thèse se propose d’étudier ce phénomène dans le polar gabonais, ce genre en plein essor représenté par Janis Otsiémi, et de démontrer que la créativité du point de vue de la langue reste indissociable de l’engagement et de la conviction de l’écrivain gabonais, et afro-subsaharien par extension. En premier abord, il est question de distinguer la langue d’écriture de l’écriture de la langue. Pour cela, étudier les stratégies d’écriture de l’écrivain, relever les divers gabonismes et africanismes présents dans le roman d’Otsiémi et les fonctions propres à chacune des particularités linguistiques, nous permet de faire état de l’esthétique littéraire et des pratiques langagières gabonaises. En second lieu, l’objectif est pour nous de procéder à une herméneutique de l’oeuvre d’Otsiémi pour dégager grâce à la subversion de l’écriture la poétique subversive de son oeuvre. Pour ce faire, situer le style de l’auteur revient à évaluerl’engagement de l’auteur vis-à-vis de la langue et de l’écriture, à faire face à une écriture hybride résultant du foisonnement des intertextes, et à aborder l’identité à la fois revalorisée et déconstruite par l’auteur, respectant ainsi le principe élémentaire du polar qu’est celui d’écrire le noir. / The Gabonese literature, strong in its dynamism, sees more writers make the choice to describe social realities in a French language reappropriated. What is for them to reinvent the French, in the image of their society, and to make their own language of writing. Our thesis proposes to study this phenomenon in the Gabonese crime novel, this booming genre represented by Janis Otsiemi, and to demonstrate that creativity from the point of view of language remains inseparable fromthe commitment and conviction of the Gabonese writer, and afro-sub-Saharan by extension. At first, it is a question of distinguishing the language of writing from the writing of the language. To do this, to study the writer's writing strategies, to identify the various gabonisms and Africanisms present in Otsiemi's novel and the functions proper to each linguistic peculiarity, allows us to describe literary aesthetics and Gabonese languages practices. In the second place, the objective is for us to proceed with a hermeneutic of the work of Otsiemi to free, thanks to the subversion of writing, the subversive poetics of his work. To do this, situating the author's style amounts to evaluating the author's commitment to language and writing, to coping with a hybrid writing resulting from the proliferation of intertexts, and to approach the identity both revalorized and deconstructed by the author, thus respecting the elementary principle of the crime novel that is to write black.

Na história japonesa, o período Meiji (1868-1912) é conhecido como aquele da transição entre a nação pré-moderna, governada por xoguns e socialmente hierarquizada, para a nação moderna, dotada deconstituição e propiciadora demaior cidadania. Esta transição, esta mudança de paradigma, pode serobservada em várias instâncias. No caso específico da cultura eliteratura, passou-se para uma etapa de contato intenso com o Ocidente, suas formas culturais e artísticas. Assim, pintura, escultura e música foram renovadas face ao novo impacto. Com a literatura não seria diferente: a tradição do romance europeu irrompe com força na cena das letras japonesas e propiciou um rearranjo de gêneros, formas e temas. Pretendemos aqui analisar alguns desses deslocamentos, tendo em vista, sempre, o ponto de partida, ou seja, trata-se de uma análise histórica da renovação do fazer literário. Para tanto, abordamos primeiramente a situação da entrada da literatura europeia no Japão através da tradução. Esse passo foi de fundamental importância para a formação da literatura moderna japonesa, pois neste momento foram estabelecidas direções quanto ao tom e à dicção da nova prosa de ficção, bem como sua relação para com a literatura autóctone japonesa (ou seja, a chamada literatura clássica). Em um segundo momento, procuramos demonstrar o surgimento do narrador enquanto função textual dotexto, por oposição ao autor explícito da ficção pré-moderna japonesa. O estabelecimento de um narrador neutro consiste em uma das etapas mais importantes da reforma da ficção que pretendemos abordar. Procuramos detalhar com exemplos essa transformação. Por fim, detivemo-nos sobre o romanceUkigumo(1887), de Futabatei Shimei (1864-1909), como exemplo de romance criado durante o período desta reforma literária. Procuramos mostrar as hesitações de seu autor quanto ao papel do narrador e ao encaminhamento danarrativa. Posicionar a obra em seu contexto, é uma etapa importante para fundamentar a interpretação aqui apresentada em relação à especificidade do romance Ukigumo. / In Japanese history, the Meiji period (1868-1912) is known as one of transition between the pre-modern nation, governed by shoguns and a tigh social hierarquy,and a modern State, endowed with a Constitution and greater citizenship. This change of paradingsignals that all spheres were affected during this transition. In the case of culture and literature, there began anew, intense exchange with the Western world and its artistic and cultural forms. Thus, painting, sculputeand music were reformed and renewed due to the new impact. Regarding literature it was no different: the tradition of the European novel breaks the scene of Japanese letters, causing a new arrangement of genres, forms and themes. We intend to analyse heresome of these displacements and shifts, always bearing in mind their departing point. That is to say, this is an historical approach to the renewal of Japanese literature. In order to do so, we shall first study the importation of European fiction to Japan through the means of translation. This is a step of fundamental importance in the formation of modern Japanese literature, since it established directionsas to tone and diction of the new fiction, as well as its relation to the native tradition (that isto say, to the so-called classical literature). Secondly, we will try to demostrate the emergence of the narrator as a textual function of the narrative, opposed to the traditional explicit author of pre-modern fiction. The establishment of a neutral narrator is the most important step in the reform offiction we here present. We tried to offerdetailed examples of this transformation. Lastly, we focusedon the novel Ukigumo(1887), by Futabatei Shimei (1864-1909) as an example of work created during this period of reform. We tried to show the authors hesitation regarding the role of the narrator as well as the development of plot. We also tried, as much as possible, to insert the work in its historical context, so as to lead to a better understanding of its structure and our interpretation of it.

The Soviet Union had existed for 70 years and was labeled as the "evil empire". Its technological achievements and geographical discoveries are amazing. However, its dark aspects such as censorship, "purges", and freedom restrictions are shocking as well. The effects of its collapse in 1991 were felt throughout the world in many aspects of peoples' day-to-day lives. Nowadays, many average Russians feel tenderness and nostalgia for what they had back then. This thesis addresses the perception of the Soviet past by two contemporary Russian writers, Elena Chizhova and Elena Katishonok. Despite the common tendency to idealize the Soviet epoch, the authors represent it as a period that is not worthy of nostalgia. The thesis explores the world picture created in both novels by means of the analysis of such themes as the space structure, death, and memory that recur and function on different levels of the target texts.

This dissertation argues that friendship operates in mid-eighteenth-century English fiction as a privileged category of virtue, knowledge, and aesthetic value. By representing social tensions raised by extra-familial friendships and appealing to readers as friends, Samuel Richardson, Sarah Fielding, Sarah Scott, and Laurence Sterne, develop ideal friendship into a reflexive trope for cultivating authorial identity, framing literary response, imagining a public sphere, and theorizing social reforms. Amiable Fictions offers a new way of thinking about the ethical frameworks that shape experimental narrative techniques at a moment when the English novel is just emerging into cultural prominence. In this study, I analyze the ways that these four novelists represent friendships as allegorical meditations on interpersonal ethics so as to imagine literary exchange as a virtual form of friendship. I explore how the idealized communicative intimacy of friendship becomes a basis for imagining more perfect spiritual and economic unions. On the level of plot, these fictions unpack the philosophical values of real friendship by staging its antagonism with persistent forms of patriarchy, aristocracy, and economic individualism. Drawing from the values of friendship that arise in the plot, these authors shape narrative exchanges as a tie of friendship. In cultivating an amiable ethos, they avoid appearing as slavish flatterers in a commercialized literary marketplace, or as overly didactic figures of institutional authority. Amiable Fictions builds on studies of the novel genre by accounting for the way a rhetoric of friendship motivates experiments in narrative form. I offer insights into developments in epistolary style, free indirect discourse, unreliable narration, anonymous authorship, and autobiographical form. I suggest that the concept of friendship orients these writers in their exploration of techniques, propelling them as they articulate a range of possibilities available for future authors of narrative fiction. This dissertation also engages current scholarly understandings of sociability, sensibility, domesticity, and public and private life in the mid-eighteenth century. These novelists deploy friendship as a moral category that challenges codes of sociability, refines understandings of sympathy, and often antagonizes the emerging cultural authority of the domestic sphere. Reframing questions of gender and sexuality and their influence on literary forms, the project highlights how male characters imitate friendship between women (and vice versa), how social reform impulses raise the need for heterosexual friendship, and how non-familial friendship conflicts with domestic norms as an alternative mediator of public and private character.