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1
Hernández, Violeta Erendira. "Making sense of nonsense." CSUSB ScholarWorks, 2006. https://scholarworks.lib.csusb.edu/etd-project/3175.
Повний текст джерелаАнотація:
The project focuses on the creation of supplemental teaching materials that can be used to support reading and writing activities in the science content curriculum taught in a bilingual fifth grade classroom. Mediated structures are used to link the curriculum in the language arts with science materials. They are also used to provide depth and complexity to the materials offered by textbooks adopted by the school district. The mediated structures discussed and developed in the project are included.
2
Taskesen, Bengu. "Sense Through Nonsense Reading Difficult Poetry." Master's thesis, METU, 2004. http://etd.lib.metu.edu.tr/upload/12605178/index.pdf.
Повний текст джерелаАнотація:
This thesis analyses the difficulties in reading modern poetry that arise out of not the references but the unconventional use of language, and presents them in a theoretical framework based on Julia Kristeva&rsquos semanalytic theory and Melanie Parsons&rsquo
s application of it to a comparison of Nonsense literature and twentieth century poetry. Then aspects of the works of G. M. Hopkins, Dylan Thomas and Edith Sitwell are discussed and poems by these poets are analysed within this framework.
3
Bastos, Lucia Kopschitz 1957. "Anotações sobre leitura e nonsense." [s.n.], 1996. http://repositorio.unicamp.br/jspui/handle/REPOSIP/270924.
Повний текст джерелаАнотація:
Orientador: Maria Bernadete Marques AbaurreTese (doutorado) - Universidade Estadual de Campinas, Instituto de Estudos da Linguagem
Made available in DSpace on 2018-07-21T13:33:02Z (GMT). No. of bitstreams: 1 Bastos_LuciaKopschitz_D.pdf: 13654633 bytes, checksum: d012276c381dd92ddef25d91f0689c93 (MD5) Previous issue date: 1996
Resumo: O que está em discussão nesta tese é a construção do sentido na leitura, discussão possibilitada aqui por uma das maneiras de se estudar o sentido, ou seja, perseguir justamente a sua falta. O nonsense é essencial à definição de sentido porque constitui a sua margem, o seu limite. Não há como definir um sem o outro: só se sabe o que é o sentido ao esbarrarmos em seus limites. Para que haja o nonsense é pre_iso que haja o sentido, mesmo que seja o sentido paradoxalmente posto em questão. Para que haja o que não é nonsense é preciso que haja, em algum lugar, o que é. O nonsense sempre se refere a um séntido ao qual não podemos nos reportar, não podemos recorrer. A investigação se dá, então, na natureza do que é negado. Por isso trabalhei aqui com dados indiciários e o que propus foi uma possibilidade de leitura nonsense. O capítulo que trata do nonsense mostra o quanto este efeito está calcado na forma que o texto tem. No capítulo sobre leitura levanto estudos que discutem a origem do significado: elenco desde autores que consideram que o significado de um texto está nele mesmo, a autores que postulam que este significado é dado pelo leitor. Faço ainda, em outro capítulo, um percurso por considerações acerca da leitura em língua estrangeira já que os dados com que trabalhei provêm dessa situação de leitura. Partindo de uma concepção dialógica da linguagem só é possível concluir que o sentido de um texto é resultado da leitura, resultado do trabalho que faz sobre o texto o leitor. Lendo, esse leitor circula dentro do uníverso de leituras possíveis determinado ao mesmo tempo por todas as outras leituras que se faça de um texto e por cada uma delas. Dentre essas possibilidades está a leitura nonsense. Nos dados analisados aqui não há um investimento para a criação proposital do efeito de nonsense. No entanto, é do efeito que causa um texto nonsense que se aproxima o efeito obtido na leitura dos trechos analisados. E é a leitura que instala essa aproximação. O que procurei fazer foi determinar os descaminhos da leitura trilhados pelo leitor sob análise
Abstract: This work presents a discussion of an alternative approach to the construction of meaning in .reading through the use of nonsense, or lack of meaning. The investigation probes the nature of what is being denied and the interactive of relationship between the text and the reader in the struggle to establish meaning. The thesis identifies a dialectical relationship between sense and nonsense and argues that the existence of nonsense is critical to the definition of sense, as it establishes the edges, or limits of meaning
Doutorado
Doutor em Linguística
4
Conley, Timothy John. "The hoax that joke bilked, sense, nonsense, and Finnegans Wake." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/MQ29487.pdf.
Повний текст джерела
5
Conley, Tim. "The hoax that joke bilked : sense, nonsense, and Finnegans wake." Thesis, McGill University, 1997. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=26682.
Повний текст джерелаАнотація:
The remarkable challenges Finnegans Wake offers to its readers and to the very process of reading are the results of an evolution of Nonsense literature. Despite the unduly "serious" framework of criticism which has been built up around it, Joyce's anomalous last work is a radical "hoax" upon interpretation. The regular confluences of linguistic deconstruction (via word association as well as recurring word and phrase matrices) and ontological metaphor, developed from authors such as Rabelais, Sterne, and Lewis Carroll, are offered by the Wake as tests to the reader's (qua reader) sensibilities. As Nonsense, Finnegans Wake departs from typified modernist modus operandi (metonymic allusion) and instead explores the limits of metaphor. The stakes of Joyce's hoax are of vital interest to the contemporary student of literature and culture, since the Wake dares the reader to find new meanings rather than to project old ones; to exult its eccentricities and its difference; and all the while to call into question (as the text itself does), its authenticity and authority.
6
Fang, Xuan, and 方璇. "Commonsense and nonsense, a cultural-philosophical adventure in Alice's wonderland." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43223989.
Повний текст джерела
7
Hondius, Ewoud. "Sense and nonsense in the law : towards clarity and plain meaning /." Deventer : Kluwer, 2007. http://swbplus.bsz-bw.de/bsz277069513inh.pdf.
Повний текст джерела
8
Stockton, William H. "Sex, sense, and nonsense the anal erotics of early modern comedy /." [Bloomington, Ind.] : Indiana University, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3274908.
Повний текст джерелаАнотація:
Thesis (Ph.D.)--Indiana University, Dept. of English, 2007.Source: Dissertation Abstracts International, Volume: 68-07, Section: A, page: 2960. Adviser: Linda Charnes. Title from dissertation home page (viewed Apr. 10, 2008).
9
Chimori, Mikiko. "Sense in nonsense : the 'Alice' books and their Japanese translators and illustrators." Thesis, University of East Anglia, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268490.
Повний текст джерелаАнотація:
This thesis makes cross-cultural comparisons between various British and Japanese illustrated versions of Alice's Adventures in Wonderland and Through the Looking-Glass, and explores the ways in which these different versions of Carroll's two masterpieces can throw light on the social and cultural changes that have taken place in these two countries since Carroll's time. My focus is, however, unambiguously on the Japanese reception of Alice, as narrative texts and as visual texts. The modern Japanese translations and illustrations of the two Alice books from 1899 to 1933, ranging over Meiji (1868-1912), Taisho (1912-1926) and Showa (1926-1989) Japan are dealt with. It is the first large-scale historical study of this kind, especially on Japanese illustrations, and the first to make detailed comparisons of different Japanese Alice translations and illustrations from a woman's perspective. It explores the ways in which Japanese translators, confronted by Carroll's nonsense fantasy, unprecedented in Japanese culture, attempted to achieve a new blend in language from Meiji to Showa Japan. It examines how Japanese translators and illustrators have interpreted Carroll's nonsense and how his nonsense has been transplanted into Japanese culture. Furthermore, particular attention is paid to the viewpoint of a young reader who is in the transitional stage from the little girl of Wonderland Alice to the early adolescent of Looking-Glass Alice and who is forced to make "Japanese sense" out of "Victorian sense". It explores how the Alice texts, both Carroll's and those of Japanese translators and illustrators, reflect women's and children's education, prevailing moral codes, and their general social and cultural circumstances, both in England and in Japan, and how particularly English elements have been transformed in the process of creating a Japanese Alice throughout the history of Japanese Alice translations.
10
Poole, Jennifer Amy Forbes. "Challenging common sense about nonsense : an integrational approach to schizophrenic language behaviour." Master's thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/8993.
Повний текст джерелаАнотація:
Includes bibliographical references (leaves 159-168).Due to certain fundamental flaws, orthodox linguistics has not succeeded in producing a coherent account of 'schizophrenic language' - the host of symptoms that are alternatively characterised as evidence of formal thought disorder or labelled as disorganised speech, a disorder in itself. The most important of these flaws are its treatment of languages as fixed codes, which doubles as an explanation of how linguistic communication works, and its postulation of the mental structures that would be necessary if languages were indeed fixed codes, and communication a matter of encoding and decoding messages. In particular, orthodox linguistics has bolstered the now-dominant neo-Kraepelinian, biomedical account of schizophrenia, which treats utterances as symptoms that give clues to brain (dis)organisation and (dys) function. Integrational linguistics, which criticises the culturally based assumptions - collectively referred to as 'the language myth' - that are at the heart of the orthodox account of languages and language, provides an alternative. It sympathises with the growing trend in cognitive science and philosophy towards 'embodiment' and 'distributed cognition', which recognises that encultured entities like languages, minds, brains, bodies, and world are intrinsically defined by their co-evolution in the species, and co-emergence during an individual's development. Integrationists argue that by focusing in the first instance on second-order cultural constructs called 'languages', orthodox linguistics fails to give an account of the first-order experience of language users. This thesis approaches the topic of 'schizophrenic language' from a broadly integrationist perspective in order to demonstrate that because orthodox linguistics is so widely taken for granted in psychiatry, its biases inform current mainstream accounts of schizophrenic language, motivate the outright dismissal of interpersonal accounts, past and present, and provide a skewed picture of the phenomenon it purports to be describing, by ultimately constructing an individual-focused, deficit-based account of what is not, as opposed to what is. That is, by holding up orthodox linguistics' idealised version of communication and speakers (which has little applicability even to 'normal' language users), it uses deviation from the ideal as description and explanation, rather than recognising the strategies actually employed by schizophrenics in their attempts to make sense, even if these attempts fail. The alternative argued for here is to apply the tenets of integrationist linguistics to schizophrenic language behaviour, to give a fuller account of communication situations involving schizophrenics and normal interlocutors. As a result, this thesis calls for a reformulation of the idea that incomprehensibility stems from deviant speech, itself the product of an irrational brain. 'Sense', 'deviance' and 'irrationality' are a moment-to-moment metalinguistic appraisals made by language users, second-order cultural constructions that shape the speech community's response to certain individuals. Describing the speech of schizophrenics as 'deviant', 'irrational', or 'nonsensical' constrains their jointly-constructed capability of making sense using the resources (which may include other individual's minds) at their disposal. Integration linguistics thus brings into focus a moral and political dimension to such descriptions which is obscured by an orthodox linguistics-biased biomedical approach.
11
Fang, Xuan. "Commonsense and nonsense, a cultural-philosophical adventure in Alice's wonderland." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43223989.
Повний текст джерела
12
Walton, Darren. "Wittgenstein and psychology: An exploration of creativity and madness through the investigation of sense and nonsense." Thesis, University of Canterbury. Psychology, 1995. http://hdl.handle.net/10092/5828.
Повний текст джерелаАнотація:
The purpose of this thesis is to diagnose and cure some of the sources of conceptual confusion in psychology. Both the concepts of creativity and insanity are used as examples of areas of concern to psychologists. Wittgenstein (1958, 1969) suggests that in psychology theory and research are directed from confused conceptions of language resulting in a paralysis of understanding. It is by following Wittgenstein's articulation of the nature of philosophy, and by understanding the relationship between philosophy and psychology, that it is possible to disentangle the conceptual confusion and gain access to accurate theorising about insanity, creativity, and the relationship between the two phenomena.
Cognitive science is criticised for perpetuating a mythology from which research is directed. Cognitive psychology relies on a misguided understanding of the nature of psychological predicates. Wittgenstein's arguments against the thoughts embodied in the cognitivist doctrine are used to disable this attempt to account for psychological concepts generally and provide a background to address the errors contained within computational accounts of creativity.
Social constructionists claim that they accurately represent the introduction of Wittgensteinian philosophy into psychology. There are several attempts made by constructionists to criticise cognitive science and present alternative research programmes for psychology. It is argued that social constructionists fail to present a convincing argument against cognitivism and furthermore misinterpret Wittgenstein's philosophy and so fail to introduce Wittgenstein's thoughts to psychology. Theorising from a constructionist perspective about the concept of insanity is used as an example to expose the types of error which result from misinterpreting Wittgenstein's arguments.
It is by contrast with these broad theoretical structures (both cognitive science and social constructionism) that the proper grammatical structure, at least from a Wittgensteinian perspective, for the concepts of insanity and creativity is developed. The relationship between grammar and evidence is explained against the background of argument in psychology relating to the study of creativity and insanity. Theoretical psychology is distinguished from philosophy with the recognition that philosophy provides conceptual clarification and psychology is involved with conceptual development. The relationship between empirical psychology and theoretical psychology is described in contrast to the relationship between philosophy and theoretical psychology. By describing Wittgenstein's conception of philosophy it is argued that Wittgenstein offered psychologists a resource which operates either to remove conceptual confusion or promote an overview to facilitate the correct employment of terms within theory.
13
Rathjen, Kirsten. "Vom Sinn und Unsinn aller Allegorie : Das Versteckspiel mit dem Leser im Romanwerk Martin Mosebachs = The sense and nonsense of allegory : the game of hide and seek with the reader in the novels of Martin Mosebach." Thesis, University of Leeds, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590155.
Повний текст джерелаАнотація:
Long and erroneously deemed a writer in the tradition of bourgeois realism, the novelist Martin Mosebacb (* 1951) has in recent years been catapulted to the forefront of the German literacy scene, winning Germany's most prestigious literary prize, the Georg-Buchner-Preis, in 2007 and being heralded by many (mostly conservative) newspaper critics as one of the most elegant and powerful writers of the day_ Whilst there has been a fervent debate about the author's anti-modem and catholic credentials, neither the authors' advocates nor detractors have offered anything more than a superficial analysis of his substantial body of literary texts. This study is the first to look at Mosebach's novelistic oeuvre. It offers both a survey of his novels and a particular focus on the aesthetics of play that has animated his work since the very beginning of his career. In the early 19805 when the reception of literature in Germany was still very much guided by the paradigm of modernity and political litterature engagee, Mosebach not only flaunted his (then) unfashionable love for tradition and aesthetic form but turned it into an instrument of satire. Behind the outer, realistic settings of the texts and thus beneath their literal surface, many of Mosebach's narrators fabricate absurd fantasies of historical continuity. These are invoked purely by aesthetic means, by counter• intuitive allegories which are embedded in complex formal compositions and are conceived as hide•and•seek games with the reader. Mosebach deploys these absurd scenarios to formulate his cultural criticism in a grotesquely distorted way and provokes the critical reader's suspicion by playing with politically incorrect taboos (or blasphemy). In this study, I uncover these meticulously crafted subtexts as well as the author's extensive formal play with leitmotifs and symmetries which takes on a dynamic of its own. Thereby, the mannerist nature of Mosebach's transformations of reality comes to the fore. Whilst the author self•ironically foregrounds many of his conservative views put forward in his essays, not least his defence of the old Roman Liturgy, he consistently subjugates them to the aesthetics of (grotesque) play. Whilst politically incorrect innuendoes and satire provide much of the novels' appeal, ] conclude that the real provocation may lie in the fact that the modern reader's customary search for deeper meaning (be it political, sociological or psychological), is frustrated. This holds in different ways for both the early and the most recent novels. Finally, I suggest that Mosebach may require a reader who is willing to assess his novelistic work by aesthetic criteria alone.
14
Arazam, Yannis. "Les lois logiques sont-elles révisables ?" Electronic Thesis or Diss., Strasbourg, 2024. http://www.theses.fr/2024STRAC027.
Повний текст джерелаАнотація:
Le problème du révisionnisme logique a traversé les réflexions des auteurs majeurs de la philosophie analytique du xxe siècle, de Wittgenstein à Dummett en passant par Quine, Putnam ou Kripke. Il s’agit pour eux de traiter à nouveaux frais d’un problème qui a pris différentes formes dans l’histoire de la philosophie. Les développements en logique mathématique suivant la révolution frégéenne ou encore en physique avec la formalisation de la mécanique quantique, ont marqué le renouveau de ce problème qui se pose avec une acuité sans précédent. Y a-t-il un sens à remettre en cause certaines lois logiques classiquement admises depuis Aristote; plus simplement encore, est-il intelligible de changer de logique ? Le rejet intuitionniste du tiers-exclu ou plus généralement le développement de « logiques alternatives » marquent-ils un tournant dans l’histoire de la logique ? La difficulté soulevée tient au caractère constitutif de la logique pour penser : si ses lois sont les normes de l’intelligibilité, alors comment les remettre en cause sans abolir par là-même toute possibilité de sens ? Le présent travail retrace l’histoire de cette difficulté dans le corpus analytique classique, et en tire de nouvelles perspectives au moyen du concept de paradigme et au contact de certains développements logiques de la seconde moitié du xxe siècleThe problem of revising logic permeated the thinking of the major authors of the analytic tradition in the 20th century. From Wittgenstein to Dummett and through Quine, Putnam or Kripke, authors have tackled afresh a problem that has taken various forms throughout the history of philosophy. Developments in mathematical logic following the fregean revolution, or even the formalization of quantum mechanics, have both renewed and sharpened the problem. Is there any sense in questioning logical laws classically acknowledged since Aristotle? More simply put, is it intelligible to change our logic ? Are the intuitionnistic refusal of the law of excluded-middle and, more generally, the emergence of "alternative logics" constitutive of a turning point in the history of logic ? The difficulty faced stems from the constitutive nature of logic for thought : if logical laws are the norms of intelligibility, how can they be challenged without undermining the very possibility of meaning ? This work traces this difficulty back to the classical analytical corpus, and gets new perspectives out of it by means of the concept of paradigm, alongside logical developments in the second-half of the 20th century
15
Bierhanzl, Jan. "L'itinéraire de la signifiance éthique dans "Autrement qu'être ou au-delà de l'essence" d'Emmanuel Levinas." Thesis, Dijon, 2012. http://www.theses.fr/2012DIJOL024.
Повний текст джерелаАнотація:
Le présent travail tente de retracer le parcours de la signifiance éthique. Bien que le trait structurel décisif du mouvement de signifiance éthique soit le « pour l’autre », nous montrons qu’en suivant la double méthode phénoménologique de la concrétisation-et-emphase, Levinas accomplit ce mouvement par d’autres traits structurels: « à sens unique », « à partir de soi », « malgré soi », « autre dans le même », « je est un autre », « pour rien » et « par l’autre ». Le chapitre II apporte un trait signifiant limite « l’un pour tous les autres », articulant l’éthique avec la justice. Néanmoins, la liste établie n’est pas exhaustive, mais simplement indicative. Ce travail n’est qu’une digression dans le mouvement de la signifiance éthique, mouvement infini, qui précède diachroniquement toute tentative d’en rendre compte et qui interrompt le sens que l’auteur de ces lignes croît mettre dans les mots. Les différentes recherches constituant le présent travail peuvent dès lors être interprétées comme différentes modalités de ce Dédire du Dit qu’est la mise en évidence de l’exception du tiers exclu – notre seul accès au Dire. Dans cette perspective, le chapitre I cherche à dépasser la dichotomie signification vécue / signification thématisée, le chapitre II la dichotomie langue / parole, le chapitre III la distinction entre sens et non-sens. L’alternance du sens détermine le statut des trois premiers chapitres: thématiser l’avant de la signifiance éthique est impossible sans thématiser l’après de la signifiance ontologique, qui, elle, est toujours déjà interrompue par l’après de l’après de l’alternance du sens, et ainsi de suiteThe paper here presented attempts to retrace the course of the ethical signifying. Although the main characteristic feature of this movement of signifying is the « for-the-other », we show that following the double phenomenological method called concretisation-and-emphasis, Levinas accomplishes this movement by means of other features: « unique sense », « starting from the self », « despite oneself », « the other in the same », « I am an other », « for nothing » and « by the other ». The chapter II brings a borderline feature « one-for-all-the others » which articulates ethics with justice. Eventhough, this list is not exhaustive, but simply indicative. This paper is not anything more than a digression in the movement of ethical signifying, an infinite movement, which precedes diachronically every attempt to give an account of it and interrupts the sense that the author believes putting in words. Then the investigations here presented can be interpreted as different modalities of the Un-saying (Dédire in french) of the Said which consists in putting in evidence the exception of the excluded third – our only acces to the Saying. In this perspective, chapter I tries to exceed the dichotomy lived significance / thematised significance, chapter II the dichotomy langue / parole, chapter III the distinction between sense and non-sense. The alternance of sense defines the status of the first three chapters: to thematise the « before » of the ethical signifying is impossible without thematising the « after » of the ontological signifying, which is always already interrupted by the « after the after » of the alternance of sense, and so on
16
Picco, Chiara <1984>. "IL SENSO DEL NONSENSO. LINGUAGGIO, SIMBOLO ED ESPERIENZA PSICOTICA." Master's Degree Thesis, Università Ca' Foscari Venezia, 2015. http://hdl.handle.net/10579/6576.
Повний текст джерелаАнотація:
Al centro di questo studio è il rapporto fra linguaggio, espressione e corporeità in un confronto fra la filosofia della percezione di Maurice Merleau-Ponty e alcune analisi sul linguaggio della psicoanalisi contemporanea. In modo particolare gli studi di Salomon Resnik, da un punto di vista teorico, e la metodologia di cura elaborata da Gisela Pankow, sono argomenti di un confronto fra discipline e prospettive di ricerca che permettono di riformulare alcuni concetti filosofici centrali per la filosofia del linguaggio e per la filosofia dell’arte. Il metodo innovativo della creazione artistica come ricostruzione dell’immagine del corpo, essenziale nella terapia della psicosi di Gisela Pankow, ha importanti riflessi sull’estetica e sulla filosofia del linguaggio. Questo lavoro offre un'analisi comparativa ed epistemologica sulla natura dei casi clinici nella più ampia prospettiva filosofica del rapporto fra linguaggio, immagine, simbolo e identità.
17
Yeramala, Lahari. "Caractérisation de complexes responsables de la dégradation des ARNm non-sens." Thesis, Université Grenoble Alpes (ComUE), 2017. http://www.theses.fr/2017GREAV008/document.
Повний текст джерелаАнотація:
Le système de contrôle appelé dégradation des ARNm non-sens (NMD) permet de détecter puis de dégrader des ARNm contenant un codon de terminaison prématuré (PTC). Les facteurs principaux de la NMD : UPF1, UPF2 et UPF3 reconnaissent les PTCs en interagissant avec les facteurs de terminaison eRF1, eRF3 et la protéine Poly(A) binding (PABP). La reconstitution d’un système de traduction in vitro a permis d’étudier la terminaison de la traduction en présence des facteurs PABP et UPF1, à l’aide de méthodes de biochimie et de cryo-microscopie électronique. L’étude du rôle du facteur de NMD UPF3B dans la terminaison de la traduction a mis en évidence une double action de cette protéine ; tout d’abord, un retardement de la reconnaissance du codon stop et également la promotion de la dissociation du ribosome. Ce travail a également permis de mettre en évidence une nouvelle interaction entre UPF3B et la kinase SMG1-8-9 et de montrer comment cette interaction affecte l’état de phosphorylation de UPF1. Les résultats de cette étude montrent une interaction complexe entre les différents facteurs de NMD et la kinase SMG1Nonsense-mediated mRNA decay (NMD) is an important eukaryotic quality control mechanism that recognizes and degrades mRNA containing a premature termination codon (PTC). Up-frameshift proteins constitute the conserved core NMD factors (UPF1, UPF2 and UPF3). They mediate the recognition of a NMD substrate, i.e. a ribosome stalled at a PTC. UPF proteins were shown to associate with eukaryotic release factors (eRF1 and eRF3) and were suggested to impede translation termination. We showed that, at a normal termination codon, Poly(A)-binding protein (PABP) stimulates translation termination by directly interacting with eRF3a. Using a reconstituted in vitro translation system, we studied translation termination in the presence of the factors PABP and UPF1 using biochemistry and single particle electron cryo-microscopy (Cryo-EM). Additionally, we analysed the role of the other NMD factors UPF2 and UPF3B in translation termination in vitro. We discovered a novel role for UPF3B in translation termination. Moreover, we observed a novel interaction between UPF3B and the SMG1-8-9 kinase complex. The presence of UPF3B affects the kinase activity of SMG1 and thus the phosphorylation state of UPF1. Our results highlight a much more complex interplay of the NMD factors with the translation termination machinery and SMG1 kinase than anticipated
18
Miot, Thierry. "L'École du sens chez Lewis Carroll." Tours, 2005. http://www.theses.fr/2005TOUR2014.
Повний текст джерелаАнотація:
Quand Alice elle-même utilise ou perçoit le mot " nonsense ", elle conçoit quelque chose comme " n'importe quoi " (" sottises " dans la traduction française de Henri Parisot), une expression souvent proférée sur un ton de reproche et donc avec des connotations négatives. Cependant, il ne faut pas comprendre ainsi le " nonsense ", car le procédé rhétorique original de Lewis Carroll naît du " non-sens ", une entité problématique inscrite dans le langage et dans la logique du sens elle-même. Le" nonsense " de Lewis Carroll parle, donc, de " non-sens ". Cependant, ce n'est pas pour réduire la notion aux seuls obstacles à une communication verbale efficace, à l'absence de sens : un sens paradoxal n'est en aucun cas dépourvu de sens, et il n'est pas non plus nécessairement terni par des connotations négatives (comme le préfixe " non " pourrait le laisser croire), car le nonsense peut être compris comme la création de plusieurs sens. En effet, Lewis Carroll excelle en montrant comment le non-sens habite la logique du sens, dans toute sa " profondeur " et peut-être plus précisément dans ses " surfaces " trompeuses. Alice, rêveuse et pourtant toujours alerte, est initiée aux paradoxes de la " logique du sens " : on la presse d'arpenter et de traverser les surfaces (la surface du tapis de cartes, du miroir, de l'échiquier,. . . ) " dans tous les sens ", en la plongeant au cœur du système qui l'implique corps et âme dans un jeu d'esprit. On la défie de garder tous ses esprits, où que la logique du sens puisse la mener. " L'école du sens " enseignée par le maître du nonsense, Lewis Carroll (dans la vraie vie professeur de logique), cadre la problématique du sens en terme de surface(s) et choisit d'en faire la preuve par l'absurde : le sens semble être plus accessible par le jeu du " non-sens ", le jeu dans le sensWhen Alice herself uses or hears the word “nonsense,” it means something like “meaninglessness” (“sottises” in Henri Parisot's French translation), an expression often uttered in a reproachful tone and thus with negative connotations. However, “nonsense” need not be understood this way, for Lewis Carroll's original rhetorical technique of “nonsense” emerges from “non-sense” – a problematic feature inscribed within language and within the logic of meaning, itself. Lewis Carroll's “nonsense” speaks, then, of “non-sense. ” However, this is not to reduce the notion to mere obstacles to effective verbal communication, to the absence of meaning: a meaning that is paradoxical is in no way deprived of meaning, nor is such a meaning necessarily blemished with negative connotations (as the prefix “non” might lead one to believe), for nonsense can be understood as the creation of several meanings. Indeed, Lewis Carroll excels in showing how non-sense is inherent in the very logic of meaning, in its very “depth,” and perhaps more precisely in its deceptive “surfaces. ” Alice, in a dream-like state, yet still alert, is initiated into the paradoxes of the “logic of meaning”: she is urged to take stock of and cross surfaces (the surface of the card table, the mirror, the chessboard,. . . ) “in all directions,” diving into the core of the system that involves her heart and soul in a game of wit. She is challenged to keep her wits, wherever the logic of meaning might lead her. The “school of meaning,” taught by the master of nonsense, Lewis Carroll (in real life a professor of logic), frames the problem of meaning in terms of surface(s) and opts for the reductio ad absurdum principle in order to prove it: meaning seems to be more accessible through the game of “non-sense” – the play within meaning
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Durand, Sébastien. "Développement de molécules chimiques capables d’inhiber l’épissage et le Nonsense-Mediated mRNA Decay (NMD)." Montpellier 2, 2008. http://www.theses.fr/2008MON20072.
Повний текст джерелаАнотація:
L'épissage des pré-ARNm, le processus nucléaire conduisant à l'assemblage des séquences "exons" de l'ARN messager par élimination des séquences intercalaires ou "introns", est une étape décisive de l'expression de la plupart des gènes chez les métazoaires. Au cours de ce processus, beaucoup d'erreurs peuvent survenir avec des conséquences plus ou moins graves pour le bon fonctionnement de la cellule. Afin de limiter les effets délétères de telles erreurs, différents mécanismes de contrôle de qualité des ARNm épissés ont été mis en place. Parmi eux, le Nonsense-Mediated mRNA Decay (NMD) permet de dégrader les ARNm contenant des codons non-sens prématurés (PTC), évitant ainsi l'apparition de protéines tronquées. De par leur ampleur en tant que mécanismes centraux de l'expression génique chez l'homme, l'épissage et le NMD sont fréquemment impliqués dans des pathologies d'origine génétique. Dans certains cas comme l'ataxie télangiectasie ou la neurofibromatose de type I, 54% des mutations responsables de la maladie affectent l'épissage. Environ un tiers des maladies génétiques sont dues à l'apparition de PTC qui induisent le NMD. Dans certains cas, une protéine tronquée pourrait conserver les mêmes propriétés que la protéine sauvage mais le mécanisme de NMD empêche sa synthèse. Par conséquent, l'épissage et le NMD représentent des cibles tout à fait intéressantes qui permettraient, soit de restaurer un épissage correct, soit de permettre l'expression de protéines tronquées et fonctionnelles. Au cours de cette thèse nous avons recherché des inhibiteurs d'épissage et/ou de NMD parmi une collection de 6 000 composés chimiques. Nous avons ainsi pu identifier des composés capables de moduler l'épissage en affectant l'activité de facteurs clefs de la sélection des sites d'épissage, les protéines SR. Nous avons également mis en évidence le premier inhibiteur spécifique du NMD qui bloque spécifiquement la fonction du facteur hUpf1. Ces molécules nous ont permis de disséquer le fonctionnement de ces processus, de proposer un nouveau modèle décrivant le transit des mRNP soumises au NMD par les P-Bodies et ouvrent maintenant la voie à la mise en place de nouvelles stratégies thérapeutiques utilisant ces composésRNA splicing involves the processing of pre-messenger RNA molecules by the excision of introns and the precise joining of exons to form the mature messenger RNA that is exported from the nucleus for translation. Exon usage is often alternative, i. E. The cell decides whether to remove a part of the pre-mRNA as an intron or include this part in the mature mRNA as an alternative exon. Alternative splicing is therefore, a genetically economical process that enables a single gene to increase its coding capacity, allowing the synthesis of several structurally and functionally distinct protein isoforms. To avoid accumulation of aberrantly spliced mRNAs, several quality control processes determine the fate of mRNA in the cell. Among these processes, Nonsense-Mediated mRNA decay (NMD), is able to degrade mRNA containing premature termination codons (PTCs), preventing accumulation of truncated with deleterious effects for the cell. As central mechanisms controlling gene expression any disturbance of either splicing or NMD can lead to genetic diseases. Indeed, the numbers of diseases shown to be caused by a defect in pre-mRNA splicing or NMD is rapidly growing. For example, in ataxia telengectasia or type I neurofibromatosis, 54% of disease-inducing mutations affect mRNA splicing. Moreover, one third of acquired and inherited pathologies are due to nonsense creation that elicits NMD. Consequently, mRNA splicing and NMD represent a potential targets for new therapeutic strategies. During this thesis, we have screened a small chemical library to find splicing and NMD inhibitors. We have identified some molecules that modulate mRNA splicing efficiency by affecting SR proteins activity. We have also isolated the first specific inhibitor of NMD that blocks hUpf1 functions. These compounds allowed us to decipher splicing and NMD mechanisms and to propose a new model to describe the NMD-subjected mRNP transit trough the processing-Bodies. The next challenge will be to demonstrate the functional utility of these molecules in preclinical models of human disease
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Percino, Eziel Belaparte. "Murilo Rubião: a bárbara porcelana." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/8/8151/tde-08012013-122559/.
Повний текст джерелаАнотація:
Murilo Rubião é visto como um caso raro na literatura brasileira: poucos autores produziram como ele uma ficção tão decididamente marcada por situações insólitas, eventos estranhos, cenas inusitadas. Não à toa, sua literatura é estudada a partir de discussões em torno do chamado fantástico contemporâneo (ou neofantástico, ou realismo fantástico, ou realismo mágico, ou realismo maravilhoso). Por agora, no entanto, a questão é outra: alguns engenhos em Rubião potencializam um horizonte de pensamento que promove reflexões sobre a noção de não-senso (não-significado). O não-senso é uma possibilidade, por assim dizer, transgenérica - ainda que por vezes possa ser decidido em melhores circunstâncias no que se convencionou chamar, genericamente, literatura nonsense, literatura do absurdo e mesmo literatura fantástica. A fim de fazer jus a este horizonte, esta dissertação cruza os contos, animada por uma lógica do acontecimento, buscada fora das tradições platônicas e aristotélicas, criando ao longo dos capítulos cenários e instâncias associativas que, por sua vez, solicitam algumas distinções: explicação laboratorial e experiência lógica, senso-significado e senso-sentido, imagem e imagem pura, ser e extra-ser. A discussão aqui travada visa contribuir para a prática de uma experiência na literatura de Rubião.Murilo Rubião is seen as a rare case in Brazilian literature: few authors have produced a fiction so strongly marked by unusual situations, strange events, and unusual scenes. Not for nothing, his literature is studied starting by discussions on the so-called contemporary fantastic (or neo-fantastic, or fantastic realism, or magic realism, or marvelous realism). For now, however, the question is another one: some of Rubiãos pyrotechnics empower a horizon of thought that promotes reflections on the notion of nonsense (non-meaning). The nonsense is, so to speak, a transgender possibility - though sometimes it can be determined, in the best circumstances, in what is generically called nonsense literature, literature of the absurd, and even fantastic literature. In order to make justice to this horizon, this dissertation travels the tales, it animated by a logic of the event, outside of the Platonic and Aristotelian traditions, creating, throughout the chapters, sceneries and associative instances which, in turn, ask for some distinctions: laboratorial explanation and logic experience, sense-meaning and sense-sense, image and pure image, being and extra-being. The discussion promoted here aims to contribute to the practice of an experience in the literature of Rubião.
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Raimondeau, Etienne. "A new link between translation termination and NMD complexes." Thesis, Université Grenoble Alpes (ComUE), 2016. http://www.theses.fr/2016GREAV048/document.
Повний текст джерелаАнотація:
Environ un tiers des maladies humaines, héréditaires ou acquises, sont dues à la génération d’un codon stop prématuré (PTC). Le système de contrôle appelé dégradation des ARNm non-sens (NMD) permet de détecter puis de dégrader des ARNm contenant un PTC. Les facteurs principaux de la NMD : UPF1, UPF2 et UPF3 reconnaissent les PTCs en interagissant avec le complexe de terminaison de traduction contenant les ribosomes, les facteurs de terminaison eRF1, eRF3 et la protéine poly(A) binding (Pab1p en levure). Nous avons pu résoudre la structure d'un tel complexe en levure comprenant un ribosome en cours de traduction en présence d’un ARNt dans le site P et de facteurs de terminaisons dans le site A. Aucune densité n’a pu être observée pour Pab1p indiquant la flexibilité de l’interaction avec ce complexe. Nous avons aussi évalué l’impact des facteurs de la NMD sur la terminaison dans un système de traduction in vitro humain. UPF3B retarde la reconnaissance du codon stop et favorise la dissociation des sous-unités ribosomales. UPF2 abolit l’effet de UPF3B tandis que l’addition de UPF1 n’a pas d’influence dans la terminaison. Par in vivo et in vitro pulldowns, nous avons montré que UPF3B interagit avec eRF3a et UPF1 et pourrait constituer le lien manquant entre la terminaison et la NMD. Nos résultats illustrent la complexité des mécanismes de la terminaison et de la NMDPremature termination codons (PTCs) account for approximately one third of inherited and acquired diseases. A surveillance pathway called nonsense-mediated mRNA decay (NMD) detects and degrades PTC-containing transcripts. NMD core factors UPF1, UPF2 and UPF3 mediate the recognition of PTCs by associating with the terminating translation machinery composed of the ribosome, the release factors eRF1 and eRF3 and the poly(A) binding protein (Pab1p in yeast). Using electron cryo-microscopy, we solved such a complex in yeast and observed the translating ribosome, containing a P-site tRNA and an A-site density for the release factors but not for Pab1p indicating that Pab1p is flexibly bound. We also probed the function of NMD factors in mammalian termination using a reconstituted human in vitro translation system. Surprisingly, we found that UPF3B delayed stop codon recognition and promoted ribosomal dissociation. The addition of UPF2 could abolish UPF3B’s effect on translation termination. UPF1 had no influence in the termination process alone or in combination with UPF2. Using in vitro and in vivo pulldowns we found that UPF3B interacts with eRF3a and UPF1, indicating that UPF3B could be the missing link between termination and NMD. Our results point to a complex interplay between the NMD factors and the termination apparatus
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Bugaud, Olivier. "Suppression traductionnelle des codons stop chez les mammifères." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS222.
Повний текст джерелаАнотація:
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’élongationNonsense 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
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Benhabiles, Hana. "Etude de la correction de mutations non sens par de nouvelles molécules pouvant servir d'approches thérapeutiques ciblées." Thesis, Lille 2, 2017. http://www.theses.fr/2017LIL2S046.
Повний текст джерелаАнотація:
Les mutations non sens introduisent un codon stop prématuré dans une phase ouverte de lecture. Ce type de mutation est retrouvé chez environ 11% des patients atteints de maladies génétiques et dans de nombreux cancers. En effet, entre 5 et 40% des mutations affectant des gènes suppresseurs de tumeurs sont des mutations non sens. La conséquence de la présence d’une mutation non sens dans un gène est la dégradation rapide de l’ARN messager correspondant, par l’activation d’un mécanisme de surveillance des ARN appelé NMD (pour nonsense-mediated mRNA decay) conduisant à une absence d’expression du gène mutant. Dans le cas des cancers, l’absence d’expression d’un gène suppresseur de tumeurs tel que TP53, perturbe un ensemble de processus biologiques dont l’apoptose, facilitant ainsi la progression tumorale.En utilisant un système de criblage moyen débit permettant d’identifier des molécules capables de ré-exprimer des gènes porteurs d’une mutation non sens en inhibant le NMD et/ou en activant la translecture, plusieurs molécules ont été identifiées. La translecture est un mécanisme naturel conduisant à l’incorporation d’un acide aminé à la position du codon stop prématuré au cours de la traduction. Parmi les molécules identifiées, je me suis intéressée à un extrait végétal nommé H7 et au composé CNSM1 (pour corrector of nonsense mutation 1) qui permettent une ré-expression très efficace du gène TP53 lorsqu’il est porteur d’une mutation non sens. J’ai caractérisé ces composés en montrant notamment la ré-expression du gène TP53 porteur d’une mutation non sens dans différentes lignées cellulaires issues de différents cancers. J’ai montré également la très faible toxicité de ces molécules, validant leur potentielle utilisation en clinique. Mon étude a aussi permis de montrer que la protéine p53 synthétisée est fonctionnelle puisqu'elle est capable d’induire l’activation transcriptionnelle d’un de ses gènes cibles, le gène TP21.En permettant la ré-expression du gène suppresseur de tumeur mutant, des molécules comme CNSM1 ou H7 restaurent la capacité des cellules à entrer en apoptose et pourraient aussi réduire certaines résistances à la chimiothérapie.De plus, par une approche d’édition du génome, j’ai confirmé le lien existant entre le blocage du cytosquelette et l’inhibition du NMD. J’ai aussi identifié deux protéines impliquées dans le réarrangement du cytosquelette qui pourraient être ciblées pour inhiber le NMD en thérapie et ré-exprimer une protéine tronquée fonctionnelle. L’utilisation de H7 ou de CNMS1 pourrait ainsi être couplée à une inhibition du NMD pour optimiser la correction des mutations non sens. Ces molécules correctrices de mutations non sens représentent de nouvelles approches thérapeutiques ciblées du cancer et des maladies rares liées aux mutations non sensNonsense mutations generate premature termination codons (PTC) within an open reading frame. This type of mutation is found in about 11% of patients with genetic disorders. Concerning cancer, 5 to 40% of mutations affecting tumor-suppressing genes are nonsense mutations. The presence of a PTC in a gene leads to rapid degradation of its mRNA mediated by the RNA surveillance mechanism named NMD (Nonsense-mediated mRNA decay) preventing the synthesis of truncated proteins. In cancer, the absence of expression of tumor suppressing genes such as TP53 interferes with many biological pathways including apoptosis enabling tumor progression.A screening system that allows identifying molecules capable of re-expressing genes harboring nonsense mutations by inhibiting the NMD system and/or by activating readthrough has been developed in the lab. Readthrough is a natural mechanism, which occurs during translation, leading to the incorporation of an amino acid at the PTC position. Among the molecules that have been identified thanks to the screen, a natural extract named H7 and a compound named CNSM1 efficiently rescues the expression of the nonsense-mutated TP53 gene carrying a PTC.CNSM1 and H7 induces the expression of full-length proteins from PTC-containing genes indicating that these compounds are capable of activating readthrough. I validated the screen results on several cancer cell lines harboring an endogenous nonsense mutation in TP53 gene and showed that the function of p53 was restored in the presence of CNSM1 or H7. I also investigated the cellular toxicity related with the use of CMNS1 on cultured cells and the in vivo effect of H7 in a mouse model harboring a nonsense mutation in dystrophin gene. My results demonstrate that these compounds have a mild cellular toxicity. In addition, using a genome editing approach I confirmed the relationship between the cytoskeletal blockage and the NMD inhibition. I identified two proteins that are implicated in the cytoskeletal rearrangement, which might be targeted to induce NMD inhibition and then the expression of truncated but functional protein from the mutated mRNA. H7 or CNMS1 might be coupled to an NMD inhibition strategy to improve the nonsense mutation correction. Knowing CNSM1 and H7 are so far the most efficient molecule capable of rescuing the expression of PTC-containing genes, these compounds represents a realistic hope for a new-targeted therapy for pathologies associated with nonsense mutations
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Okutman, Özlem. "Genetics of male infertility : genes implicated in non-obstructive azoospermia and severe oligozoospermia." Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ049/document.
Повний текст джерелаАнотація:
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 MAGEAmong 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
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Loret, Camille. "Maladie de Charcot-Marie-Tooth : création de modèles cellulaires neuronaux via les technologies hiPSCs et CRISPR-Cas9 et test de nouvelles stratégies thérapeutiques." Electronic Thesis or Diss., Limoges, 2024. http://www.theses.fr/2024LIMO0067.
Повний текст джерелаАнотація:
La maladie de Charcot-Marie-Tooth (CMT) est la neuropathie périphérique héréditaire la plus fréquente chez l’humain. Elle touche les motoneurones (MN) et les cellules de Schwann (CS). La majorité des gènes impliqués, dont SH3TC2 et GDAP1, peuvent être affectés par des mutations non-sens. En 2021, peu de modèles cellulaires humains existaient, et aucun traitement curatif n'était disponible pour les patients. Les travaux de cette thèse se centre sur SH3TC2, responsable de la forme démyélinisante autosomique récessive la plus fréquente des CMT, nommée CMT4C ou AR-CMTde-SH3TC2 et sur GDAP1 notamment responsable d’une forme axonale AR-CMTax-GDAP1. Dans un premier temps, nous avons analysé une cohorte de 103 patients mutés sur SH3TC2 et montré que plus de 80 % des patients possédaient au moins un allèle avec une mutation non-sens, associé à une gravité clinique accrue. Nous avons également identifié 22 nouvelles mutations pathogènes sur ce gène. La seconde partie de ce travail a consisté à créer les premiers modèles cellulaires neuronaux humains pour SH3TC2. À partir de cellules souches pluripotentes induites (hiPSCs) issues d’un individu contrôle, nous avons utilisé la technologie CRISPR-Cas9 pour produire, avec plus de 90% d’efficacité, deux modèles humains in vitro contenant des mutations non-sens induisant un codon stop prématuré (PTC) : un modèle homozygote p.(Arg954*) (PTC de type UGA) et un modèle homozygote p.(Gln71*) (PTC de type UAG). Ces hiPSCs contrôle et mutées ont ensuite été différenciées en CS. Nous avons mis en évidence une expression précoce de SH3TC2 dans les CS contrôle. Dans les modèles CS AR-CMTde-SH3TC2, une expression réduite de SH3TC2, un retard de maturation, une capacité réduite à soutenir les MN en coculture, et des anomalies dans le recyclage des récepteurs à la transferrine ont été observées. Enfin, nous avons testé plusieurs molécules thérapeutiques ciblant les mutations non-sens, des agents de translecture et des inhibiteurs du mécanisme de surveillance des ARN non-sens (NMDi). Sur un modèle de progéniteurs neuronaux dérivés d’hiPSCs portant la mutation homozygote non-sens p.(Ser194*) (UGA) sur GDAP1, nous avons testé une de ces molécules et montré qu’elle stabilisait l'ARNm muté GDAP1, restaurait son expression protéique et corrigeait la morphologie mitochondriale. Dans les modèles CS créés dans cette thèse pour SH3TC2, nos premiers résultats suggèrent l’effet positif de deux de ces molécules sur la réexpression de la protéine pour les deux types de codons UGA et UAG. Dans la quatrième partie de ce travail, nous avons développé un modèle 3D de coculture CS/MN permettant d’induire la myélinisation, étape ultime pour étudier les maladies démyélinisantes comme l’AR-CMTde-SH3TC2. Les molécules thérapeutiques identifiées pourront être testées sur ces modèles cellulaires de coculture et potentiellement in vivo pour évaluer leur capacité à induire une remyélinisation. Ce travail de thèse souligne l'importance des modèles cellulaires adaptés pour comprendre les mécanismes physiopathologiques de la CMT et ouvre des perspectives prometteuses pour de nouvelles approches thérapeutiquesCharcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy in humans. It affects motor neurons (MNs) and Schwann cells (SCs). Most of the genes involved, such as SH3TC2 and GDAP1, can be affected by nonsense mutations. As of 2021, few human cellular models existed, and no curative treatment was available for patients. This thesis primarily focuses on SH3TC2, responsible for the most common autosomal recessive demyelinating form of CMT, known as CMT4C or AR-CMTde-SH3TC2, and on GDAP1, notably responsible for an axonal form, AR-CMTax-GDAP1. In the first part of this work, we analyzed a cohort of 103 patients with SH3TC2 mutations and demonstrated that more than 80% of the patients carried at least one allele with a nonsense mutation, associated with increased clinical severity. We also identified 22 new pathogenic mutations in this gene. The second part of my work involved creating the first human neuronal cell models for SH3TC2. Using induced pluripotent stem cells (hiPSCs) derived from a control individual, we employed CRISPR-Cas9 technology to generate, with over 90% efficiency, two in vitro human models containing nonsense mutations inducing a premature stop codon (PTC): a homozygous p.(Arg954*) model (UGA-type PTC) and a homozygous p.(Gln71*) model (UAG-type PTC). These controls and mutated hiPSCs were then differentiated into Schwann cells (SCs). We observed early SH3TC2 expression in control SCs. In AR-CMTde-SH3TC2 SC models, reduced SH3TC2 expression, delayed maturation, impaired ability to support MNs in co-culture, and abnormalities in transferrin receptor recycling were noted. Finally, we tested several therapeutic molecules targeting nonsense mutations, including readthrough agents and inhibitors of nonsense-mediated mRNA decay (NMDi). In a model of neuronal progenitors derived from hiPSCs carrying the homozygous nonsense mutation p.(Ser194*) (UGA) on GDAP1, we tested one of these molecules and demonstrated that it stabilizes the mutated GDAP1 mRNA, restores its protein expression, and corrects mitochondrial morphology. In the SC models created in this thesis for SH3TC2, our early results suggest a positive effect of two of these molecules on protein re-expression for both UGA and UAG codons. In the fourth part of this work, we developed a 3D co-culture model of SCs/MNs that enables myelination, the ultimate step to studying demyelinating diseases such as AR-CMTde-SH3TC2. The identified therapeutic molecules can be tested on these co-culture cellular models and potentially in vivo to evaluate their capacity to induce remyelination. This thesis highlights the importance of appropriate cellular models to understand the pathophysiological mechanisms of CMT and opens promising perspectives for new therapeutic approaches
26
Meulemans, Laetitia. "Caractérisation fonctionnelle de variations splicéogéniques à l'origine d'anomalies d'épissage en phase dans des gènes de prédisposition aux cancers : implications en génétique médicale Skipping nonsense to maintain function : the paradigm of BRCA2 Exon 12 Functional characterization of MSH2 variants resulting into in-frame splicing alterations." Thesis, Normandie, 2021. http://www.theses.fr/2021NORMR008.
Повний текст джерелаАнотація:
Aujourd’hui, le défi majeur en génétique médicale est l’interprétation clinique des variations détectées dans le génome des patients. Dans un contexte de maladie monogénique, l’identification de la variation pathogène permet d’optimiser la prise en charge des patients et de leurs apparentés. Les variations non-sens ainsi que celles localisées au niveau des sites canoniques d’épissage (IVS±1/2) sont généralement considérées causales. Toutefois, il est possible que certaines d’entre elles induisent des anomalies d’épissage en phase permettant potentiellement la production d’une protéine fonctionnelle. Afin de tester cette hypothèse, nous avons choisi comme modèles d’étude deux gènes majeurs de prédisposition aux cancers : BRCA2, pour le syndrome sein-ovaire et MSH2, pour le syndrome de Lynch. Des approches expérimentales complémentaires ont été mises à profit afin de caractériser l’impact de ce type de variations non seulement au niveau de l’épissage mais également au niveau de la protéine. Notre étude portant sur des variations de BRCA2 a démontré que certaines variations IVS±1/2 et non-sens (i) induisent un saut en phase de l’exon 12 du fait de l’altération de sites d’épissage ou d’éléments de régulation et (ii) sont de ce fait responsables du maintien de l’activité BRCA2, tout en étant hypomorphes. Ces travaux montrent, pour la première fois dans un gène de prédisposition au cancer, que certaines variations présumées nulles peuvent contourner la perte totale de fonction du fait de leur impact sur l’épissage. Nos données remettent ainsi en question le caractère pathogène de ces variations. Dans le cadre de notre étude portant sur des variations IVS±1/2 de MSH2, nous avons caractérisé trois biotypes d’anomalies d’épissage en phase : (i) des sauts d’exon, (ii) des délétions de portions exoniques et (iii) des rétentions introniques, avec pour conséquence au niveau protéique des délétions ou insertions de plus ou moins grande taille dans différents domaines fonctionnels. Toutes les isoformes protéiques MSH2 résultant de ces variations splicéogéniques se sont avérées inactives, confirmant ainsi leur caractère pathogène. L’ensemble de ces travaux souligne l’importance d’exercer une certaine prudence dans l’interprétation des variations considérées a priori pathogènes mais susceptibles de générer des anomalies d’épissage en phase. Dans ce contexte, la combinaison d’approches expérimentales complémentaires pour appréhender l’impact biologique au niveau de l’ARN et de la protéine est essentielle pour une interprétation fiable de ce type de variations. Ces données mettent également en exergue la problématique de l’interprétation clinique des variations hypomorphes dans les gènes de prédisposition aux cancersToday, the major challenge in medical genetics is the clinical interpretation of nucleotide variants detected in a patient’s genome. In the context of a monogenic disease, the identification of the pathogenic variant allows the optimization of the medical care of patients and their relatives. Nonsense variations as well as those located at the canonical splice sites (IVS±1/2) are generally considered pathogenic. However, it is possible that a fraction of them induce in-frame splicing anomalies that can potentially result in the production of a functional protein. To test this hypothesis, we used as model systems two major cancer-predisposition genes: BRCA2, implicated in hereditary breast and ovarian cancer syndrome and MSH2, involved in Lynch syndrome. We took advantage of complementary experimental approaches to characterize the impact of this type of variants not only in RNA splicing but also at the protein level. Our study on BRCA2 demonstrated that a subset of IVS±1/2 and nonsense variants (i) induce in-frame skipping of exon 12 via the modification of splice sites or of splicing regulatory elements and (ii) are able to maintain BRCA2 activity though being hypomorphic. These data provide the first evidence, in a cancer-predisposition gene, that certain presumed null variants can bypass total loss of function due to their impact on splicing. Thus our findings call into question the pathogenic nature of these variants. In our study on MSH2 IVS±1/2 variants, we characterized three biotypes of in-frame splicing defects responsible for deletions or insertions at the protein level in different MSH2 functional domains: (i) exon skipping, (ii) deletions of exonic portions and (iii) intron retentions. All the MSH2 protein isoforms resulting from these spliceogenic variants were found to be inactive, thus confirming their pathogenic classification. Altogether, our findings highlight the need to exercise caution in the interpretation of putative pathogenic variants susceptible to induce in-frame splicing modifications. In this context, the combination of complementary experimental approaches assessing the biological impact at the RNA and protein level is essential for a reliable interpretation of this type of variants. Furthermore, our results stress the problem of the clinical interpretation of hypomorphic variants in cancer-predisposition genes
27
"Sense Through Nonsense Reading Difficult Poetry." Master's thesis, METU, 2004. http://etd.lib.metu.edu.tr/upload/12605178/index.pdf.
Повний текст джерела
28
"Sense and nonsense about culture and climate." Sloan School of Management, Massachusetts Institute of Technology, 1999. http://hdl.handle.net/1721.1/2759.
Повний текст джерелаАнотація:
by Edgar H. Schein.Title from cover. "September 1999."
Includes bibliographical references (leaves 18-19).
Partially supported by a Singapore-MIT Alliance grant and an NSF grant. DMI-9610486
29
Huang, Shu-Hua, and 黃淑樺. "Co-constructed Humor: Creating Sense in Nonsense." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/50361817140648662056.
Повний текст джерелаАнотація:
碩士靜宜大學
英國語文學系研究所
98
Humor often occurs in everyday conversations and there are various genres such as mocking, teasing, joke-telling, anecdotes, and situational joking. The present study investigates the phenomenon of co-construction in situational humor, which occurs quite often between close friends. The researcher hypothesizes that the success of co-construction depends on the conversationalists’ shared knowledge schemas and their tacit agreement. It aims, firstly, to illustrate the relationship between the participants’ knowledge schemas and how they contribute to the co-constructed humor. Secondly, it aims to figure whether there is a fixed discourse structure for the phenomenon concerned. The participants were six female Taiwanese students who joined a study group for a research method class. The researcher herself was one of the participants. The conversations analyzed were recorded when the participants were having discussions. They were analyzed through sequential conversation analysis and the researcher’s in-group knowledge. The notion of knowledge schema is applied to support the analyses. The analyses of the conversations show that the participants’ contributions are all related to the evoked topics. This indicates that the participants obey the cooperative principle when interacting in the play frame, as proposed in Raskin (1985). The discourse structure of co-constructed humor is found to be consistent. Moreover, schema conflicts in the play frame seem to cause more diverse results than in the serious frame. The researcher’s attempt to apply knowledge schemas to co-constructed humor is successful. This fills up the gap in the literature, in which knowledge schemas are rarely used in analyzing situational humor.
30
Squires, Jeffrey E. "Making sense out of nonsense : Mechanistic insight into selenoprotein synthesis factors." Thesis, 2008. http://hdl.handle.net/10125/20460.
Повний текст джерелаАнотація:
Thesis (Ph.D.)--University of Hawaii at Manoa, 2008.Selenium is an essential micronutrient linked to various aspects of health. Selenium exerts its biological activity through incorporation of the amino acid, selenocysteine (Sec), into a unique class of proteins termed selenoproteins. Sec incorporation occurs cotranslationally at UGA codons in archaea, prokaryotes, and eukaryotes. UGA codons specify Sec coding rather than termination by the presence of secondary structures in mRNAs termed selenocysteine insertion (SECIS) elements, and trans-acting factors that associate with SECIS elements. Selenoprotein mRNAs are potential targets for degradation via nonsense-mediated decay, due to the presence of in-frame UGA codons. When UGA recoding is inefficient, as occurs when selenium is limiting, termination occurs at these positions. Based on predicted exon-intron structure, fourteen of the 25 human selenoprotein mRNAs are predicted to be sensitive to nonsense-mediated decay. Among these, sensitivity varies, resulting in a hierarchy of selenoprotein synthesis. Potential factors dictating this hierarchy are the SECIS binding proteins, SBP2 and nucleolin. To investigate the role of these proteins in the hierarchy of selenoprotein synthesis, we carried out knockdowns of SBP2 expression and assessed the effects on selenoprotein mRNA levels. We also investigated in vivo binding of selenoprotein mRNAs by SBP2 and nucleolin, via immunoprecipitation and quantitation of bound mRNAs. We report that SBP2 exhibits preferential binding to some selenoprotein mRNAs over others, whereas nucleolin exhibits minimal binding differences. Thus SBP2 is a determinant in dictating the hierarchy of selenoprotein synthesis via differential selenoprotein mRNA translation and sensitivity to nonsense-mediated decay.
Selenophosphate synthetase 1 (SPS1) and selenophosphate synthetase 2 (SPS2) have been implicated as essential components in selenoprotein biosynthesis. In vitro studies have demonstrated that SPS2, but not SPS1, generates the active selenium donor for Sec synthesis, monoselenophosphate. To establish the functions of these two proteins in vivo, siRNAs were used to knockdown SPS1 and SPS2 expression, and DNA constructs were designed to overexpress the two proteins in HEK-293 and MSTO-211H cells. Knockdown of SPS1 and SPS2 decreased the protein levels of several selenoproteins whereas the overexpression of SPS1 and SPS2 increased selenoprotein levels. These results reconfirm the role of SPS2 and establish SPS1 as a factor that regulates selenoprotein biosynthesis.
Includes bibliographical references (leaves xxx-xxx).
Also available by subscription via World Wide Web
83 leaves, bound 29 cm
31
"From "nonsense" to "making sense:" How education leaders interpret and implement supplemental educational services." STATE UNIVERSITY OF NEW YORK AT ALBANY, 2009. http://pqdtopen.proquest.com/#viewpdf?dispub=3336697.
Повний текст джерела
32
Abdullah, Sarwar. "Tractatus: Logic and the Challenge of Ethics." 2013. http://hdl.handle.net/10222/36282.
Повний текст джерелаАнотація:
The subject of this thesis is primarily the ethical point of Wittgenstein’s Tractatus. In the work, Wittgenstein investigates the connection between ethics and the world by examining the nature of the proposition. In the Lecture on Ethics, Wittgenstein reinvestigates this connection more directly by explaining the nature of the ethical expression. I argue that the ethical point of the book is to help one to understand the ephemeral characteristics of ethics insofar as they cannot be articulated by demonstrating what can be articulated. In the Lecture, Wittgenstein also points to a deep challenge encountering the Tractarian pictorial language. Logic reminds us that we are held captive by pictorial language and could never get outside it. Ethics, on the other hand, is a constant attempt to get outside of it by usage of simile. Although this attempt seems to be hopeless, it is unavoidable and significant. It characterizes the human condition.
33
Faucher, Benoît. "Le paradoxe dans les Alices de Lewis Carroll : la force du littéraire dans la théorisation de l'irrésoluble /." Thèse, 2006. http://hdl.handle.net/1866/7913.
Повний текст джерела
34
PRUSAK, MONIKA. "Il senso musicale del Nonsense: Petrassi e Ligeti. Due esempi di "nemadrigalismo" nel secondo Novecento." Doctoral thesis, 2017. http://hdl.handle.net/11573/1053474.
Повний текст джерелаАнотація:
Le opere vocali scelte per questo lavoro sono state finora poco studiate e analizzate, per cui la loro eco in letteratura risulta piuttosto limitata. La ricerca prende in esame i Nonsense (1952) e il Sesto Non-Senso (1964) di Goffredo Petrassi e i Nonsense Madrigals (1988-93) di György Ligeti, per analizzare l’incontro tra il contenuto letterario nonsense e la sua elaborazione musicale, le circostanze della composizione e il legame tra il nonsense e le idee stilistiche dei due musicisti. La scelta delle composizioni non è casuale, bensì volta a presentare due differenti rappresentazioni del nonsense nelle opere vocali a cappella che segnano la ripresa della forma madrigalistica in diversi contesti della seconda metà del XX secolo. Questo studio si articola in quattro capitoli che, partendo da una prova di definizione del nonsense e delle sue regole, giunge all’analisi del senso musicale che risulta dalla messa in musica di testi letterari nonsense in circostanze particolari di composizione. Il primo capitolo Nonsense: origini e strumenti del genere letterario analizza il genere e i testi impiegati nelle composizioni oggetto di questo lavoro. I due capitoli seguenti, Nonsense e Sesto Non-Senso di Goffredo Petrassi e Nonsense Madrigals di György Ligeti, prendono in esame le partiture, inserite nel contesto storico-culturale, e all’interno della produzione degli autori. Il quarto capitolo, Il senso musicale del nonsense: riflessioni finali, oltre ad analizzare i metodi e le operazioni del nonsense usate da Petrassi e Ligeti nelle loro composizioni, aspira a trovare delle risposte ai quesiti legati al significato della messa in musica di contenuti nonsense, ovvero al senso musicale del nonsense.
Lo studio è stato condotto sulla base del materiale reperito in due Istituti di ricerca, Fondazione Paul Sacher di Basilea (Ligeti e Petrassi) e Istituto di Studi Musicali “G. Petrassi” di Latina (Petrassi), nei repertori disponibili on-line e nelle pubblicazioni sull’argomento. La più grande difficoltà di questo lavoro è stata quella di inquadrare le ragioni che hanno spinto Goffredo Petrassi a comporre i Nonsense e il Sesto Non-Senso, soprattutto perché le affermazioni del compositore al riguardo sono state sempre piuttosto ermetiche e contrastanti. Si è rivelata molto fruttuosa, invece, la ricerca sui Nonsense Madrigals di György Ligeti, grazie alla meticolosa conservazione dei suoi documenti da parte del compositore e della Fondazione svizzera.
La ricerca è iniziata con l’esame della letteratura del genere nonsense, anche in musica, per passare successivamente all’analisi delle fonti: i testi e le partiture. Solo dopo queste fasi si è potuto prendere in esame il contenuto nonsense delle musiche di Petrassi e di Ligeti. Ai fini di un’analisi chiara e sistematica si è dimostrato fondamentale il libro di analisi letteraria del nonsense di Susan Stewart, che ha fornito uno spunto rilevante per l’analisi delle partiture.