Much women's writing in the late eighteenth and early nineteenth centuries attempts to depict other women visually through textual description, use of optical devices, and discussion of bodies and appearances. This thesis argues that they were trying to see and show other women as a way of understanding themselves and each other by examining intersections between visual culture and text through mirrors, miniatures, and portraits. This thesis demonstrates how these works reflect larger shifts in the optical unconscious of the eighteenth century. I focus on works by Joanna Baillie and Louisa Stuart Costello, who theorize the viewing process in their prose and manipulate the viewing process in their drama and poetry, respectively. By manipulating the gaze these authors show readers new ways of seeing women, and subsequently, themselves, and seek to make them conscious of their optical unconscious; their works become the optical devices that allow this to happen. / McAnulty College and Graduate School of Liberal Arts / English / MA / Thesis

In Elizabeth Costello (2003) and Slow Man (2005), J. M. Coetzee stages a doubling of voices in a number of ways on both fictional and meta-fictional levels. It occurs between one novel and the other, co-opting ¡§lectures¡¨ from yet a third work of his (The Lives of Animals, 1999) into the sequence to further complicate this practice of doubling. It also happens between characters that cross over from one work into another, between Elizabeth Costello who visits herself on Paul, in Slow Man, as the latter¡¦s ¡§author¡¨ and saving angel, and Paul, the slow man himself who tries to wean himself from such abstruse claims. Such a joint motif of crossing-over, resistance, and further attempts at claiming control makes a strong case against the integrity of generic and identity boundaries ¡V boundaries that traditional novels mostly adhere to in their stories. Together, in the sequence, however, these acts of transgression tend to double back upon one another, so much so that doubling practically becomes the main plot. This thesis examines how such a motif of doubling enhances the volume of voices that are too often muffled behind the loud insistence on limits and identity. It looks into the ¡§debates¡¨ between the generic forms in which the novels are written, namely narratives, essays, lectures and letters. Taking these debates into account, this thesis asks the fundamental question of how the characters ¡§communicate,¡¨ and what the value of ¡§communication¡¨ is when it produces only the effect of ¡§the hazard of language.¡¨ This may well be exactly the ultimate ¡§value¡¨ of the motif of doubling in this sequence, namely that by rubbing one voice against another, these novels succeed in giving shape and body to the ¡§countervoices¡¨ that lie checked under the human ethical bond of language. It takes a he and a she, a man who is looking for care and a writer who thinks she has the right cure to offer in writing, to construe the real conflicts between one man¡¦s cure and a woman¡¦s offer of care. Between the search for cure and the offer of care, there lies the true gap of beings that cannot be bridged. They can be crossed and crossed over at best, and it is the purpose of this thesis to count, to illustrate and to fathom some of these gaps of beings, and, as Coetzee tries to do, albeit in his typical self-reflexive mode of writing, to imagine the imaginary with which a cross-over is possible by way of writing.

Thesis (M.A.)--Marshall University, 2004. / Title from document title page. Document formatted into pages; contains i, 81 p. Includes abstract. Includes bibliographical references (p. 76-81).

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Les RASopathies avec phénotype Noonan associent le syndrome de Noonan (SN), le syndrome cardio-facio-cutané (SCFC) et le syndrome de Costello (SC). Leurs manifestations dermatologiques restent peu étudiées.Objectifs Colliger les différentes manifestations dermatologiques des SN, SCFC et SC afin d’établir leur nature et leur prévalence, et définir d’éventuelles corrélations phénotype/génotype au sein de chacune de ces affections.Méthodes Les patients atteints d’un SN, SCFC et SC confirmé sur le plan moléculaire par la présence d’une mutation germinale pathogène étaient inclus dans une étude menée durant 5 ans dans les départements de Génétique, Dermatologie et Pédiatrie des CHU de Bordeaux, Marseille, Montpellier, Nancy, Nantes, Paris AP-HP (Hôpital Robert-Debré et Hôpital Necker-Enfants Malades), Rennes, Saint-Pierre (La Réunion) et Toulouse.Résultats Cent quatre-vingt-quatorze patients atteints de SN, SCFC et SC étaient inclus. Cent-vingt et un patients atteints de SN étaient inclus. La tendance aux hématomes était la manifestation la plus fréquente au cours du SN-PTPN11 (53.8%). Les ML et les tâches café-au-lait atypiques (≥3) étaient observés respectivement dans 94% et 80% des SNML liés à des mutations spécifiques de PTPN11. Des formes atypiques de SNML étaient associées au SN-RAF1 et SN-NRAS. En analyse univariée, les patients sans mutation PTPN11 présentaient (i) un risque de troubles de la kératinisation augmenté (P=0.001), dont la kératose pilaire (KP) (P=0.005), l’ulerythema ophryogenes (UO) (P=0.0001) et la kératodermie palmoplantaire (KPP) (P=0.06), et (ii) un risque augmenté d’alopécie du scalp (P=0.035) et des cils (P=0.06) par rapport aux patients sans mutation PTPN11.Quarante-cinq patients atteints de SCFC étaient inclus, parmi lesquels 77,8% avec mutation BRAF. Les anomalies pilaires étaient constantes, incluant une alopécie du scalp et des sourcils et des cheveux frisés ou bouclés respectivement dans 73% et 69% des cas. Une KP, un UO, une KPP et de multiples naevi (MN >50) étaient observés respectivement dans 82%, 44%, 27% et 29% des cas. L’alopécie des sourcils, l’association UO et KPP, la KP diffuse, et les MN constituaient des signes pertinents de différenciation du SCFC avec le SN et le SC. L’acitrétine orale permettait de traiter avec succès la KPP, tandis que le traitement de l’UO par sirolimus à 1% en topique échouait. Aucune corrélation phénotype-génotype n’était notée.Vingt-et-un patients atteints de SC étaient inclus, parmi lesquels 60% avec la mutation p.G12S-HRAS. Les anomalies pilaires étaient constantes, comprenant des cheveux frisés ou bouclés et une alopécie du scalp respectivement dans 70% and 60% des cas. Un acanthosis nigricans, des papillomes, une KPP, et une cutis laxa acrale étaient notés respectivement dans 65%, 65%, 55% et 80% des cas. Des papules linéaires à disposition pavimenteuse de la lèvre supérieure étaient présentes dans 55% des cas, tandis que l’alopécie des sourcils ou le lymphoedème n’étaient pas observés. Aucune corrélation phénotype-génotype n’était notée. Un patient avec SC atypique avec mutation c187_207dup21/p.Glu63_Asp69dup-HRAS présentait un phénotype cutané distinct associant des MN, un lymphoedème et des manifestations dermatologiques de SC, évoquant une nouvelle forme phénotypique de chevauchement entre un SC et un SN et/ou un SCFC.Conclusion La connaissance précise des manifestations dermatologiques des RASopathies et l’identification de thérapeutiques permet une optimisation de leur prise en charge. / Background Data on dermatological manifestations of RASopathies with Noonan phenotype including Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFCS) and Costello syndrome (CS) remain heterogeneous and based on little dermatological expertise.Objectives To describe the dermatological manifestations of NS, CFCS and CS compare them with the literature findings, and test for dermatological phenotype-genotype correlations with or without the presence of PTPN11, BRAF and pG12S-HRAS mutations respectively for NS, CFCS and CS.Methods We performed a large, 5-year, prospective, multicentric, collaborative dermatological and genetic study.Results A total of 194 patients with NS, CFC and CS were included. One hundred and twenty-nine patients with NS were enrolled, including 65 with PTPN11-NS, 34 with PTPN11-NS with multiple lentigines (NSML), and 30 without PTPN11-NS. Easy bruising was the most frequent dermatological finding in PTPN11-NS, present in 53.8%. Multiple lentigines and café-au-lait macules (≥3) were present in, respectively, 94% and 80% of NSML linked to specific mutations of PTPN11. Atypical forms of NSML could be associated with NS with RAF1 or NRAS mutations. In univariate analysis, patients without a PTPN11 mutation showed (i) a significantly higher frequency of keratinization disorders (P=0.001), including keratosis pilaris (P=0.005), ulerythema ophryogenes (P=0.0001) and palmar and/or plantar hyperkeratosis (P=0.06, trend association), and (ii) a significantly higher frequency of scarce scalp hair (P=0.035) and scarce or absent eyelashes (P=0.06, trend association) than those with PTPN11 mutations. Forty-five patients with CFCS were enrolled with mutations in BRAFin 77.8%. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair respectively in 73% and 69%. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmo-plantar hyperkeratosis (PPHK), and multiple melanocytic naevi (MMN; MN >50) were noted respectively in 82%, 44%, 27% and 29%. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP, and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical 1% sirolimus failed. No significant dermatological phenotype-genotype correlation was determined. Twenty-one patients with CS were enrolled with p.G12S mutation of HRAS identified respectively in 60%. Hair abnormalities were ubiquitous, including wavy or curly hair and scalp alopecia respectively in 70% and 60%. Acanthosis nigricans with pachydermatoglyphia, papillomas with periorificial location, PPHK, and acral cutis laxa were noted respectively in 65%, 65%, 55% and 80%. Cobblestone papillomatous linear papules of the upper lip was present in 55%, while scarcity of eyebrows and lymphedema were almost absent. No significant dermatological phenotype-genotype correlation was determined. One patient with CS with c187_207dup21/p.Glu63_Asp69dup mutation of HRAS had a new distinct cutaneous phenotype including MMN and severe lymphedema similar to NS and/or CFCS findings.Conclusions A thorough knowledge of RASopathies skin manifestations would help in making a positive diagnosis.

Les mutations germinales activatrices de la voie RAS sont responsables de maladies rares regroupées sous le nom de RASopathies : le Syndrome de Noonan, le Syndrome de Noonan avec de Multiples Lentigines, la Neurofibromatose de type 1, le Syndrome de Malformations Capillaires et Malformations Artério-Veinseuses, le Syndrome Cardio-Facio-Cutané, le Syndrome de Legius et le Syndrome de Costello. Cette thèse s’intéresse au syndrome de Costello causé par une mutation hétérozygote de novo du gène HRAS. Ce syndrome est révélé dans les premiers mois de la vie et se caractérise par un retard de croissance postnatal, des traits du visage épais, un déficit intellectuel, des anomalies cutanées, ainsi qu’une prédisposition à développer des tumeurs. De plus, les patients atteints du syndrome de Costello développent une cardiomyopathie hypertrophique, de l’hypertension, une hypotonie et une myopathie d'origine moléculaire inconnue. En lien avec une association de malade et le service de génétique du CHU de Bordeaux, nous avons mené une exploration des anomalies protéomiques dans les tissus d’une souris modèle du syndrome de Costello ainsi que dans des fibroblastes de patients et des cellules modèles exprimant les formes mutées de HRASG12S et HRASG12A. Cette analyse globale et sans a priori a révélé des altérations au niveau du métabolisme énergétique et plus particulièrement de la composition des mitochondries. Le déficit fonctionnel des mitochondries, centrale énergétique du corps humain, a été caractérisé par des approches de biochimie, de bioénergétique et de biologie cellulaire. De plus, l’analyse des données ‘omiques’ a permis de suggérer une nouvelle hypothèse dans la physiopathologie du syndrome de Costello. Cette hypothèse considère l’implication d’un micro-ARN, le miR-221* dans l’inhibition du métabolisme oxydatif. Les analyses génétiques réalisées sur les cellules de patients et les cellules modèles ont démontré l’inhibition de l’expression de la protéine AMPK, un régulateur majeur du métabolisme mitochondrial, par le miR-221* sous le contrôle de HRASG12S et HRASG12A. Ces découvertes ont permis d’élaborer une stratégie thérapeutique visant à réduire la cardiomyopathie dans le syndrome de Costello. Les analyses précliniques effectuées sur les modèles cellulaires et le modèle murin ont permis d’évaluer l’efficacité d’une stimulation pharmacologique du métabolisme mitochondrial. Cette thèse révèle donc l’implication des mitochondries dans le syndrome de Costello et l’analyse moléculaire réalisée propose une série de données ‘Omiques’ qui permettront de progresser dans la compréhension de cette maladie rare. / Germline activating mutations of the RAS pathway are responsible for rare diseases grouped under the name of RASopathies: Noonan Syndrome, Noonan Syndrome with multiple Lentigines, Type 1-neurofibromatosis, Capillaries malformations and arteriovenous malformations syndrome, Cardio-Facio-Cutaneous Syndrome, Legius Syndrome and Costello Syndrome. This Ph.D thesis focuses on Costello syndrome that is caused by a heterozygous de novo mutation of the HRAS gene. This syndrome is revealed in the first months of life and is characterized by postnatal growth retardation, thick facial features, intellectual deficit, skin abnormalities, and a predisposition to developing tumors. In addition, patients with Costello syndrome develop hypertrophic cardiomyopathy, hypertension, hypotonia and myopathy of unknown molecular origin. In connection with a patients association and the genetics department of Bordeaux University Hospital, we conducted an exploration of proteomic abnormalities in the tissues of a mouse model of the Costello syndrome as well as in patients’ fibroblasts and cell models expressing mutated forms of HRASG12S and HRASG12A. This global and unbiased analysis revealed alterations in energy metabolism and more particularly in the composition of mitochondria. The functional deficiency of mitochondria, energy plants of the human body, has been characterized by biochemistry, bioenergetics and cell biology approaches. In addition, the 'omic' analysis of Costello syndrome suggested a new pathophysiology hypothesis that considered the involvement of a microRNA, miR-221* in the alteration of oxidative metabolism. Functional genetic analyzes performed on patient cells and cell models demonstrated the inhibition of the expression of the major mitochondrial metabolism regulator AMPK protein by miR-221* under the control of HRASG12S and HRASG12A. These findings led to the development of a preclinical therapeutic strategy to reduce cardiomyopathy in Costello syndrome. Preclinical investigations performed on the cellular models and the murine model made it possible to evaluate the efficacy of a pharmacological stimulation of mitochondrial metabolism. This thesis thus reveals the involvement of mitochondria in Costello syndrome and the molecular analysis carried out makes available a series of 'Omics' data that will allow progress in the understanding of this rare disease.

The thesis relates Coetzee’s focus on animals to his more familiar themes of the possibility of fiction as a vehicle for serious ethical issues, the interrogation of power and authority, a concern for the voiceless and the marginalised, a keen sense of justice and the question of secular salvation. The concepts developed in substantial analyses of The Lives of Animals and Disgrace are thereafter applied to several other works of Coetzee. The thesis attempts to position J.M. Coetzee within the animal rights debate and to assess his use of his problematic persona, Elizabeth Costello, who controversially uses reason to attack the rationalism of the Western philosophical tradition and who espouses the sympathetic imagination as a means of developing respect for animals. Costello’s challenge to the philosophers is problematised by being traced back to Plato’s original formulation of the opposition between philosophers and poets. It is argued that Costello represents a fallible Socratic figure who critiques not reason per se but an unqualified rationalism. This characterisation of Costello explains her preoccupation with raising the ethical awareness of her audience, as midwife to the birth of ideas, and perceptions of her as a wise fool, a characterisation that is confirmed by the use of Bakhtin’s notion of the Socratic dialogue as one of the precursors of the modern novel. Along with the Platonic/Socratic binary, Bakhtin’s concepts of polyphony, dialogism and monologism are applied to analyses of Coetzee’s fiction, which, in keeping with his anti-authoritarianism, is shown to be polyphonic. Costello’s apparently insensitive and repeated comparison of industrialised animal farms to Nazi concentration camps is likewise scrutinised. It is argued that the point of the comparison is to question the normality and humanity of societies that choose to ignore the suffering of animals in the animal exploitation industries. Her raising the question of this willed ignorance is related to Socrates’ maxim that evil is a result of ignorance, and Coetzee’s concern with the psychic cost to their humanity of those complicit in these industries is considered. David Lurie’s evocation of Holocaust imagery in Disgrace is also examined, as is the role of art and the sympathetic imagination in attaining a degree of grace. Platonic ideas on eros, beauty, art and immortality are found to be central to Coetzee’s fiction, not only to that relating to Costello but also to Disgrace and much of his other work. While acknowledging the importance of Plato, Coetzee continuously extends, tests and subverts his ideas, frequently subjecting them to carnivalistic play. Unexpected connections are made between Coetzee’s conception of the parent-child relationship, both biological and intellectual, and his notions of creativity, power and justice. Ideas of eating and fasting are explored in his fiction and related to the hunger-artistry of Franz Kafka. Coetzee’s ideas on animals, writing and diet are found to be essential to his notions of secular salvation and an ethical way of life. / Thesis (DLitt)--University of Pretoria, 2010. / English / unrestricted

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Reproduction de : Thèse d'exercice : Médecine. Génétique médicale : Paris 12 : 2008. / Titre provenant de l'écran-titre. Bibliogr. f. 70-76.

This thesis articulates the resonances between J.M. Coetzee's lifelong engagement with mathematics and his practice as a novelist, critic, and poet. Though the critical discourse surrounding Coetzee's literary work continues to flourish, and though the basic details of his background in mathematics are now widely acknowledged, his inheritance from that background has not yet been the subject of a comprehensive and mathematically- literate account. In providing such an account, I propose that these two strands of his intellectual trajectory not only developed in parallel, but together engendered several of the characteristic qualities of his finest work. The structure of the thesis is essentially thematic, but is also broadly chronological. Chapter 1 focuses on Coetzee's poetry, charting the increasing involvement of mathematical concepts and methods in his practice and poetics between 1958 and 1979. Chapter 2 situates his master's thesis alongside archival materials from the early stages of his academic career, and thus traces the development of his philosophical interest in the migration of quantificatory metaphors into other conceptual domains. Concentrating on his doctoral thesis and a series of contemporaneous reviews, essays, and lecture notes, Chapter 3 details the calculated ambivalence with which he therein articulates, adopts, and challenges various statistical methods designed to disclose objective truth. Chapter 4 explores the thematisation of several mathematical concepts in Dusklands and In the Heart of the Country. Chapter Five considers Waiting for the Barbarians and Foe in the context provided by Coetzee's interest in the attempts of Isaac Newton to bridge the gap between natural language and the supposedly transparent language of mathematics. Finally, Chapter 6 locates in Elizabeth Costello and Diary of a Bad Year a cognitive approach to the use of mathematical concepts in ethics, politics, and aesthetics, and, by analogy, a central aspect of the challenge Coetzee's late fiction poses to the contemporary literary landscape.