Inaugural-Dissertation--Freiburg i. Br. / Includes bibliographical references (p. [5]-6).

[No abstract available] / Arts, Faculty of / English, Department of / Graduate

Un des rôles de la mitochondrie, qui possède son propre ADN (ADNmt), est la production de l'énergie nécessaire à la cellule, qu'elle synthétise sous forme d'ATP grâce aux oxydations phosphorylantes (OXPHOS). Ainsi, une altération du métabolisme énergétique mitochondrial peut provoquer l'apparition de pathologies mitochondriales dont, généralement, la sévérité est inversement proportionnelle à l'âge de début. De nombreuses études s'intéressent aux mécanismes d'apparition et de développement de ces maladies afin de mieux les comprendre et de pouvoir proposer des thérapies. Cependant, à ce jour, il est encore difficile de transformer l'ADNmt de façon ciblée (remaniement ou mutation). De plus, il existe encore peu de modèles animaux de pathologies mitochondriales qui permettraient de réaliser des études intégratives et d'essayer d'éventuelles molécules thérapeutiques. Dans le cadre de cette thèse, nous avons étudié deux types de modèles impliquant la modification du métabolisme mitochondrial. Dans un premier temps, nous nous sommes intéressés à la réalisation d'un modèle murin exprimant un grand nombre de caractéristiques du syndrome de Leigh, une maladie neurologique progressive. Pour cela nous avons utilisé une neurotoxine (MPTP) qui est connue pour sa toxicité envers les neurones dopaminergiques et aussi comme inhibiteur de la chaine respiratoire. Nous avons analysé l'activité de chaque complexe OXPHOS de différents tissus cérébraux et de tissus périphériques (cœur, foie, muscle et rein), prélevés sur des souris traitées et non-traitées. Nous avons retrouvé une inhibition des complexes III et/ou IV de la chaîne respiratoire dans le foie, le cortex, le striatum et le cervelet. Ces résultats, ajoutés à une neuro- dégénérescence accrue retrouvée dans une étude précédente, sont tous caractéristiques du syndrome de Leigh. Ces souris traitées par le MPTP semblent donc être un bon modèle pour l'étude de cette pathologie mitochondriale. Dans un second projet, nous nous sommes intéressés à l'effet des haplogroupes de l'ADNmt sur le métabolisme mitochondrial. En effet, bien qu'ils soient définis par des mutations neutres de l'ADNmt (polymorphismes), plusieurs études ont démontré des associations entre les haplogroupes et les pathologies, suggérant que les haplogroupes sont capables d'avoir un effet protecteur ou aggravant dans l'apparition d'une pathologie. Récemment, notre laboratoire a montré que certains haplogroupes avaient la capacité d'influencer le fonctionnement du métabolisme énergétique mitochondrial. Mon projet de recherche a donc consisté à mettre en place un modèle afin d'étudier les mécanismes cellulaires et moléculaires impliqués dans ce phénomène. Pour cela, nous avons recherché des haplogroupes d'intérêt dans la population française afin d'élaborer une collection de " cybrides " où chaque lignée de cellules possède un haplogroupe particulier mais un fonds génétique nucléaire commun à toutes les lignées. Nous avons caractérisé ces cybrides de manière biochimique (analyse de l'activité et des paramètres cinétiques de chaque complexe) et phénotypique (courbes de croissance). L'ensemble de ces résultats a été intégré dans un modèle informatique spécifiquement développé dans notre laboratoire pour modéliser la physiologie de la mitochondrie. Ce projet nous a permis de mettre en évidence l'influence des haplogroupes de l'ADNmt sur le métabolisme mitochondrial et de proposer une vision modulée des pathologies mitochondriales tant pour leur étude que pour leur diagnostic, en faisant ressortir la notion de médecine personnalisée. A l'avenir, il sera nécessaire de tenir compte du contexte génétique de l'ADNmt pour trouver de nouvelles stratégies ou de nouvelles cibles pour les thérapies des maladies mitochondriales. / The mitochondrion is an intracellular organelle responsible for the cellular energy production, by synthesizing ATP through the oxidative phosphorylation (OXPHOS). One of the characteristics of this organelle is that it has its own DNA (mtDNA) encoding for subunits of OXPHOS complexes. Any alterations of mitochondrial energy metabolism cause mitochondrial pathologies whose severity is generally inversely proportional to the age of onset. Some scientific studies are looking at the mechanisms of occurrence and development of these diseases in order to better understand them and to be able to offer therapies. However, there is no tool that can transform mtDNA in a targeted way by mutation or DNA rearrangement. Moreover, there are still few animal models of mitochondrial pathology that would allow integrative studies on the one hand, and on the other hand, to try out possible therapeutic molecules. In this thesis, we studied two types of models involving the modification of mitochondrial metabolism either by chemical treatment or by the use of mutations found in individuals. In a first part, we were interested in the realization of mouse model with a large number of characteristics of the Leigh syndrome, a progressive neurological disease characterized by neuropathological lesions associating a damage of the brain stem and the basal ganglia. For this study, we have used the 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) neurotoxin, known for its toxicity to dopamine neurons and also as an inhibitor of mitochondrial respiratory chain. We analyzed the activity of the OXPHOS complexes I to IV on brain tissues (cerebelum, cortex, striatum and substancia nigra) and peripheral tissues (heart, liver, muscle and kidney) from treated and untreated mice. Inhibition of complexes III and/or IV in the liver, cortex, striatum and cerebellum was found. These results, combined with an increased neurodegeneration found in a previous study, are all characteristics of Leigh Syndrome. Mice treated with MPTP seem to be a good model for this mitochondrial pathology. In the second project, we looked at the effect of mtDNA haplogroups (haplotypes grouping) on mitochondrial metabolism. Although, haplogroups are defined by neutral mutations of mtDNA (polymorphism), several studies have shown associations between haplogroups and some pathologies suggesting that haplogroups are able to have a protective effect or being a risk factor in the pathology development. Recently, our laboratory has confirmed that some haplogroups may not be neutral and have the ability to influence the mitochondrial energy metabolism functioning. Therefore, my research project consisted of setting up a model to study these cellular and molecular mechanisms. We looked for haplogroups of interest in the population in order to elaborate a cellular collection where each cell line has a particular haplogroup but with a common nuclear genetic background in all the cell lines. This collection was obtained by cybride constructions. We characterized these cybrides biochemically by analyzing the activity of each complex, determining kinetic parameters (KM and Vmax) and titration specific respiratory chain inhibitors. Concomitantly, we defined cell parameters via growth curves. All these results were integrated into a computer model specifically developed in our laboratory to model mitochondrial processes. This project gives us some evidence of the mtDNA haplogroups' influence on mitochondrial metabolism and to propose a modulated vision of mitochondrial pathologies for their study and their diagnosis, highlighting the notion of personalized medicine. As each haplogroup modulates in the different way the mitochondrial metabolism, each individual could have a personal response to the same mutation or pathology. In future, the mtDNA genetics background should be taken into account to find new strategies or new targets for the therapies of mitochondrial diseases.

This thesis, comprised of a stage play and exegesis, asks whether the Mike Leigh Method, commonly used by Auteur directors could be adapted to benefit a playwright during the redrafting and development process. I seek to answer this question by examining differing methodologies of drama creation and charting my process as I work to redraft my character driven stage play Deceased Estate through the adaptation and application of the Mike Leigh Method. I contend that Leigh’s method affords a set of honed and proven guidelines that can help the playwright get to the heart of the character driven drama and offer an adapted method template that can be used and furthered by other Playwrights wishing to develop their work in this manner.

Based on the author's thesis (doctoral--Oxford). / Includes bibliographical references (p. 184-221) and index.

Plant imagery abounds in Elizabeth Barrett Browning's novel-poem, Aurora Leigh, and critical readings have not thoroughly explored the meaning of and intent behind that imagery. Plant metaphor and images in Aurora Leigh are used to challenge the concept of Victorian women's inherently inferior "nature" and to present an argument for female equality. When traced throughout the work, plant imagery foreshadows Aurora and Marian's ultimate personal independence and familial harmony and helps the reader to understand the poem's controversial ending. Ties to three of Browning's literary influences in the selection of plant images are explored: Emanuel Swedenborg, Mary Wollstonecraft, and Samuel Taylor Coleridge. Each of these three understood and used nature imagery to significant effect in their own writings, and Browning adopted and developed those images in her work.

Plant imagery abounds in Elizabeth Barrett Browning's novel-poem, Aurora Leigh, and critical readings have not thoroughly explored the meaning of and intent behind that imagery. Plant metaphor and images in Aurora Leigh are used to challenge the concept of Victorian women's inherently inferior "nature" and to present an argument for female equality. When traced throughout the work, plant imagery foreshadows Aurora and Marian's ultimate personal independence and familial harmony and helps the reader to understand the poem's controversial ending. Ties to three of Browning's literary influences in the selection of plant images are explored: Emanuel Swedenborg, Mary Wollstonecraft, and Samuel Taylor Coleridge. Each of these three understood and used nature imagery to significant effect in their own writings, and Browning adopted and developed those images in her work.

Thesis (Ph. D.)--University of Pennsylvania, 1932. / Bibliography: p. 233-238.

abstract: Miguel de Cervantes Saavedra created the character of Don Quixote in his book El ingenioso hidalgo Don Quijote de la Mancha, published in 1605. Since its creation, stories from the book have been reimagined in art, in literature and in music. Frequently, Cervantes – the man and author – and Quixote – the novel’s protagonist and hero – have been inextricably linked in character. Subsequent adaptors of the novel have been influenced by this connection: composers Jules Massenet (1842-1912), Jacques Ibert (1890-1962) and Mitch Leigh (1928-2014) all wrote their own versions of the Quixote saga. Though their approaches to the story are varied, the basic characteristics of it remain: Love, Life and Dreams. Those themes are reflected in the old knight’s death scene in each of their respective works. Here, the lives of the adaptors are briefly discussed and a dramatic and musical (Schenkerian), analysis of Quixote’s last hours are presented. / Dissertation/Thesis / Doctoral Dissertation Music 2016

Samuel Johnson and Leigh Hunt, as generally representative spokesmen of the Eighteenth Century and the Romantic Age, provide some interesting comments on the theatre of their times. Their individual idiosyncrasies colour their views to some extent. Such inconsistencies, as they pertain to the theatre, are the subject of Chapter I of this essay. Physical conditions in the theatre of Johnson's and Hunt's times, which could not but influence the reception of acted drama, are noted in Chapter II. Johnson, whose views towards the drama are generally those of the literary critic, evaluated the plays of Shakespeare and others mainly in terms of their literary worth. But he was not unaware of the peculiar demands of the theatrical métier, and his well-known prejudice against the players did not prevent him from making a just appraisal of the theatrical fare of his time, according to Johnsonian canons of taste. Hunt shared in the generally idolatrous regard of the Romantics towards Shakespeare. He wrote when the offerings of current playwrights reflected, to him, the age's dearth of dramatic character. He thought some of the earlier offerings, notably those of the Restoration playwrights, were unsuitable to the present mores of taste. But in his voluminous theatre criticism he is principally concerned with the stage presentation of plays, rather than their value as closet drama. As playwrights, Johnson and Hunt made manifest some of their critical principles; and a study of Irene and A Legend of Florence provides a concluding commentary on the worth of their criticism, translated into practice. / Arts, Faculty of / English, Department of / Graduate