Decreased expression of the tumor suppressor gene BRCA1 (breast cancer 1, early onset) is frequently observed in sporadic breast tumors, with the decrease not attributed to mutations or hypermethylation of the promoter. A critical regulator of the BRCA1 promoter is the GA-Binding Protein (GABP), a heterotetramer of GABPα and GABPβ. Previous analysis of the GABPβ promoter revealed a regulatory multi-protein complex containing Nuclear Respiratory Factor 1 (NRF-1), which was aberrant in SK-BR-3 cells, resulting in decreased GABPβ and BRCA1 expression. To identify the unknown co-regulators of the NRF-1-containing complex at the GABPβ promoter, an immobilized-template assay containing the complex binding site was utilized. Despite optimization of binding and elution conditions through variations in salt content, Mg2+ concentration and pH, non-specific DNA-binding proteins were present in the column eluate. Further experimentation is therefore required to distinguish between non-specific proteins and complex co-activators. As this complex containing NRF-1 is also able to modulate BRCA1, a regulator of luminal progenitor differentiation, a defect in NRF-1 or complex co-activators could contribute to the abnormal morphogenesis and differentiation of BRCA1-deficient tumors. We therefore investigated the role of NRF-1 in mammary cell morphogenesis and its link to the GABP/BRCA1 pathway. As both GABPβ and NRF-1 are known regulators of nuclear-encoded mitochondrial proteins, this association also provides a link between mitochondrial metabolism and breast differentiation, both of which are frequently disrupted in breast cancer. An inducible lentiviral system was used to generate NRF-1 knockdown cell lines to examine its effect on morphogenesis. Growth in 3D culture resulted in abnormal cell structures having impaired cell polarization and lumen formation. In monolayer culture, prolonged NRF-1 knockdown did not result in decreased BRCA1 or GABP expression. However, these cells did display notable mitochondrial dysfunction, accompanied by the downregulation of several NRF-1 target genes involved in mitochondrial biogenesis including Tfam and cytochrome c. These results suggest a role for NRF-1 in mediating mammary morphogenesis through maintenance of functional mitochondria. Further investigation into the role of the NRF-1-containing complex at the GABPβ promoter during differentiation might also provide insight into the altered cell metabolism and differentiation observed in cancer cells. / Thesis (Master, Biochemistry) -- Queen's University, 2012-09-06 14:39:04.852

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20977号 / 医博第4323号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小柳 義夫, 教授 小川 誠司, 教授 朝長 啓造 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Cette thèse se propose de comprendre la réception de Maurice Barrès (1862-1923) des premières années de sa carrière au lendemain de la Seconde Guerre mondiale, en insistant sur différents « moments » de cette réception. Il s’agit d’abord de comprendre comment se constitue son autorité d’écrivain, dans le contexte des milieux symbolistes des années 1890. Nous étudions notamment les rapports de Barrès avec les rédacteurs de La Revue blanche – des rapports qui définissent l’identité même de la revue – jusqu’à la rupture de l’affaire Dreyfus. Nous nous intéressons ensuite à sa réception au sein de La NRF, à travers les lectures – à la fois critiques et fascinées – qu’en font trois figures majeures de la revue : André Gide, Albert Thibaudet et Jacques Rivière. De même, nous tentons de comprendre comment les surréalistes ont gardé un lien ambigu avec cet écrivain au cours des années 1920, en étudiant de plus près le procès Barrès (mai 1921) et la réception particulière que fait Louis Aragon de cette figure, dans sa phase surréaliste, mais aussi dans la suite de sa carrière. Enfin, nous terminons par étudier le cas particulier de Joseph Delteil, écrivain proche du surréalisme, mais dont la position est tiraillée entre ancrage régionaliste et avant-garde, et qui trouve dans l’exemple barrésien un modèle (provisoire) de résolution de ces contradictions. L’étude de cette réception, à travers les exemples cités, se donne ainsi pour but de comprendre comment une posture d’auteur a pu essaimer dans des milieux idéologiques et esthétiques opposés au traditionalisme, et à travers des manifestations ambiguës de fidélité littéraire. / The purpose of this Dissertation is to understand the reception of Maurice Barrès (1862-1923), going from the first years of his career to the aftermath of the Second World War, while insisting on specific “moments” of this reception. This will firstly be done by comprehending how a writer’s authority is shaped, in the context of 1890’s Symbolist milieu. Consequently, we will analyse the relationships between Barrès and the copywriters of the La Revue blanche going till the clash caused by the Dreyfus affair. We will then take interest in his reception within the La NRF, through the interpretation that made three major figures of the review: André Gide, Albert Thibaudet and Jacques Rivière – readers that were both critic to the nationalist writer as fascinated by his auctorial posture. At the same time, we will try to understand how the Surrealists have kept an ambiguous tie with this writer during the 1920’s, by closely studying Barrès’s trial (May 1921) and the particular welcome that Louis Aragon gave to this figure, during his surrealist phase, but also during the rest of his career. Finally, we will finish by analysing the particular case of Joseph Delteil, a writer close to Surrealism but whose position was torn between his regionalist grounding and an avant-garde one, and who finds through Barrès a model of resolution of these contradictions. The study of Barrès’s reception, by means of the quoted cases, is thus made in the purpose of understanding how an author’s posture was able to dispense, in the ideologist and esthetical milieu opposed to traditionalism, as well as among the ambiguous manifestations of the literary loyalty.

Breast cancer is a disease associated with excess exposures to estrogens. While the mode of cancer causation is unknown, others have shown that oxidative stress induced by prolonged exposure to estrogens mediates renal, liver, endometrial and mammary tumorigenesis though the mechanism(s) underling this process is unknown. In this study, we show that 4-hydroxyl 17β-estradiol (4-OHE2), a catechol metabolite of estrogen, induces mammary tumorigenesis in a redox dependent manner. We found that the mechanism of tumorigenesis involves redox activations of nuclear respiratory factor-1 (NRF1); a transcriptions factor associated with regulation of mitochondria biogenesis and oxidative phosphorylation (OXPHOS), as well as mediation of cell survival and growth of cells during periods of oxidative stress. Key findings from our study are as follows: (i) Prolonged treatments of normal mammary epithelial cells with 4-OHE2, increased the formation of intracellular reactive oxygen species (ROS). (ii) Estrogen-induced ROS activates redox sensitive transcription factors NRF1. (iii) 4-OHE2 through activation of serine-threonine kinase and histone acetyl transferase, phosphorylates and acetylate NRF1 respectively. (iv) Redox mediated epigenetic modifications of NRF1 facilitates mammary tumorigenesis and invasive phenotypes of breast cancer cells via modulations of genes involved in proliferation, growth and metastasis of exposed cells. (v) Animal engraftment of transformed clones formed invasive tumors. (vi) Treatment of cells or tumors with biological or chemical antioxidants, as well as silencing of NRF1 expressions, prevented 4-OHE2 induced mammary tumorigenesis and invasive phenotypes of MCF-10A cells. Based on these observations, we hypothesize that 4-OHE2 induced ROS epigenetically activate NRF1 through its phosphorylation and acylation. This, in turn, through NRF1-mediated transcriptional activation of the cell cycle genes, controls 4-OHE2 induced cell transformation and tumorigenesis.

Cancer cells adapt to high levels of oxidative stress in order to survive and proliferate, making the transcription factors involved in antioxidant defence regulation targets of interest. The transcription factor NF E2 Related Factor 2 (NRF-2) regulates cellular defence genes including those encoding intracellular redox-balancing proteins such as enzymes involved in glutathione metabolism. Glutathione in particular is an important intracellular antioxidant molecule. NRF-2 binds to the Antioxidant Response Element (ARE) in the promoter of its target genes. Under basal conditions, Kelch-like ECH-associated protein 1 (KEAP1) acts as an inhibitor that targets NRF-2 for ubiquitination. During oxidative stress, NRF-2 dissociates from KEAP1 and enters the nucleus to bind to the ARE sequence. It is hypothesized that the elevated Reactive Oxygen Species may be depleting the glutathione levels within the cancer cell. System xc- is a cystine/glutamate antiporter that exports glutamate while importing cystine to synthesize glutathione. In response to oxidative stress, the cells increase system xc- activity in order to provide cystine for glutathione synthesis. There is evidence that expression of xCT, the specific subunit of system xc-,is regulated by NRF-2. However this has not yet been demonstrated in human breast cancer cells, which is the focus of this project. Basal expression of NRF-2, KEAP1 and xCT was characterized in three breast cancer cell lines (MDA-MB-231, MCF-7 and T47D) and compared to two non-cancer cell lines (184B5 and MCF10A). Basal protein levels of NRF-2 and KEAP1 showed no differences between cell lines. Basal protein levels of xCT were increased in MCF10A cells than T47D cells. MCF-7 cells were treated with hydrogen peroxide (H2O2) resulting in NRF-2 protein accumulation in the nucleus. With H2O2 treatment, xCT mRNA levels increased in MCF-7 cells. Additionally, transient overexpression of NRF-2 increased extracellular glutamate levels in MCF-7 cells. These data support a model that under oxidative stress, NRF-2 is localized to the nucleus and transcriptionally upregulates xCT. This is the first study in which the regulation of xCT has been linked to oxidative stress via NRF-2 in human breast cancer cells. / Thesis / Master of Science (MSc)

Gabriel Bounoure (1886-1969) a été durant plus de trente ans un acteur important de la vie littéraire française, collaborateur régulier de nombreuses revues prestigieuses. Il fut même, selon d’excellents juges, l’un des plus grands critiques littéraires de son temps. Il fut par ailleurs diplomate. Il vécut ainsi près de 30 ans à Beyrouth (1923-1952) avant de s’installer au Caire puis à Rabat. Au cours de sa carrière diplomatique, il a assumé de hautes responsabilités dans les domaines de la culture et de l’éducation. Gabriel Bounoure, garda, dans son exil oriental, des relations étroites avec la France. Par ses fonctions diplomatiques mais également par ses critiques qui, loin de s’attacher exclusivement aux écrivains les plus en vue de l’époque (Claudel, Gide) ou aux figures littéraires marquantes du XIXe siècle (Rimbaud, Nerval) ont contribué à faire découvrir des poètes alors jeunes comme Henri Michaux. Parallèlement, il éprouvait pour l’Orient une attirance et une affinité profondes. Il révéla ainsi au public français de jeunes auteurs francophones arabes comme Georges Schéhadé.Les liens entre Bounoure et l’espace méditerranéen sont complexes. La Méditerranée était alors le lieu de changements historiques décisifs. Quel rôle politique Bounoure a-t-il joué ? Quel acteur de la vie littéraire française fut-il à cette même époque ? De quelle façon ces deux facettes de sa personnalité, poétique et politique, ont-elles évolué ? Enfin, dans quelle mesure la réflexion politique et la réflexion critique se sont articulées ? Cette thèse rassemble ses articles critiques éparpillés dans les revues, donne à lire des témoignages et exploite de nombreuses archives inédites. / For more than thirty years, Gabriel Bounoure (1886-1969) played a major role in the French literary life, a regular contributor to many prestigious journals. According to excellent judges, he was even one of the greatest literary critics of his time. He was also a diplomat. He lived for nearly 30 years in Beirut (1923-1952) before moving to Cairo and Rabat. During his diplomatic career, he held positions of high responsibility in culture and education. During his eastern exile, Gabriel Bounoure remained closely linked with France, as a diplomat but as a critic as well, who did not focus exclusively on the writers most popular at the time (Claudel, Gide) or on prominent literary figures of the nineteenth century (Rimbaud, Nerval). He helped to discover young poets like Henri Michaux. Meanwhile, he felt an attraction for and a deep affinity with the East. He thus introduced to the French audience young Arab francophone writers like Georges Schéhadé.The links between Bounoure and the Mediterranean area are complex. The Mediterranean was then the place of decisive historical changes. What political role did Bounoure play? What was his role in the French literary life at the time? How did these two facets of his personality, poetic and political, evolved? Finally, to what extent did his thoughts and views both as a diplomat and a critic meet?This thesis gathers his critical articles scattered in journals, offers testimonials and uses numerous unpublished archives.

L’ensemble des interventions réalisées par Paulhan dans l’après-guerre peut se lire à l’aune de ce programme : comment reconstruire une communauté littéraire menacée par les dissensions héritées de la guerre ainsi que par la politisation accrue des enjeux ? Comment redéfinir les valeurs qui permettent de la rassembler à un moment de renouvellement profond des acteurs et des institutions qui en constituaient les références, mais aussi des usages et des pratiques de lecture ? Ce sont ces questions que nous entendons examiner. Une large part de notre travail est consacrée à l’activité revuiste de Paulhan : en effet, Les Cahiers de la Pléiade, comme La N.R.F., sont conçus par celui-ci comme un moyen privilégié pour ressouder une communauté littéraire éclatée et pour tenter de reconfigurer les hiérarchies qui structurent le champ littéraire. Nous proposons d’abord un récit chronologique de la renaissance de La N.R.F. dès 1953, en nous appuyant sur un important ensemble d’archives inédites. Nous abordons ensuite la question de la place du roman dans la revue : quel paysage romanesque la revue donne-t-elle à voir ? Est-elle à même de promouvoir de jeunes romanciers et de dessiner des directions au sein du champ littéraire des années 1950 ? On s’intéresse enfin aux réflexions théoriques de Paulhan sur la valeur littéraire. Nous examinons la position de Paulhan face à trois phénomènes décisifs qui modifient en profondeur la définition de cette valeur : la renégociation des rapports entre littérature légitime et non légitime, avec l’exemple de la défense de la littérature érotique ; la relève générationnelle ; le constat d’une crise du jugement critique. / All the interventions made by Paulhan in the post-war period could be understood in the light of this programme: how do we rebuild a literary community which unity is threatened by the divisions inherited from the war and by an increased politicization of its challenges ? How do we redefine its binding values in a time when the actors and the institutions that used to constitute its main references, as well as our reading practices, are profoundly renewed ? Those are the issues which will be discussed here. An important part of our work is devoted to Paulhan’s activity as a reviewer : He indeed conceived Les Cahiers de la Pléiade, as well as La N.R.F as a privileged way to reunite a fragmented literary community and to try reconfiguring the hierarchies which structure the literary field. We will first offer a chronological narrative of the rebirth of the N.R.F from1953, on the basis of a large set of unpublished archives. We will then consider the status of the novel in the journal: Which perspective does it reveal on the situation of the novel ? Is it able to promote young novelists and to suggest directions within the literary field of the 1950’s ? At last, we will study Paulhan’s theoretical reflections on literary value. We examine his positions on three crucial phenomena that radically modify the definition of this value: the renegotiation of the relationship between legitimate and non-legitimate literature, with the example of his support of erotic literature ; the handing over to the next generation ; the acknowledgment of a crisis of critical judgment.

La NADH:ubiquinone oxydoréductase (complexe I) est le plus gros complexe enzymatique du système mitochondrial d'oxydation phosphorylante (43 sous-unités chez l'homme). Très peu de données sont disponibles concernant les mécanismes régulant l'expression de ces protéines. <br />Cette étude a été initiée par l'étude des promoteurs de deux gènes du complexe I mitochondrial humain. Les résultats montrent que le gène NDUFS8 qui code pour la sous-unité 23 kDa (TYKY) est transcrit sous le contrôle des facteurs de transcription YY1 et Sp1 tandis que gène NDUFS7 codant pour la sous-unité 20 kDa (PSST) est régulé par NRF-1 et Sp1. <br />Dans la deuxième partie de ce travail, une méthode d'analyse du protéome mitochondrial humain par électrophorèse bidimensionnelle a été développée. Le but est d'aborder de manière globale et sans a priori l'expression des protéines du complexe I : déterminer qui est régulé et comment en réponse à un stimulus déterminé? <br />Des cartes de référence ont été développées à partir de mitochondries extraites de placenta humain en utilisant deux types de gradient de pH : l'un est adapté aux protéines acides et neutres, l'autre aux protéines basiques. Sur ces cartes, 85 protéines mitochondriales ont été identifiées par spectrométrie de masse dont 17 sous-unités du complexe I. Cette technique d'analyse protéomique a ensuite été utilisée pour étudier la régulation de l'expression des protéines mitochondriales par le fer. Sur le plan technique, les premiers résultats sont encourageants : les gels d'électrophorèse bidimensionnelle préparés avec des mitochondries extraites de cellules en culture sont de bonne qualité et des variations reproductibles de l'expression de sous-unités du complexe I et d'autres protéines mitochondriales ont pu être détectées. Sur le plan fondamental, les données obtenues sont préliminaires. Il sera nécessaire de réaliser de nouvelles expériences pour confirmer les premières observations et analyser la cinétique des variations détectées.

Šiame magistro baigiamajame darbe yra nagrinėjama, kaip ir kokiu mastu, struktūrinant reikalavimus pagal J.A.Zachmano karkasą ir panaudojant Toronto grupės pasiūlytą nefunkcinių reikalavimų dekomponavimo metodiką (NFR), galima bent iš dalies formalizuoti reikalavimų nuleidimą iš verslo lygmens į programų sistemos lygmenį. Darbo teorinėje darbo dalyje, remiantis atliktos mokslinės literatūros analizės rezultatais, pasiūlyta kaip pritaikyti Toronto metodiką reikalavimams nuleisti iš verslo į programų sistemos lygmenį Zachmano tipo karkasuose. Darbo eksperimentinėje dalyje šie pasiūlymai patikrinti praktiškai, atliekant konkrečios sistemos reikalavimų nuleidimą iš verslo į programų sistemos lygmenį. Tyrimo rezultatai parodė, kad NFR metodika tinkama ne visų reikalavimų nuleidimui žemyn, nes joje yra per silpnos dinamikos modeliavimo priemonės. / The aim of the master thesis is to investigate possibilities to use the NFR (non-functional requirements) approach proposed by Toronto group to perform the flowdown of requirements from business to software level in the methodical requirements engineering frameworks that organize requirements in a way similar to the J.A. Zachman’s Enterprise Architecture. Using results of the library research, the theoretical part of the thesis proposes a methodology how to apply NRF approach to perform flow down of the higher level requirements to lower ones in cases when requirements are organized according to principles proposed by J.A. Zachman. The experimental part of the thesis is devoted to the validation of the proposed approach using a simplified banking system example. The main conclusion of the thesis is that the NFR approach is applicable only to some part of requirements because the modelling means provided by this approach are not sufficient to model the system dynamic.

As of 2007, according to the Census Bureau, there were more than 37 million people over the age of 65 and 38.22 million people with disabilities (5 years and older). In 2008, the National Response Framework (NRF) replaced the National Response Plan (NRP). One of the criticisms that lead to this change in policy is that during Hurricane Katrina, response to a number of vulnerable populations was not effective as should have been. This thesis addresses the concern for vulnerable populations in regards to planning and preparing for emergencies by assessing their inclusion in the state emergency plans of FEMA Region IV. Vulnerable populations is defined (in this paper) as individuals living with a disability, individuals 65 years or older and individuals with combination of the two. This research is based upon the assumption that there is a need for emergency management at all levels of government for all residents. In order to assess the inclusion of specific vulnerable populations in state emergency plans this thesis will look at the policy change made in the national plans. Using a content analysis, comparative analysis of national plans and an overall analysis of FEMA Region IV States, a standard of measurement is identified and significant influences affecting state emergency management are found. The Region IV states being compared are Alabama, Georgia, Florida, Kentucky, Mississippi, North Carolina, South Carolina, and Tennessee. The claim is that the inclusiveness of state emergency plans in regards to response to vulnerable populations does not match that of the NRF. This research also suggests there are issues with the guiding documents for state emergency plans. The findings of this analysis can lead to a number of future research endeavors related to how states improve emergency preparedness and response.