La sclérose latérale amyothrophique (SLA) est une maladie neurodégénérative charactérisée par la perte des neurones moteurs menant à la paralysie et à la mort. Environ 20% des cas familiaux de la SLA sont causés par des mutations de la superoxyde dismutase 1 (SOD1), conduisant vers un mauvais repliement de la protéine SOD1, ce qui a comme conséquence un gain de fonction toxique. Plusieurs anticorps spécifiques pour la forme mal repliée de la protéine ont été générés et utilisés comme agent thérapeutique dans des modèles précliniques. Comment le mauvais repliement de SOD1 provoque la perte sélective des neurones moteurs demeure non résolu. La morphologie, le bilan énergétique et le transport mitochondrial sont tous documentés dans les modèles de la SLA basés sur SOD1, la détérioration des mitochondries joue un rôle clé dans la dégénération des neurones moteurs. De plus, la protéine SOD1 mal repliée s’associe sélectivement sur la surface des mitochondries de la moelle épinière chez les modèles de rongeurs de la SLA. Notre hypothèse est que l’accumulation de la protéine SOD1 mal repliée sur les mitochondries pourrait nuire aux fonctions mitochondriales. À cette fin, nous avons développé un nouvel essai par cytométrie de flux afin d’isoler les mitochondries immunomarquées avec des anticorps spécifiques à la forme malrepliée de SOD1 tout en évaluant des aspects de la fonction mitochondriale. Cette méthode permettra de comparer les mitochondries portant la protéine SOD1 mal repliée à celles qui ne la portent pas. Nous avons utilisé un anticorps à conformation spécifique de SOD1, B8H10, pour démontrer que la protéine mal repliée SOD1 s’associe avec les mitochondries de la moelle épinière des rat SOD1G93A d’une manière dépendante du temps. Les mitochondries avec la protéine mal repliée SOD1 B8H10 associée à leur surface (B8H10+) ont un volume et une production excessive de superoxyde significativement plus grand, mais possèdent un potentiel transmembranaire comparable aux mitochondries B8H10-. En outre, la présence de la protéine mal repliée SOD1 reconnue par B8H10 coïncide avec des niveaux plus élevés de la forme pro-apoptotique de Bcl-2. L’immunofluorescence de sections de moelle épinière du niveau lombaire avec l’anticorps spécifique à la conformation B8H10 et AMF7-63, un autre anticorps conformationnel spécifique de SOD1, démontre des motifs de localisations distincts. B8H10 a été trouvé principalement dans les neurones moteurs et dans plusieurs points lacrymaux dans tout le neuropile. Inversement, AMF7-63 a marqué les neurones moteurs ainsi qu’un réseau fibrillaire distinctif concentré dans la corne antérieure. Au niveau subcellulaire, SOD1 possèdant la conformation reconnu par AMF7-63 est aussi localisée sur la surface des mitochondries de la moelle épinière d’une manière dépendante du temps. Les mitochondries AMF7-63+ ont une augmentation du volume comparé aux mitochondries B8H10+ et à la sous-population non marquée. Cependant, elles produisent une quantité similaire de superoxyde. Ensemble, ces données suggèrent qu’il y a plusieurs types de protéines SOD1 mal repliées qui convergent vers les mitochondries et causent des dommages. De plus, différentes conformations de SOD1 apportent une toxicité variable vers les mitochondries. Les protéines SOD1 mal repliées réagissant à B8H10 et AMF7-63 sont présentes en agrégats dans les fractions mitochondriales, nous ne pouvons donc pas prendre en compte leurs différents effets sur le volume mitochondrial. Les anticorps conformationnels sont des outils précieux pour identifier et caractériser le continuum du mauvais repliement de SOD1 en ce qui concerne les caractéristiques biochimiques et la toxicité. Les informations présentes dans cette thèse seront utilisées pour déterminer le potentiel thérapeutique de ces anticorps. / Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of motor neurons resulting in paralysis and death. Approximately 20% of familial ALS cases are caused by mutations in superoxide dismutase (SOD1), which leads to misfolding of the SOD1 protein, resulting in a toxic gain of function. Several antibodies have been generated that are specific for the misfolded form of the protein, and have been used as therapeutics in pre-clinical models. How misfolded SOD1 provokes a selective loss of motor neurons remains unresolved. Mitochondrial morphology, bioenergetics and transport are all documented is SOD1-mediated ALS models, thus mitochondrial impairment plays a key role in motor neuron degeneration. Moreover, misfolded SOD1 selectively associates with the surface of spinal cord mitochondria in ALS rodent models. We hypothesize that the accumulation of misfolded SOD1 on mitochondria could impair mitochondrial function. To this end, we developed a novel flow cytometric assay to immunolabel isolated mitochondria with misfolded SOD1 antibodies while also evaluating aspects of mitochondrial function. This method will allow for a comparison of mitochondria bearing misfolded SOD1 to those without. We utilized the B8H10 conformation specific SOD1 antibody to demonstrate that misfolded SOD1 associates with SOD1G93A rat spinal cord mitochondria in a in a time dependent manner. Mitochondria with B8H10-reactive misfolded SOD1 associated with their surface (B8H10+) have a significantly larger volume and produce excessive amounts of superoxide, but have a similar transmembrane potential compared to B8H10- mitochondria. In addition, the presence of B8H10-reactive misfolded SOD1 coincides with higher levels of the pro-apoptotic form of Bcl-2. Staining of lumbar spinal cord sections with both B8H10 and another conformation specific SOD1 antibody, AMF7-63, yielded distinct localization patterns. B8H10 was found predominantly in motor neurons and numerous puncta throughout the neuropil. Conversely, AMF7-63 marked motor neurons as well as a distinctive fibrillar network that was concentrated in the anterior horn. At the subcellular level, AMF7-63-reactive misfolded SOD1 also localized to the mitochondrial surface of spinal cord mitochondria in a time-dependent manner. AMF7-63+ mitochondria have an increased volume compared to B8H10+ mitochondria and the unlabelled subpopulation. However, they produce similar amounts of superoxide. Together, these data suggest that there are multiple species of misfolded SOD1 that converge at the mitochondria to cause damage. Moreover, different SOD1 conformations may ellicit varying toxicities towards mitochondria. Both B8H10 and AMF7-63-reactive misfolded SOD1 are present in aggregates in mitochondrial fractions and can therefore not account for any different effects produced in terms of mitochondrial volume. Conformational antibodies are invaluable tools to identify and characterize the continuum of misfolded SOD1 species with regards to biochemical characteristics and toxicity. The information presented in this thesis will be used in determining the future therapeutic potential of these antibodies.

Cette thèse de doctorat se propose de reprendre l'ensemble de la philosophie pratique de Kant en aval, c'est-à-dire à partir de l'ouvrage chronologiquement tardif dans le corpus kantien, La Religion dans les limites de la simple raison (1793), dont la Première partie assigne à la volonté un défi : le « mal radical ». Le « mal radical » n'est pas le mal absolu ou diabolique, mais il consiste en une inversion (Verkehrtheit) de l'ordre des principes au sein du vouloir, et ne peut être déraciné que par l'entière conversion du cœur. Avec le mal s'ouvre l'antinomie du judaïsme, considéré par le philosophe comme le contre-modèle de la foi par excellence, et du christianisme, criterium unique et anhistorique de la religion, seul à même de résoudre le problème de l'homme nouveau. Si, selon Kant, le judaïsme est nouménalement nul parce qu'incapable de véhiculer le contenu de la religion rationnelle, le philosophe, qui considère l'interdit biblique de l'idolâtrie comme « le commandement le plus sublime du Livre de loi des Juifs », lui reconnaît néanmoins le mérite de mettre l'accent sur le respect. Le christianisme, quant à lui, met l'accent sur l'amour, dont Kant retient la signification pratique, à savoir qu'il est l'état de perfection de l'intention vers lequel nous devons tendre / This doctoral thesis suggests taking back the whole of Kant's practical philosophy downstream, i.e. from the chronologically late work in the Kantian corpus, The Religion within the limits of the simple reason (1793), the first part of which assigns to the will a challenge: “radical evil”. “Radical evil” is neither the absolute nor devilish evil, but it consists of an inversion (Verkehrtheit) of the order of the principles within the will, and can only be eradicated by the utter conversion of the heart. With the evil opens the antinomie of the Judaism which the philosopher considers as the paramount counter-model of the faith, and the Christianity, held to be the one and only unhistorical criterium of the religion the only to solve the problem of the new man. If, according to Kant, the Judaism is noumenally invalid because it is not able to convey the contents of the rational religion, the philosopher, who considers the biblical prohibition of the idolization as “the most sublime command of the Book of law of the Jews”, grants it nevertheless the merit of emphasizing respect. Christianity, as for him, emphasizes love, which, in practical meaning that Kant retains, is the state of perfection of the intention towards which we have to aim

Diante de pesquisas realizadas com o 5Ultra-som pulsado de baixa intensidade na regeneração de pele de ratos submetidos a queimaduras provocadas por calor (ALVES, 1988) e em pacientes portadores de úlceras tróficas de perna (HILÁRIO, 1993) se propôs estudar os efeitos do ultra-Som pulsado de baixa intensidade em pacientes com Mal de Hansen (MH) cujas manifestações cutâneas eram caracterizadas como o Mal Perfurante Plantar (MPP) e úlceras do tegumento, sendo que o emprego do ultra-som pulsado e de baixa intensidade mostrou-se eficaz na reparação das referidas lesões. O presente trabalho foi realizado em pacientes assistidos pelo Sistema Único de Saúde (SUS) na cidade de Bebedouro-SP lotados no setor de Vigilância Epidemiológica. A casuística constitui-se de seis pacientes apresentando MPP nos quais aplicou-se o ultra-som pulsado (U.S.P.) em uma freqüência de três vezes por semana no mesmo período circadiano. Os tratamentos tiveram duração variando entre vinte e quarenta minutos consoante a extensão das lesões cutânea. Independente do tempo das lesões não foi estabelecido previamente o número de aplicações a serem executadas, mas as aplicações foram realizadas até a obtenção da cicatrização total das lesões. A evolução das lesões até a cicatrização foi feita mediante o emprego de um software especialmente desenvolvido para tal finalidade e documentados fotograficamente. Não houve correlação entre o número de aplicações com o tamanho da lesão ou com o tempo decorrido do aparecimento das mesmas, embora a extensão e a forma das diferentes ulcerações não sejam equivalentes, quer no tempo de evolução, quer na profundidade das lesões, os resultados dos tratamentos com U.S.P. e de baixa intensidade mostraram-se segundo a metodologia de avaliação ser altamente satisfatório para o tratamento de lesões cutâneas decorrente da Hanseníase / Based on researches carried out with the low intensity pulsed ultrasound on the regeneration of burned rat skin previously exposed to heat and on legs trophic ulcers we proposed to study the effects of the low intensity pulsed ultrasound on Hansen’s disease patients whose cutaneous manifestations were characterized as the MPP. The study was carried out on six patients supported by the Public Health Care System (SUS/PHCS) in the city of Bebedouro- SP, crowded on the Epidemiological Observation ward. The low intensity pulsed ultrasonic radiation administrations were carried out three times a week on the same circadian. Irradiation time varied from twenty to forty minutes according to the extension of the lesion. The number of the administrations, which were carried out until the complete lesion cicatrisation in all patients, was not previously stipulated. Evaluation of cicatrisation was carried out making use of software and photographs taken at the beginning of the treatment and after every ten administrations of the pulsed ultrasound until the complete ulcers cicatrisation. It was not observed any correlation between number of ultrasound applications and area of the lesion or age of them. Although extension and shape were not equivalent, according to these results, pulsed low intensity ultrasound can be considered as an adjunctive treatment for cutaneous manifestations of Hansen’s disease

Esta tese discorre sobre como a obra do escritor português Mário de Sá-Carneiro apresenta uma ligação com o mal, tomando como sustentação teórica as discussões propostas por George Bataille, Elizabeth Roudinesco e Martin Heidegger. A tese aponta como as personagens e os eu líricos optam pelo escapismo para outras realidades, para lugares míticos e para as múltiplas identidades, como forma de serem mais livres e de burlarem as regras morais que estão postas pela sociedade portuguesa da época. É por meio deste escapismo que se tem a possibilidade de criar uma vida envolta em mistério e repleta de momentos singulares. Com a ausência de uma moral que possa tolher o indivíduo de seus mais íntimos segredos é que a literatura de Sá-Carneiro envereda para a morte, o suicídio, o crime, o incesto, o homossexualismo e outros comportamentos que podem sugerir sua ligação com o mal. Com um universo deslocado do real, os textos têm como cena as noites parisienses, os refinados e sofisticados artistas e a crença de que a arte é sagrada e que, como tal, elege seus poucos representantes, e estes passam a ter seus caminhos ungidos por tal distinção. São as relações entre o escapismo, o mistério, a morte, as perversões e a arte que dão os subsídios para a inscrição da obra de Mário de Sá-Carneiro como um receptáculo daquilo a que chamamos de literatura do mal. / This paper describes how Mário de Sá-Carneiros works have a connection with evil. The theory is supported by George Bataille, Elizabeth Roudinesco and Martin Heideggers proposed discussions. The thesis notes how characters and poetic personae choose escaping to other realities, mythical places and multiple personalities as means of setting free or bending the moral rules which the Portuguese society held during that period. This escapism enables a mysterious, particular lifestyle. By lacking morals that may curb peoples most secret desires, Sá-Carneiros literature trails towards death, suicide, crime, incest, homosexuality and other unrighteous behaviors. By detaching from reality, the texts portray Parisian nights and sophisticated artists. It was believed that art was sacred and for that reason few were chosen to represent it. As a result, artists were allegedly annointed for such a distinction. The relationship between escapism, mystery, death, perversions and art shapes Mário de Sá-Carneiros work into what we call literature of evil.

Este trabalho é uma reflexão sobre Grande sertão: Veredas de João Guimarães Rosa. Tendo como foco a temática da violência, primeiramente abordamos os questionamentos éticos, religiosos e intelectuais do velho Riobaldo sobre esse problema em sua associação com o mal, conforme ele o trama nos causos iniciais da obra. Ganham relevo aqui as indagações sobre as causas ou razões da violência e a especulação sobre a doutrina quelemeniana e seus compassos e descompassos com o ponto de vista do autor. Em segundo lugar, estudamos a relação da massa dos camaradas e dos comandantes com o código de honra, cuidando de salientar os vários jogos aí observáveis: por exemplo, jagunço por eleição/jagunço por condição, tradição/invenção, liberdade/fatalidade. Em seguida, discutimos a chefia autoritária de Urutu-Branco, fruto, ao mesmo tempo, de uma vontade despótica e ausente, e encerrada em aporias que embaralham as tentativas do narrador de dar sentido à sua existência, calcular perdas e ganhos e cerzir as veredas de sua redenção. Finalmente introduzimos o conceito de trauma e experimentamos sua fertilidade e limites para pensar o caráter ambíguo da violência no Grande sertão: Veredas: às vezes, assimilável e representável, às vezes, de tal modo desnorteante que se apequenam melancolicamente essas possibilidades. É neste ponto também que se concentram comentários sobre violência e forma narrativa. / This piece of work is a reflection on Grande Sertão: Veredas by João Guimarães Rosa (The Devil to Pay in the Backlands). Firstly, focusing on violence subject we approach the ethical, religious and intellectual enquiries of the old aged Riobaldo into this matter and its association with evil, according to the way he plots it on the initial tales of the book. Significance is given to the enquiries about the causes and the reasons of violence itself and the speculation about the Quelemenian doctrine (from the book character Quelemém) and its agreements and disagreements with the author´s view. Secondly, we study the jagunços and commanders relation to the code of honour, taking into account several dualities: for instance, tradition/invention, liberty/fatality. Subsequently, we discuss the Urutu-Branco´s authoritarian leadership, result, at the same time, of an absent and despotic will, and surrounded by aporias which puzzle narrator´s attempts of giving himself reasons to live, evaluating gains and losses and asserting his own redemption. Finally, we introduce the concept of trauma and we experiment its limits and fertility to think of the ambiguous character of violence on Grande Sertão: Veredas: on some occasions, acknowledgeable and representable; on other occasions, so bewildering that those possibilities become melancholically smaller. Precisely at this point, we also concentrate comments on violence and narrative form.

O presente trabalho visa compreender a relação entre a ordem do mundo e o homem nas obras de Voltaire, ou seja, elucidar a posição e condição do homem num mundo ordenado por leis e a compreensão desse mundo do ponto de vista humano. Para tanto se enfrentou os temas que tal relação oferecia ao autor: a liberdade e a necessidade, o destino, a providência e o mal. Estes tópicos, como se sabe, constituem os assuntos tradicionais da teodicéia, de sorte que o presente trabalho é concebido também como a elucidação da leitura crítica de Voltaire do otimismo filosófico. / The present work tries to understand the rapports between the order of the world and man in Voltaires works, that is, it aims at shedding some light on man as part of an ordered world and on the understanding of that ordered world from a human standpoint. In order to do that it focused the subjects which the comprehension of that relation required: liberty and necessity, destiny, providence and evil. Those topics, as one knows, constituted the traditional themes of the theodicy, so that the present work can also be considered as an account of Voltaires critique of the philosophical optimism.

Cette thèse sur la poésie écrite a pour sujet, la connaissance du genre dans la période comprise entre 1970 et 2000. Elle propose sur une base d’auteurs et de textes une ébauche de critique des styles et des formes comme celle du contenu. Quatorze pays qui composent le corpus. Il s’agit du Benin, Burkina Faso, du Cameroun, de la Centrafrique, du Congo, de la RD Congo, de la Cote d’lvoire, du Gabon, de la Guinée, du Mali, du Niger, du Sénégal, du Tchad et du Togo. Ce travail est traité sur trois parties : les itinéraires littéraires, les thèmes importants et les styles.Du point de vue thématique, les poèmes ont permis de déceler plusieurs itinéraires dont le plus pertinent montre les étapes de la déliquescence sociale. Depuis les années 70 se sont succédé les thèmes du désenchantement, du désarroi et du mal-être correspondant aux périodes des années 70/80 ; 80/90 et de 90 à 2000. Toutes ses idées étaient étiquetées dès les premières œuvres de Tchicaya U Tamsi, le précurseur de cette génération de poètes. Parallèlement, se développe une autre orientation qui, elle, donne sur l’espoir. Ce sont les thèmes de la race, de l’amour et de la révolution. Quant à l’écriture poétique, il se passe une éclosion de formes dont certaines revêtent des caractères de plus en plus osés. Très souvent, l’imagination va puiser, dans les tréfonds des cultures, des matériaux de création. Des poèmes intégralement allégoriques (oscillant entre rêve et réalité) aux poèmes, fusion parfaite entre plusieurs genres poétiques (là où on est amené à parler d’influence de la poésie orale sur la poésie écrite) à côté des poèmes plus classiques bâtis sur la recherche de formes fixes. / This thesis on written poetry has for object the knowledge of the kind between 1970 and 2000. It provides on a base of authors and texts, critical insight of the styles and the shapes like the content’s. Fourteen countries are included in the corpus. There are Benin, Burkina Faso, Cameroon, Central Afiican Republic, Congo, DR Congo, Cote d'Ivoire, Gabon, Guinea, Mali, the Niger, Senegal, Chad and Togo. This work is treated in three parts : the literary routes, important themes and the styles. On the thematic point of view, the poems have helped identify several routes of which the most relevant shows stages of the social deliquescence. Since the 70, themes of disillusionment, dismay and discomfort succeeded one another, corresponding to periods of the years 70/80, 80/90 and the 90s to 2000. All this ideas were labeled in the early works of Tchicaya U Tamsi, the precursor of this generation of poets. Meanwhile, a different trend, which carries hope, develops itself. These are the themes of race, love and revolution. As for poetry writing, an outbreak of forms happens, some carries more and more daring characters. Very often, the imagination will draw from the depths of cultures from creation materials. From fully allegorical poems (oscillating between dream and reality) to poems, perfect fusion between several poetic genres (where one is led to speak of the influence of oral poetry on written poetry) alongside more traditional poems built on the quest of fixe shape.

Made available in DSpace on 2015-04-14T13:54:56Z (GMT). No. of bitstreams: 1 409453.pdf: 847485 bytes, checksum: 9527cf124f22862667eea563d0d8c8be (MD5) Previous issue date: 2009-01-13 / O problema do mal tornou-se uma constante inquieta??o na vida de Agostinho. Seu pensamento ? marcado pelas mais diversas influ?ncias, sobretudo das doutrinas maniqu?ia e neoplat?nica. Contudo, as respostas oferecidas por tais correntes filos?ficas n?o satisfizeram o inquieto cora??o do hiponense. O ensaio de uma resposta a esse problema ocorreu tardiamente, em O livre-arb?trio, obra na qual Agostinho busca enfrentar, juntamente com seu interlocutor, Ev?dio, o problema da origem do mal moral, vinculandoo ? vontade humana. Nesta disserta??o, pretende-se evidenciar como o bispo de Hipona busca inocentar Deus da acusa??o de ser o autor do mal, mostrando que a causa da presen?a do mal no mundo deriva do abuso do livre-arb?trio, visto que, considerado em si mesmo, este atributo da vontade ? um bem e um dom do Criador concedido ao homem.

Made available in DSpace on 2015-04-14T13:55:05Z (GMT). No. of bitstreams: 1 427823.pdf: 408542 bytes, checksum: 2a89eceaf16f9f9596ccad07761cf568 (MD5) Previous issue date: 2010-12-14 / A presente disserta??o ? uma an?lise da obra de Hannah Arendt, retratando o seu pensamento em rela??o aos conceitos do mal e da moralidade, partindo dos questionamentos sobre a incompreens?vel forma totalit?ria de governo ocorrida na Alemanha nazista, que n?o s? trouxeram os horrores da viol?ncia humana, mas os questionamentos filos?ficos perceb?veis e influenciadores de uma ?poca pol?tica din?mica e amea?adora. O trabalho ir? mostrar a forma como a autora utiliza a hist?ria do antissemitismo e totalitarismo para fazer as rela??es filos?ficas da quebra da tradi??o e da pol?tica atual moderna. A abordagem do mal, para Arendt, inicia no momento da nega??o da liberdade pelo totalitarismo, o qual considera fundamento b?sico da conceitualiza??o de pol?tica. Com essa aus?ncia de liberdade pelo totalitarismo, verificou-se a invers?o do conceito de pol?tica, caracterizada pela for?a, tendo o poder desp?tico como resultado e a consequente perpetua??o do movimento pelo terror. O mal, conforme a autora afirma, ocorre pela aus?ncia do pensar, ent?o encontra no ju?zo reflexionante de Kant, o conceito que mais se aproxima de sua interpreta??o da forma??o de um ju?zo livre. O Estudo reflete tamb?m, sobre a mentira e a propaganda ideol?gica de massa, sua base para a invers?o dos valores morais. Valores esses, que Arendt demonstra n?o encontrar sustenta??o, nem na religi?o, nem nos princ?pios kantianos, levando a autora a buscar, ent?o, os princ?pios socr?ticos. Com esses conceitos da autora o trabalho far? uma rela??o com modelos atuais e com governos democr?ticos que permite um liberalismo econ?mico e pol?tico, oportunizando a posse desse espa?o pelos indiv?duos quando os princ?pios morais desvirtuam-se da forma p?blica.

Made available in DSpace on 2015-04-14T13:55:25Z (GMT). No. of bitstreams: 1 464250.pdf: 443912 bytes, checksum: 5aa71f054c86ca739b56e8d32700b345 (MD5) Previous issue date: 2014-12-05 / Most if not all arguments that purport to demonstrate that God does not exist or that the probability of His existence is low depend, explicitly or implicitly, on the idea that there are gratuitous evils or that, if God existed, He would have created a better world. The goal of this MA thesis is to evaluate the difficulties that the consequential complexity of history could pose to the formulation of this type of arguments. Additionally, I seek to briefly investigate how the molinist model of divine providence, which postulates God s knowledge of what became known in the literature as counterfactuals of freedom, incorporates or should incorporate the question of the causal complexity of the world. / A maioria ou talvez mesmo todos os argumentos que procuram demonstrar a n?o exist?ncia ou a baixa probabilidade da exist?ncia de Deus a partir do mal existente no mundo dependem, explicita ou implicitamente, da ideia de que h? males gratuitos no mundo ou da ideia de que, se Deus existisse, Ele teria criado um mundo melhor que este. O objetivo desta disserta??o ? avaliar as dificuldades que a complexidade consequencial da hist?ria coloca para a formula??o desses tipos de argumentos. Adicionalmente, procuro investigar brevemente como o modelo providencial molinista, que pressup?e o conhecimento por Deus dos chamados contrafatuais da liberdade, incorpora ou deveria incorporar a quest?o da complexidade causal do mundo.