Nas Confissões de Agostinho de Hipona, o episódio do furto das peras, localizado no livro segundo, é possivelmente um dos dois momentos mais importantes no percurso dos seus seis primeiros livros. No entanto, tem boa parte de seu potencial filosófico desprezado. Os comentários são numerosos, mas os melhores tratam-no do ponto de vista de sua composição. Já os trabalhos filosóficos sobre o episódio não têm nem a mesma frequência, nem o mesmo fôlego. O que é de se lamentar bastante, visto o potencial que o episódio tem de fazer pensar. A fim de mudar um pouco este cenário, o que se pretende com essa dissertação é uma leitura mais atenta deste episódio. Planeja-se, em dois capítulos, cumprir dois estudos a seu respeito. Um primeiro, e mais introdutório, visa reunir os resultados daqueles estudos literários sobre o episódio. Estes importam, na medida em que preparam a leitura mesma do texto. Seus símbolos não são simples de compreender, e, além do mais, dão o que pensar. O segundo capítulo se dedica ao estudo filosófico do ato imoral, tal como ele se apresenta no feito no episódio. Por fim, para, entre outras razões, se solucionar algumas dificuldades de ordem teórica que aparecem na leitura do episódio, o terceiro capítulo pretende pensar o episódio dentro da estrutura confessional que o sustenta. Ver-seá que o livro segundo é um ótimo laboratório para o estudo do conceito de confissão em Agostinho. / In the Confessions of Augustine of Hippo, the episode of the theft of pears, located on the second book, is possibly one of the two most important moments in the course of its first six books. However, most of its philosophical potential is ignored. There are numerous comments, but the most elaborated ones deal with it from the point of view of its composition. The philosophical works on the episode are not as numerous and are not as extensive. Which is unfortunate, because of the potential that the episode has to induce to deeper thinking. In order to change a little this scenario, this thesis has been developed to propose a more attentive reading of this episode. It has been planned to introduce two studies, in two chapters. A first, and more introductory, aims to bring together the results of those literary studies about the episode. They are important to prepare the reader, so that they will be able to truly understand te text. Its symbols are not something simple to understand, and, moreover, they require deeper thinking. The second chapter is dedicated to the study of philosophical immoral act, the way it happens in the episode.

Uma vez verificada certa dificuldade interpretativa quanto à proposta do De uera religione (vii, 13) de fundamentar a religião pela história e pela profecia, já que não se encontra nesse tratado uma lista bem definida e abrangente dos fatos e das profecias que, concatenados numa argumentação cerrada, formariam o fundamento da religião católica em oposição às heresias e aos cismas, a questão naturalmente consiste em saber se essa lacuna é suprida nos escritos subsequentes, ou seja, nos escritos do presbiterado de Agostinho. Seguindo a hipótese de que o fundamento histórico-profético da religião, a qual está intimamente unida à filosofia (De uera religione, v, 8), surge na pregação presbiteral, seja em sermões, seja em ensinamentos orais como as Enarrationes in Psalmos 1-32, pode-se descobrir que tal fundamentação aparece nos sermões que tratam do credo católico, o Sermão 214 e o De fide et symbolo, mas também nas interpretações histórico-proféticas da Enarratio in Psalmo 1 e da Enarratio in Psalmo 7. Quanto à contraparte moral dessa fundamentação da religião, isso pode ser visto no Sermão 252, já que ali a reflexão sobre os fatos e as profecias acerca de Cristo e da Igreja, bem como sobre as profecias escatológicas, são utilizadas para uma exortação moral: os fiéis devem se abster de todo interesse temporal e carnal na Igreja e buscar, por conseguinte, o que é eterno e espiritual, para que assim possam entrar no Reino dos Céus, que é mais excelso do que qualquer bem terreno. / Once verified certain interpretative difficulty in the proposal of De uera religione (vii, 13) to found religion on history and prophecy, since there is not in this treatise a clear and comprehensive list of facts and prophecies that, concatenated in a tight argumentation, could form the foundation of Catholic religion in opposition to the heresies and schisms, the natural question is whether this gap is supplied in subsequent writings, that is, in the writings of Augustine\'s priesthood. Following the hypothesis that the historical and prophetic foundation of religion, which is closely linked to philosophy (De uera religione, v, 8), appears in the priestly preaching, whether in sermons, whether in oral teachings as Enarrationes in Psalmos 1-32, this can be seen in the sermons dealing with the Catholic creed, Sermon 214 and De fide et symbolo, but also in the historical and prophetic interpretations of Enarratio in Psalmo 1 and Enarratio in Psalmo 7. Concerning the moral counterpart of the foundation of religion, we can see it in Sermon 252, because the meditation on eschatological prophecies and on facts and prophecies about Christ and the Church is used for a moral exhortation: the faithful must abstain from all temporal and carnal interest in the Church and seek, therefore, what is eternal and spiritual, so that they may enter the Kingdom of Heaven, that is higher than any earthly good.

The Salvador/Warts/Hippo (Hippo) pathway defines a novel signalling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis and cancer development in mammals. The Hippo pathway was initially utilised in D. melanogaster, where the Expanded protein acts in the Hippo signalling cascade to control organ size. Willin is the proposed human orthologue of Expanded and the aim of this thesis is to investigate whether willin can activate the mammalian Hippo signalling pathway. Ectopic willin expression causes an increase in phosphorylation of the core Hippo signalling pathway components MST1/2, LATS1 and YAP, an effect which can be antagonised by ezrin. In MCF10A cells, willin over-expression antagonises a YAP-induced epithelial-to-mesenchymal transition via the N- terminal FERM (Four-point-one Ezrin Radixin Moesin) domain of willin. Preliminary results show that willin is expressed within the sciatic nerve of rat and mice, and within the neuromast cells in the zebrafish; suggesting that willin and the Hippo pathway may play a vital role in the developmental regulation within the peripheral nervous system. To conclude, willin influences Hippo signalling activity by activating the core Hippo pathway kinase cassette in mammalian cells.

Les Cnidaires et les Cténaires sont deux embranchements extérieurs aux Bilatériens qui, de par leur position phylogénétique, constituent des modèles d'étude cruciaux pour comprendre l'origine et l'évolution de mécanismes moléculaires ou encore de types cellulaires à grande échelle chez les Métazoaires. Ils sont les deux seuls embranchements non-Bilatériens à posséder des cellules nerveuses ainsi que des cellules musculaires. La première partie de mon travail de thèse s'inscrit dans le contexte de la compréhension de l'origine du système nerveux des Métazoaires. Des études récentes suggèrent une origine double du système nerveux ; ainsi celui des Cténaires aurait été acquis de manière convergente par rapport à celui des Cnidaires et des Bilatériens. Cela repose sur des données récentes de phylogénomique proposant les Cténaires en tant que groupe-frère de tous les autres Métazoaires et sur l'absence supposée chez les Cténaires de quasiment tous les systèmes de neurotransmission connus y compris le système cholinergique. A l'encontre de ces hypothèses, j'ai pu mettre en évidence l'existence d'un système cholinergique chez le Cténaire Pleurobrachia pileus ainsi que son étroite association avec le système nerveux. Cette conclusion repose sur une multiplicité d'approches à l'échelle moléculaire (analyses d'orthologie, immunolocalisation, hybridations in situ), cellulaire (imagerie calcique) et de l'organisme (approche pharmacologique). Dans la seconde partie de ma thèse, j'aborde la question de la conservation des mécanismes moléculaires impliqués dans le contrôle de la prolifération cellulaire à l'échelle des Métazoaires. J'ai pu mettre en évidence la conservation des acteurs. / Due to their phylogenetic position outside from Bilateria, cnidarians and ctenophores are key phyla to understanding the origin and early evolution of molecular mechanisms, cell types, or body plan features at the level of Metazoa. Unlike other non-bilaterian phyla (sponges and placozoans), they possess neurons and muscle cells. The first part of my work relates to the problem of the origin of the metazoan nervous system. Recent studies have suggested a dual origin for nerve cells, with ctenophore neurons having emerged independently from those of cnidarians and bilaterians. This hypothesis relies on phylogenomic analyses supporting ctenophores as sister-group to all other metazoans, and on the purported absence in ctenophores of almost all well-known neuro-transmission systems, including the cholinergic system. Refuting this claim, I present substantial evidence in favour of acetylcholine (Ach) being used in the ctenophore Pleurobrachia pileus as an extra-cellular messenger, including within the nervous system. This conclusion arises from the conjunction of multiple approaches at the molecular scale (orthology analyses, Ach immuno-localisation, gene in situ hybridisation), at the cellular scale (calcium imaging on muscle cells exposed to Ach) and at the organism scale (pharmacological treatments with an Ach analogue and Ach antagonists). In the second part of my thesis, I address the conservation of molecular mechanisms involved in the control of cellular proliferation. Notably, the Hippo pathway is known for its role in bilaterians in the negative control of cellular proliferation. I show that components of this pathway are conserved in Pleurobrachia pileus and in Clytia hemisphaerica and that the nuclear vs. cytoplasmic localisation of the transcriptional co-factor Yorkie is correlated to the extent of proliferation within C. hemisphaerica tissues. Finally, RNAseq differential gene expression analyses along a cellular conveyor belt of the C. hemisphaerica medusa suggests a tendency for conservation of function among a set of genes whose mammalian orthologues have documented roles in the arrest of cellular proliferation.

Este trabalho tem por objetivos, além de apresentar uma tradução da primeira parte do De libero arbitrio libri tres, de Agostinho de Hipona, empreender um estudo, dos três livros, em seus diferentes aspectos, retóricos e filosóficos. O De libero arbitrio, apesar de seu sentido de unidade, tem características específicas em cada uma de suas três partes. O livro I, de forte influência estóica, apresenta-se um diálogo; o livro II, se mantém a mesma estrutura dialógica, apresenta, porém, evidentes características neoplatônicas. Se as duas primeiras partes podem dizer-se dialéticas, a terceira, no entanto, sofre grave transformação, tanto em sua dispositio, quando Agostinho abdica da forma dialogal para empreender um longo discurso contínuo, como em sua elocutio, ao lançar mão de uma linguagem que, de modo inequívoco, evidencia uma mudança não só de auditório como de pensamento. O De libero arbitrio, em seu livro III, torna-se, a certa altura, uma obra de teologia, em que a concepção platônicosocrática de mundo, do Agostinho dos primeiros dois livros, cede espaço a uma visão mais cristã, influenciada sobremodo pela teologia do apóstolo Paulo, uma visão menos otimista do ser humano como ser autônomo e capaz de soerguer-se, por sua livre iniciativa. Essa mudança conceitual considerável, em seus aspectos discursivo e filosófico, evidencia uma alteração muito mais profunda, uma espécie de turning point, não apenas na obra e na vida do próprio homem, então não mais o filósofo e sim o presbítero de Hipona; não mais o pensador neoplatônico, e sim o doutor eclesiástico; mas também um turning point para a época, demarcando, de certo modo, o fim de toda uma civilização, o fim do mundo antigo, com a derrocada da visão clássica do homem, e o conseqüente princípio da era medieval. / This work has as main objectives, besides offering a translation of the first part of the De libero arbitrio libri tres of Augustine of Hippo, undertake a study of the three books, in its different aspects, rhetorical and philosophical. The De libero arbitrio, in spite of its sense of unity, has specific characteristics in each of its three parts. Book I, predominantly influenced by Stoicism, shows itself a dialog; book II, although maintaining the same dialogical structure, shows, nevertheless, evident Neoplatonic characteristics. If the two first parts may be called dialectical, the third, however, is the object of a severe metamorphosis, as in its dispositio, when Augustine resigns the cross-examination form to undertake a long uninterrupted discourse; as in its elocutio, when he adopts a style that undoubtedly makes clear a change not only in his auditory, but in his thought as well. The De libero arbitrio, then, in its third book becomes at a certain point a theological work, in which the Platonic-Socratic comprehension of the world of the young Augustine (of the first two books) yields to a more Christianized view, much influenced by the theology of the apostle Paul, which sustains a less optimistic image of man as a autonomous being, capable of raising himself through his free choice of the will. This remarkable conceptual change, in its discursive and philosophical aspects, shows a still deeper mutation, a kind of \"turning point\", not only in the works and life of the man, no longer the philosopher, but the presbyter of Hippo; no longer the Neoplatonic thinker, but the Doctor of the Church; but also a \"turning point\" to the epoch, delimiting, to a certain extent, the end of a civilization, the end of Antiquity, with the overthrow of the classical view of man and the consequential beginning of the mediaeval era.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22641号 / 医博第4624号 / 新制||医||1044(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 山下 潤, 教授 湊谷 謙司, 教授 江藤 浩之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

This paper attempts to compare the ecc1esio1ogies of the fourth century Bishop of Hippo and the controversial twentieth century theo1ogian. In doing so, a study is made of each writer independently in order to extract his conceptual models of the Church. Special significance is given to the names each attributed to the Church and the consequences of these names as they pass from an analogical to an ecc1esio1ogica1 sphere. A study is also made of the functions of office within the Church with respect to the fulfillment of specific ministries. Here the two divide, Augustine meets the Donatist challenge by condemning disunity, while urging contemporary Christians to true internal reform, reminding them of the necessity of grace available only through the Church to heal their natures. Special attention is given to two specific topics from Augustine: the use of force to compel at least outward conformity, and the belief in the inability of man to do any good outside the Body of Christ. Kung diverges in another way in different times. He emphasizes the communal nature of the Church as those called by God and, on earth, represented by the ministry of ecclesiological office, including Ecumenical Councils and the Papacy. The Church, according to Kung, is the Kingdom of God moving towards manifestation and must reflect its apocalyptic nature by its witness and proclamation of the Word. He finds fault with the teaching office of the Church for its adherence to verbal propositions and concludes advocating a non-propositional attachment to kerygma. The contrast between the writers is sharply emphasized by a comparison of their positions on certain points, including authority, the Papacy and finally the four marks or distinguishing characteristics of the Church. The attitudes towards the first two differ markedly on some points, but a consistency of approach towards the four marks of the Church, with the exception of the Apostolic characteristic, can be seen. Several conclusions are propounded but the essence of each lies in the attitude of each writer towards human nature. Augustine finds the same wholly depraved without grace, which is given through the Word and human collaboration. Kung finds a response to divine call sufficient and is less concerned with limits on freedom in the name of love of neighbor. The interplay between these two schools of thought has punctuated Church history in the same manner as it does human history.

Melanoma, a malignant neoplasm of melanocytes, is the most lethal form of skin cancer. A majority of melanomas are driven by activating mutations in the kinase BRAF, which drives cellular proliferation through constitutive stimulation of the mitogen-activated protein kinase (MAPK) signaling pathway. Intriguingly, expression of oncogenic BRAF alone in vivo is insufficient to promote melanoma; rather, its expression leads to the development of benign nevi (moles) comprised of growth-arrested melanocytes. The acquisition of additional genetic or epigenetic changes is therefore critical for melanocytes to evade arrest and drive melanomagenesis, however the identity of these changes remains incompletely understood. Here we demonstrate that expression of oncogenic BRAF leads to activation of the Hippo tumor suppressor pathway in vitro, which acts to limit melanocyte proliferation through the inhibition of the pro-growth transcriptional co-activators YAP and TAZ. Melanocyte-specific inactivation of Hippo signaling in vivo, via deletion of the Hippo kinases Lats1/2 alone, or in conjunction with oncogenic Braf expression, potently induces melanoma development in mice. Collectively, our data reveal that the Hippo tumor suppressor pathway represents an important barrier to melanoma development, and implicates YAP and TAZ as new therapeutic targets for the treatment of human melanoma.

In the distal lung, alveolar epithelial type I cells (AT1s) comprise the vast majority of alveolar surface area and are uniquely flattened to allow the diffusion of oxygen into the capillaries. This structure along with a quiescent, terminally differentiated phenotype has made AT1s particularly challenging to isolate or maintain in cell culture. As a result, there is a lack of established models for the study of human AT1 biology, and in contrast to alveolar epithelial type II cells (AT2s), little is known about the mechanisms regulating their differentiation. Here we engineer a human in vitro AT1 model system through the directed differentiation of induced pluripotent stem cells (iPSC). We first define the global transcriptomes of primary adult human AT1s, suggesting gene-set benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, that are enriched in these cells. Next, we generate iPSC-derived AT2s (iAT2s) and find that activating nuclear YAP signaling is sufficient to promote a broad transcriptomic shift from AT2 to AT1 gene programs. The resulting cells express a molecular, morphologic, and functional phenotype reminiscent of human AT1 cells, including the capacity to form a flat epithelial barrier which produces characteristic extracellular matrix molecules and secreted ligands. Our results indicate a role for Hippo-LATS-YAP signaling in the differentiation of human AT1s and demonstrate the generation of viable AT1-like cells from iAT2s, providing an in vitro model of human alveolar epithelial differentiation and a potential source of human AT1s that until now have been challenging to viably obtain from patients.

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