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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Atypical teratoid rhabdoid tumor (ATRT) is a highly malignant pediatric central nervous system tumor. The prognosis is often poor, with a 2‐year survival rate estimated at 15%. This dismal prognosis highlights the need to develop new treatment modalities for this devastating pediatric tumor. Recently, a tumor suppressing signaling pathway known as Hippo has emerged as a possible cancer treatment target. The Hippo signaling pathway is involved in organ growth and maintenance, and is dysregulated in many diverse cancers. We used quantitative real‐time PCR to evaluate the mRNA expression profile of Hippo pathway genes. We then used determined the protein expression of various Hippo components using Western blots. The results of this study suggest that Hippo plays a definite role in atypical teratoid rhabdoid tumor.

Thesis advisor: Richard Kearney / By the 20th century the Confessions had become a “classic” of western civilization, yet it seems to elude any easy explanation and categorization. While scholars of Late Antiquity puzzled over the nature, structure, and meaning of the work, a parallel reception was occurring by some of the most original thinkers across both traditions of Contemporary philosophy, including Ludwig Wittgenstein, Martin Heidegger, Hannah Arendt, Hans Jonas, Karl Jaspers, Hans-Georg Gadamer, Paul Ricoeur, Jean-Francois Lyotard, Jacques Derrida, Jean-Luc Marion, Jean Louis Chrétien and Stanley Cavell. This study will focus on four of these thinkers, Wittgenstein, Gadamer, Ricoeur and Marion, and the ways that the Confessions has influenced their attempts to address fundamental questions on subjects ranging from time and memory to history and hermeneutics, evil and the will, the self and personal identity, language and narrative, conversion, skepticism and materialism, God and onto- theology, and ultimately the very practice of philosophy itself, its autobiographical and especially its confessional character. In turn, this study also asks whether the engagements of these highly original contemporary philosophers can uncover new dimensions of this highly original work that has been read and interpreted throughout a centuries-long history of reception. The hermeneutic wager is that the past illumines the present philosophical terrain, but also that present insights allow us to read a classic text of the past with new understanding. This study will benefit from the interconnected nature of the problems that these writers confront, in their “family resemblance” of shared affinities and marked differences. Chapter One, “Scholarly Engagements: A Problematic Classic,” introduces some of the key interpretive problems which arose in the course of a century of scholarly engagements, including occasion, veracity, composition, and sources of Saint Augustine’s Confessions. Chapter Two “The Early Wittgenstein: Tractatus, Testimony and Confession” discusses the confessional philosophy of Ludwig Wittgenstein, and the deep affinities he shared with Saint Augustine in his life and his first major work, the Tractatus Logico-Philosophicus (1922), despite its reception and use as a foundational for Logical Empiricism and its spirited offspring. Chapter Three: “The Later Wittgenstein: Philosophical Investigations as Philosophical Confession” discusses the influence of Saint Augustine on Wittgenstein’s second major work, the Philosophical Investigations (1953), which uses a quotation from the Confessions as a point of departure for his own philosophical confession of errors and temptations. Chapter Four “Saint Augustine and Gadamer: Hermeneutic Anticipations and Affinities” discusses the hermeneutical insights of Saint Augustine, through the ways he encountered or struggled with texts in the Confessions, as well as through his idea of the “inner word” which would be for Gadamer the foundation of a philosophical hermeneutics. Chapter Five, “Ricoeur: Sin, Time, Memory, and Narrative” discusses Ricoeur’s engagement with Saint Augustine on the question of evil as well as his appropriation of the Augustinian aporia of time from the Confessions as pivotal for his narrative turn. Chapter Six, “Jean-Luc Marion’s Confessions” lays out Marion’s phenomenological unfolding of the Confessions beyond and before metaphysics, offering his reading of six dimensions of the inaccessibility of the self explored by Saint Augustine in the Confessions. This study will conclude by highlighting the themes that have suggested themselves across the many readings of this classic text. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Philosophy.

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.

O donatismo, uma dissidência religiosa cristã, ocupou um lugar de destaque na cristandade africana entre os séculos IV e V, dividindo-a e polarizando-a em duas vertentes, sendo o foco da atenção de importantes pensadores do período, como Agostinho de Hipona e Optato de Milevo. Sua singularidade advém de se tratar, em sua gênese, de uma querela quanto à conduta moral do clero. Em uma época de dissidências doutrinárias principalmente trinitárias, o donatismo foi considerado como um desdobramento das perseguições perpetradas por Diocleciano; estas teriam deixado vestígios indeléveis, sementes para novos desentendimentos geradores de cismas e divisões. O presente estudo busca explorar as noções básicas de retórica, ou retórica cristã (conforme esta era entendida por Agostinho), e a delimitação do ethos constituído para a vertente donatista pelo bispo de Hipona, seu adversário. A partir da premissa de que o que estava realmente em jogo na querela era a definição de qual das vertentes era verdadeiramente a portadora do legado de Cristo, a presente pesquisa procura abordar duas questões fundamentais na gênese da mesma: a concepção de via salvífica e o batismo. Almeja-se, portanto, investigar o ethos retórico imputado aos donatistas por Agostinho por meio de uma consideração da representação e das justificativas da dissidência presentes nos tratados anti-donatistas desse tão célebre autor. / Donatism was a particularly significant Christian dissidence within African Christianity between the 4th and 5th centuries AD, one that split Christians into two highly polarized factions and became an object of study for important thinkers of the period, such as Augustine of Hippo and Optatus of Milevis. Its uniqueness comes from the fact that it originally consisted of a quarrel concerning the moral conduct of members of the clergy. At a time of doctrinarian disagreements that were mostly of a Trinitarian nature, Donatism was regarded as having unfolded from the religious persecutions perpetrated by Diocletian; the latter were seen as having left an indelible mark upon Christianity, and as having sowed the seeds for future discord and schisms. It is the intention of the present study to investigate the basic notions of rhetoric, particularly as applied to Christian values, present in the thought of Augustine, as well as the characteristics of the ethos said author gradually built for his adversaries, the Donatists. Starting from the premise that what was really at stake in the controversy was determining which of the two factions was the true bearer of the legacy of Christ, the investigation seeks to approach two issues at the heart of the quarrel: namely, the notion of a true path to salvation and the sacrament of baptism. Its aim is, therefore, to analyze the rhetorical ethos Augustine characterized the Donatists with by means of a consideration of the way this particular dissidence was portrayed in the anti-Donatist treatises produced by the celebrated bishop of Hippo.

Thesis advisor: Stephen J. Pope / Transitional justice responds to injustices and violations of human rights following a period of repressive rule or civil war. This dissertation argues that the needs of post-conflict societies are best served by local, participatory approaches to transitional justice. In the case of Guatemala, it was essential for the nation to embrace its common religious narrative as a resource for rebuilding the republic. The Guatemalan Catholic Church worked to build peace out of the ashes of state sponsored terror. It demonstrated the prophetic role of the Church by offering a collective voice condemning those in positions of authority for their neglect of the basic human rights of the majority of Guatemalans. The CEG also highlighted the reconciliatory function of the Church by promoting forgiveness and reconciliation within the public square. This experience calls for theological ethical reflection on how the Catholic Church could best serve the needs of civil society in the wake of nearly forty years of political violence. Responding to the need for critical theological reflection, this dissertation proposes a transformationalist understanding of the relation of love to justice for transitional justice. It draws its inspiration from a selective reading of Augustine and Augustinian scholarship. An Augustinian approach to transitional justice brings together the high moral ideas of love, justice, forgiveness, and peace while at the same time acknowledging the ever-present reality of sin and human weakness. It attempts to transform a post-conflict society into a moral community whose citizens are on a journey toward the destination of temporal peace. It realizes that we may never reach our destination of temporal peace, but we can glimpse it from afar. This dissertation offers the following ten Augustinian insights as a framework for a theological approach to transitional justice. 1) Charity is the motivating force for transitional justice and the pursuit of socio-political reconciliation; 2) Charity transforms our understanding of justice from noninterference and retribution to rehabilitating and reconciling; 3) Transitional justice ought to be contextual, paying attention to the unique concerns of a given post-conflict society; 4) Distinguishing, without bifurcating, the ends of the temporal and celestial commonwealths offers a positive, but not naïve, evaluation of the Church’s potential to be an instrument of social transformation; 5) Post-conflict societies need to foster conditions that allow for pluralism and social cohesion through civic friendship; 6) Post-conflict societies must develop social practices to train citizens in the civic virtues of love, justice, and friendship; 7) Transitional justice requires an ethical retrieval of the truth through the healing of memory; 8) Transitional justice upholds the moral obligation to admonish and correct sinful social behavior; 9) Transitional justice ought to foster the just and prudential protection of society through the use of coercive force on behalf of society’s most vulnerable citizens; and 10) Post-conflict societies need to cultivate and sustain an ethos of active hope that, far from inducing political passivity, promotes civic engagement. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Theology.

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.

The paralogous multi-functional adaptor proteins YAP and TAZ are nuclear effectors of the Hippo pathway, a central regulator of developmental organ size control, tissue homeostasis and tumour suppression. YAP/TAZ target the TEAD transcription factor family to promote cell survival and inhibit apoptosis. TEAD proteins contain a DNAbinding domain and a YAP/TAZ interaction domain. PCR analysis of medaka fish TEAD cDNA revealed the presence of alternative TEAD splice-forms with variations at the C-terminus of the DNA-binding domain. Structural analysis indicated the YAPbinding domain of TEAD proteins is folded and globular. NMR spectroscopy showed that the TEAD binding domain of YAP does not contain secondary structure. YAP and TAZ both contain WW domains, which are small protein-protein interaction modules. Two YAP isoforms are known, YAP1 and YAP2 that contain one and two WW domains, respectively. To date, only a single WW isoform of TAZ has been described. PCR analysis of medaka TAZ cDNA identified both single WW and tandem WW isoforms of TAZ. NMR spectroscopy was used to characterise structural, conformational, and peptide binding features of the tandem WW domains from YAP and TAZ. The YAP WW2 solution structure confirms that the domain has the canonical anti-parallel β-sheet WW fold. WW1 of YAP and both WW domains of TAZ undergo conformational exchange. The region linking the two WW domains is flexible and allows interaction of both WW domains with peptides containing single and dual PPxY binding motifs. In addition to YAP and TAZ, tandem WW domains are also present in the core and upstream Hippo pathway proteins Salvador and Kibra. Both proteins contain one atypical WW domain; the tandem WW domains of these two proteins are unstable. Understanding structure and function of Hippo pathway components could contribute to drug development and will also contribute to knowledge of protein folding and interactions.

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.

O donatismo, uma dissidência religiosa cristã, ocupou um lugar de destaque na cristandade africana entre os séculos IV e V, dividindo-a e polarizando-a em duas vertentes, sendo o foco da atenção de importantes pensadores do período, como Agostinho de Hipona e Optato de Milevo. Sua singularidade advém de se tratar, em sua gênese, de uma querela quanto à conduta moral do clero. Em uma época de dissidências doutrinárias principalmente trinitárias, o donatismo foi considerado como um desdobramento das perseguições perpetradas por Diocleciano; estas teriam deixado vestígios indeléveis, sementes para novos desentendimentos geradores de cismas e divisões. O presente estudo busca explorar as noções básicas de retórica, ou retórica cristã (conforme esta era entendida por Agostinho), e a delimitação do ethos constituído para a vertente donatista pelo bispo de Hipona, seu adversário. A partir da premissa de que o que estava realmente em jogo na querela era a definição de qual das vertentes era verdadeiramente a portadora do legado de Cristo, a presente pesquisa procura abordar duas questões fundamentais na gênese da mesma: a concepção de via salvífica e o batismo. Almeja-se, portanto, investigar o ethos retórico imputado aos donatistas por Agostinho por meio de uma consideração da representação e das justificativas da dissidência presentes nos tratados anti-donatistas desse tão célebre autor. / Donatism was a particularly significant Christian dissidence within African Christianity between the 4th and 5th centuries AD, one that split Christians into two highly polarized factions and became an object of study for important thinkers of the period, such as Augustine of Hippo and Optatus of Milevis. Its uniqueness comes from the fact that it originally consisted of a quarrel concerning the moral conduct of members of the clergy. At a time of doctrinarian disagreements that were mostly of a Trinitarian nature, Donatism was regarded as having unfolded from the religious persecutions perpetrated by Diocletian; the latter were seen as having left an indelible mark upon Christianity, and as having sowed the seeds for future discord and schisms. It is the intention of the present study to investigate the basic notions of rhetoric, particularly as applied to Christian values, present in the thought of Augustine, as well as the characteristics of the ethos said author gradually built for his adversaries, the Donatists. Starting from the premise that what was really at stake in the controversy was determining which of the two factions was the true bearer of the legacy of Christ, the investigation seeks to approach two issues at the heart of the quarrel: namely, the notion of a true path to salvation and the sacrament of baptism. Its aim is, therefore, to analyze the rhetorical ethos Augustine characterized the Donatists with by means of a consideration of the way this particular dissidence was portrayed in the anti-Donatist treatises produced by the celebrated bishop of Hippo.