Les trois proto-oncogènes RAS, soit HRAS, KRAS et NRAS (H/K/NRAS), sont les gènes les plus fréquemment mutés dans les cancers humains. Les énormes défis liés au ciblage thérapeutique des RAS soulignent la nécessité d’approfondir notre compréhension de la biologie de ces protéines et de trouver des stratégies alternatives pour traiter les cancers qu’elles induisent. Les petites GTPases RAS sont des régulateurs fondamentaux du développement et se lient à des protéines effectrices distinctes pour transmettre des signaux afin de réguler diverses voies de signalisation intracellulaires. Les effecteurs de RAS sont définis par un domaine de liaison à RAS (RBD) qui reconnaît la conformation active de RAS liée au GTP et active les voies de signalisation en aval. Par exemple, les effecteurs RAF et PI3K régulent les voies de signalisation MAPK et PI3K-AKT, respectivement, pour contrôler la prolifération, la survie et la tumorigenése. Alors que RASSF5 dirige RAS vers la voie Hippo, suppresseur de tumeur, mais cela reste moins bien compris. Il est intéressant de noter que la famille des domaines d'association à RAS (RASSF) comprend 10 effecteurs RAS supposés en aval, chacun comprenant un RBD, mais seul le RASSF5 se lie à H/K/NRAS. Les RASSF sont des suppresseurs de tumeurs connus et comptent parmi les protéines les plus fréquemment régulées à la baisse dans les cancers. La superfamille des petites GTPases RAS compte chez l’humain environ 160 protéines regroupées en cinq sous-familles : RAS, RHO, RAN, RAB et ARF. Alors que H/K/NRAS sont les mieux caractérisées et ont été au centre de la recherche sur le cancer, les fonctions cellulaires, la régulation et les protéines effectrices de nombreuses autres GTPases de la superfamille RAS restent obscures. Ma recherche doctorale visait donc à étudier le rôle des effecteurs de RASSF en cartographiant les interactions de BRAF et de quatre protéines de RASSF avec 83 GTPases appartenant aux sous-familles RAS, RHO et ARF et à utiliser ces connaissances pour démêler l'interaction complexe entre les GTPases et les effecteurs. Nous avons abordé des questions clés sur la spécificité des RBD envers les GTPases et avons révélé et validé 39 interactions RASSF-GTPase. Nous avons constaté qu'alors que BRAF démontre une spécificité restreinte pour les H/K/NRAS classiques, RASSF fait preuve de plasticité dans ses interactions avec les GTPases. RASSF5 interagit avec 10 GTPases distinctes de la sous-famille RAS (H/K/NRAS, RAP2B/2C, RRAS1/2, MRAS et RIT1/2) qui favorisent la croissance. La présence d’un complexe RASSF5-GTPase à la membrane plasmique redistribue la protéine YAP dans le cytosol et active la signalisation Hippo. Nous avons également montré que l'interaction de RASSF5 avec les kinases MST est essentielle pour l'activation de la voie Hippo médiée par le complexe RASSF5-GTPase. Nous avons également révélé que RASSF3, RASSF4 et RASSF8 lient les GTPases de la sous-famille RAS inhibitrices de croissance. RASSF8 subit une séparation de type liquide-liquide et réside avec YAP dans des gouttelettes non-membranaires. De plus, l'expression des partenaires GTPase de RASSF8 redistribue les condensats de RASSF8 et YAP de grandes structures périnucléaires. YAP et la voie Hippo entraînent une résistance aux inhibiteurs de RAS dans les cancers induits par RAS. Ainsi, nos découvertes sur l'association de RASSF5 et RASSF8 avec la voie Hippo pourraient aider à élucider les liens manquants entre les signalisations RAS et Hippo. Nous avons également identifié RASSF3 comme le premier effecteur canonique de MIRO1/2, des GTPases mitochondriales essentielles pour le fonctionnement et l'homéostasie des mitochondries. L'interaction de RASSF3 avec MIRO dans les mitochondries entraîne un effondrement du réseau mitochondrial. Pour comprendre la dynamique du réseau des GTPases, nous développons un outil de GTPase piégée inductible par la rapamycine. Ainsi, le piège qui garde la GTPase surexprimée inactive peut être libérée et la GTPase activée de manière conditionnelle en utilisant le traitement à la rapamycine. Cet outil sera utile pour élucider le rôle précis de chaque GTPase dans la régulation des effecteurs en aval in cellulo. Par conséquent, cette étude révèle la nature complexe des interactions entre GTPases et effecteurs et met en lumière l'importance biologique des protéines RASSF. / The three RAS proto-oncogenes, namely HRAS, KRAS and NRAS (H/K/NRAS) are the most frequently mutated genes in human cancers. H/K/NRAS small GTPases are fundamental regulators of development and bind distinct effector proteins to transmit signals to diverse cellular pathways. RAS effectors are defined by a RAS-binding domain (RBD) which recognizes the GTP-bound activated conformation of RAS and activates downstream signalling pathways. For example, RAF and PI3K effectors regulate the MAPK and PI3K-AKT signalling pathways, respectively, to control proliferation, survival and tumorigenesis. Whereas RASSF5 directs RAS to the tumour suppressor Hippo pathway but this remains less understood. Interestingly, the RAS Association domain family (RASSF) comprises 10 purported downstream RAS effectors, each of which comprises an RBD, but only RASSF5 binds to H/K/NRAS. RASSF are known tumour suppressors and are among the most frequently downregulated proteins in cancers. There are approximately 160 proteins in the human RAS superfamily that are clustered into five subfamilies: RAS, RHO, RAN, RAB and ARF. While H/K/NRAS are the best-characterized and have been a principal focus of cancer research, cellular functions, regulation and effectors for many other GTPases of the RAS superfamily remain recondite. My doctoral research therefore aimed to investigate the role of RASSF effectors by mapping the interactions of BRAF and four RASSF proteins with 83 GTPases belonging to the RAS, RHO and ARF subfamilies and use this knowledge to unravel the complex interplay between GTPase and effectors. I uncovered 39 RASSF–GTPase interactions and addressed key questions on RBD specificity towards GTPases. I found that while BRAF demonstrates restricted specificity for classical H/K/NRAS, RASSF shows plasticity in its interaction with GTPases. RASSF5 interacts with 10 distinct growth-promoting GTPases of the RAS subfamily (H/K/NRAS, RAP2B/2C, RRAS1/2, MRAS and RIT1/2). RASSF5–GTPase complex at the plasma membrane redistributes YAP to the cytosol and activates Hippo signalling. I also showed that RASSF5 interaction with MST hippo kinases is essential for RASSF5–GTPase complex-mediated activation of the Hippo pathway. I further revealed that RASSF3, RASSF4 and RASSF8 bind distinct growth-inhibiting RAS subfamily GTPases. RASSF8 undergoes liquid-liquid phase separation and resides in membraneless, phase-separated YAP condensates. Further, the expression of GTPase partners of RASSF8 redistributes RASSF8 and YAP condensates to large peri-nuclear structures. These findings show several GTPase–RASSF complexes play a role in Hippo signalling which may serve as potential therapeutic targets for RAS- or YAP-driven cancers. I also identified RASSF3 as the first canonical effector of MIRO1/2, mitochondrial GTPases that are essential for mitochondrial functions and homeostasis. RASSF3 interaction with MIRO at the mitochondria results in a collapse of the mitochondrial network. To understand the dynamics of the GTPase network, I am further developing a rapamycin-inducible trapped GTPase (RITG) tool, wherein a GTPase can be overexpressed while remaining occluded, and can be conditionally released or activated. This tool can be useful in elucidating the role of GTPases in the regulation of downstream effectors in cellulo. Overall, this study reveals the complex nature of GTPase–effector interactions and uncovers the biological significance of RASSF proteins.

Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Augustine of Hippo remains one of the most prominent and influential figures in the world of Catholicism, famous for his many writings and sermons on Catholic Christianity as well as his ardent defence of it. His debate with Fortunatus, a member of the Manichaean faith presented Augustine with one of his defining moments as a member of the Catholic clergy. This is because Augustine had only been a presbyter in the Church at Hippo for a few months when this debate took place and therefore had much at stake against his wily opponent. To make matters even more complicated for Augustine, he himself had been a Manichee for at least nine years and knew Fortunatus as a skilled debater. But rhetoric, or the art of persuasion, was a field in which Augustine excelled, having both a natural proclivity for speaking as well as the formal education behind it. Chapter one begins with an introduction to the debate, the primary characters, and the religions involved. Chapter two continues with an exposition of Augustine and his association with Manichaeism and then goes on to describe Augustine‟s anti-Manichaean works. From this point, chapter two continues with a section on Manichaeism, its spread, its myth and its practice. From this contextual basis, chapter three deals with the methodology of Critical Discourse Analysis and the three most important characters in the form of Halliday, Fairclough and van Dijk. This chapter is followed by another chapter on theory: Argumentation Theory. Chapter four includes subsections on van Eemeren and his methodologies of Pragma-Dialectics and Strategic Maneuvering. The analysis chapters of this dissertation begin with chapter five which deals with concepts from Critical Discourse Analysis and Argumentation Theory. This chapter includes subsections on categories of enquiry, followed by a section on a number of recurring devices, namely: answering questions, changing the topic and quoting scripture. A Critical Discourse Analysis section follows with subsections that include difference, evaluation and knowledge as a common ground component of contexts. This in turn is followed by sections on Argumentation Theory and Strategic Maneuvering, which include subsections on economy, efficacy and coherence; realism and wellfoundedness; logical reasoning process and pragmatic inferences; reasonableness versus effectiveness; the rhetorical perspective; discussion strategies; dialectical aims versus rhetorical aims and deceptive manoeuvring. The final analysis chapter, the Contra Fortunatum in context, includes subsections on the opening of the debate, the structure of the debate and the topics of discussion. Within this last section subsections on the Nebridian conundrum, the origin of evil, and free will occur. The next subsection dicusses topics not mentioned in the debate: the Manichaean myth, Mani and the previous friendship between Fortunatus and Augustine. Following this there are sections on Manichaeism presenting itself as a form of Christianity, the debaters talking past each other and the issues of audience composition and power relations between the various role players. Chapter seven takes a concluding look at the issue of who should be designated the winner of the debate. / AFRIKAANSE OPSOMMING: Augustinus van Hippo bly een van die mees prominente en invloedryke figure in die wêreld van die Katolisisme, bekend vir sy vele skrywes en preke oor die Katolieke Christendom sowel as sy ywerige verdediging daarvan. Sy debat met Fortunatus, ʼn lid van die Manichese geloof, het aan Augustinus een van die bepalende oomblikke in sy rol as Katolieke geestelike besorg. Die rede hiervoor is dat Augustinus ten tyde van die debat nog net ʼn paar maande ʼn presbiter in die kerk in Hippo was; daarom was daar baie op die spel in die debat teen hierdie gedugte opponent. Om dinge selfs nog meer ingewikkeld vir Augustinus te maak, was hy self vir ten minste nege jaar 'n Manicheër en was hy bekend met Fortunatus se retoriese vermoëns. Retoriek, of die kuns van oorreding, was egter 'n veld waarin Augustinus uitgeblink het. Hy het beide ʼn natuurlike aanvoeling vir redevoering sowel as ʼn formele opleiding gehad. Hoofstuk een van die proefskrif begin met ʼn inleiding tot die debat, die hoofkarakters en die gelowe wat betrokke is. Hoofstuk twee gaan voort met ʼn uiteensetting van Augustinus en sy assosiasie met die Manichese geloof en beskryf ook Augustinus se anti-Manichese werke. Van hier af gaan hoofstuk twee dan verder met 'n afdeling oor die Manichese geloof, die mitologie en lewenswyse, sowel as die verspreiding van die Manicheïsme. Met hierdie kontekstuele agtergrond as basis handel hoofstuk drie oor die metodologie van Kritiese Diskoersanalise en die drie belangrikste eksponente van hierdie teoretiese rigting, Halliday, Fairclough en Van Dijk. Hierdie hoofstuk word gevolg deur nog ʼn teoretiese hoofstuk wat handel oor Argumentasieteorie. Hoofstuk vier sluit onderafdelings in oor Van Eemeren en sy metodologieë van Pragma-Dialektiek en Strategiese Maneuvers. Die ontledingshoofstukke van hierdie proefskrif begin by hoofstuk vyf wat handel oor Kritiese Diskoersanalise en Argumentasieteorie. Hierdie hoofstuk sluit onderafdelings in oor kategorieë van ondersoek, opgevolg deur ʼn gedeelte oor 'n aantal herhalende tegnieke: die beantwoording van vrae, die verandering van die onderwerp en skrifaanhalings. ʼn Volgende afdeling oor Kritiese Diskoersanalise volg daarop met onderafdelings wat verskil, evaluasie en kennis as ʼn gemeenskaplike komponent op die terrein van konteks insluit. Hierop volg 'n afdeling oor Strategiese Maneuvers. Laasgenoemde sluit onderafdelings in oor ekonomie, doeltreffendheid en koherensie; realisme en gegrondheid; logiese denkprosesse en pragmatiese gevolgtrekkings; redelikheid versus effektiwiteit; die retoriese perspektief; besprekingstrategieë; dialektiese doelwitte versus retoriese doelwitte en maneuvers van misleiding. Die finale ontledingshoofstuk, getiteld die Contra Fortunatum in konteks, sluit onderafdelings in oor die openingsreëls van die debat, die struktuur van die debat en tematiek daarvan. In die laaste afdelings word die kwessies van die Nebridiese vraagstuk, die oorsprong van boosheid en die vrye wil ingesluit. Die volgende onderafdeling bevat onderwerpe wat nie in die debat behandel word nie: die Manichese mite, Mani en die vroeëre vriendskap tussen Fortunatus en Augustinus. Daarop volg die afdelings oor die Manichese strategie om hierdie godsdiens as Christelike godsdiens voor te stel, die deelnemers se taktiek om verby mekaar te praat asook oor die samestelling van die gehoor en kwessie van die magsverhoudinge tussen die onderskeie rolspelers. Die laaste hoofstuk sluit samevattend af met 'n kort bespreking van die kwessie van wie as die wenner van die debat beskou moet word.

La prolifération cellulaire et la croissance tissulaire sont étroitement contrôlées au cours du développement. Chez la Drosophila melanogaster, ces processus sont régulés en partie par la kinase stérile-20 Slik (SLK et LOK chez les mammifères) et le suppresseur de tumeur Hippo (Hpo, MST1/2 chez les mammifères) dans les cellules épithéliales. La surexpression de la kinase Slik augmente la taille des tissus chez les mouches adultes. Cependant, les mutants slik-/- meurent avant d'avoir terminé leur développement. Lorsqu’elle est surexprimée dans les cellules épithéliales des ailes en voie de développement, cette protéine favorise la prolifération cellulaire. En outre, l'expression de Slik dans une population de cellules conduit à une surprolifération des cellules voisines, même quand elles sont physiquement séparées. Ceci est probablement dû à la sécrétion de facteurs de croissance qui stimulent la prolifération de manière paracrine. En utilisant des méthodes génétiques et transcriptomiques, nous essayons de déterminer les molécules et les mécanismes impliqués. Contrairement à ce qui a été publié, nous avons constaté que Slik ne transmet pas de signal prolifératif en inhibant le suppresseur de tumeur Merlin (Mer, NF2 chez les mammifères), un composant en amont de la voie Hippo. Plutôt, elle favorise la prolifération non-autonome et la croissance des tissus en signalisation par la kinase dRaf (la seule kinase de la famille Raf chez la drosophile). Nous prouvons que dRaf est nécessaire chez les cellules voisines pour conduire la prolifération chez ces cellules. De plus, nous avons utilisé le séquençage du transcriptome pour identifier de nouveaux effecteurs en aval de Slik. Ce qui permettra de mieux comprendre les effets de SLK et LOK chez les humains. / Cell proliferation and tissue growth are tightly controlled during development. In epithelial tissues in Drosophila melanogaster, these processes are regulated in part by the Sterile-20 kinase Slik (SLK and LOK in mammals) and the tumor suppressor Hippo (Hpo, MST1/2 in mammals). Slik overexpression leads to an increase in tissue size in flies, whereas, slik-/- mutants die before completing development. Overexpressing this protein in the developing wing disc epithelium promotes cell proliferation, consistent with the overgrown wing phenotype in the adults. Moreover, expression of Slik in one population of cells leads to an overproliferation of neighboring cells, even when they are physically separated by a central lumen. This can be explained by secretion of paracrine growth factors, stimulating non-autonomous proliferation that is specific to Slik. We used genetic and transcriptomic assays to define the molecules and mechanism involved in Slik-mediated signaling. Contrary to what has been suggested, we found that Slik does not promote proliferation through the tumor suppressor Merlin (Mer, NF2 in mammals), an upstream component of the Hippo pathway, nor through other components of the Hippo pathway. Rather, Slik promotes non-autonomous proliferation and tissue growth signaling through dRaf (the single Raf family kinase orthologue in Drosophila). We found that dRaf is required in the signal receiving cells to stimulate proliferation. We performed RNA-seq to identify novel downstream effectors of Slik. Characterizing the signaling pathway downstream of Slik in Drosophila will shed light on how SLK and LOK function in mammals, and provide insights into their potential involvement during development and in cancer.

The aim of this thesis is to map the effect of hippo rehabilitation on a change in school evaluation, interpersonal communication, behaviour and skills of the pupils with a health handicap. The thesis is divided into two parts. The theoretical part summarizes necessary information about hippo rehabilitation as a whole and its usability in treatment of disorders and diseases. In the first chapter, a brief history of hippo rehabilitation and its emergence as a treatment method is presented; followed by definitions of terms, division and characterization of the individual disciplines. The following part is devoted to the healing effect of hippo rehabilitation on both physical and psychological components of a human being, through the impact of specific and non-specific factors of the therapy. The third part describes the way the hippo rehabilitation is carried out in practice, as well as the conditions necessary for its performance. The healing effects and mechanisms of the individual disciplines are also dealt with. The last chapter of the theoretical part deals with hippo rehabilitation in terms of its effect on human functions and characteristics that influence school success. This part also includes a description of symptoms and signs of the individual disabilities and a possible impact of hippo...

Nos séculos IV e V ocorreram contínuos esforços por uma unificação e homogenização do credo cristão, algo que provocou o embate e o confronto entre as diversas vertentes, cada qual arrogava para si o título de verdadeiros cristãos e imputando aos seus adversários a alcunha de falsos cristãos. O ethos retórico cristão é constituído a partir da premissa de que haveria uma única Verdade, assim sendo, na medida em que ser cristão é, por definição, empreender a imitatio Christi, tentava-se determinar aquele que advoga por Cristo do dito herege. Em meio a estas intensas disputas retóricas, Agostinho de Hipona foi um dos autores de maior destaque, participando dos principais debates de sua época. O donatismo, o arianismo e o pelagianismo foram três dos seus principais adversários. Cada qual representando um diferente desafio, Agostinho necessitava responder e enfrentar estas vertentes na defesa do que ele acreditava ser a verdadeira via salvífica cristã. O donatismo foi considerado como um desdobramento das perseguições perpetradas por Diocleciano; estas teriam causado um cisma político e doutrinário, cindindo a Igreja cristã na África romana. O arianismo, uma dissidência trinitária e protagonista inconteste do século IV, defendia uma hierarquia dentro da Trindade e contestava sua própria definição. O pelagianismo, uma frequente preocupação de Agostinho nos seus últimos 20 anos, negava o conceito do pecado original e questionava papel da Graça divina na salvação. A partir da premissa de que o que estava realmente em jogo era a definição de qual das vertentes era verdadeiramente a portadora do legado de Cristo, a presente pesquisa procura comparar o processo de construção do ethos retórico destas três vertentes. Almeja-se, portanto, investigar o ethos retórico imputado por Agostinho aos seus adversários, cotejando os tratados polêmicos feitos pelo bispo de Hipona contra donatista, arianos e pelagianos. / There were continuous efforts in the 4th and 5th centuries aiming to unify and homogeneity of the Christian faith, causing clashes between different doctrines each one claiming to be the true Christians and calling the adversaries as false Christians. The Christian rhetorical ethos is constituted by the fundament that there is only one Truth: to be Christian is, by definition, undertaking the imitatio Christi. Then it would be possible to distinguish the one who preached for Christ and the one so -called heretical. Among those intense rhetorical disputes, Augustine of Hippo was one the most prominent authors, contributing to the greatest discussions from his time. Donatism, Arianism, and Pelagianism were his main enemies. Each one of them representing a different challenge, Augustine needed to answer and defy those three branches in defence of his own belief as the Christian redemption. The Donatism was seen as a development from the persecutions made by Emperor Diocletian, causing a political and doctrinal breaking causing the Christian Roman African Church division. The Arianism, a Trinitarian schism and without any doubt protagonist of the 4th century doctrinal debate, defending a hierarchy among the people of the Trinity, challenging its own concept. Pelagianism, a recurrent Augustines preoccupation in his last twenty years of life, denied the idea of original sin and defied the role of divine grace in the redemption. Based on the starting point the was actually in dispute was which one of these three branches were the true bearer of Christ legacy, this research aims to compare the construction process of the rhetoric ethos from those tree branches. In order to do that, this thesis investigates the rhetoric ethos ascribed for Augustine of Hippo to his adversaries, focusing on the polemic tracts made by Augustine of Hippo against the Donatists, Arians, and, Pelagians.

Esta dissertação compreende a tradução, descrição, análise e anotação crítica das cartas que compõem a correspondência, produzida de ca. 394/395 a 419, entre Aurélio Agostinho (Tagaste, atual Souk Ahras, 354 - Hipona, atual Annaba, 430/431), presbítero e posteriormente bispo em Hipona, e Eusébio Jerônimo (Estridão, atual Liubliana, 331 - Belém, 419/420), monge então residente em Belém. Esta dissertação também compreende um estudo introdutório dessa correspondência, dividido em duas partes: uma interpretação de elementos nas cartas à luz do gênero epistolar helenístico, sua teoria e prática, conforme estas foram descritas tanto por outros escritores gregos e latinos, antigos e cristãos, quanto por críticos modernos; em seguida, uma contextualização histórica do texto, por sua vez fundamentada nos estudos da correspondência e na historiografia moderna, com enfoque na biografia de nossos autores, os quais viveram em uma época marcada por questões caras ao desenvolvimento da patrística latina como a discussão acerca da interpretação e tradução das Sagradas Escrituras, o combate às heresias, e, mais importante, o papel político e social da Igreja Católica na busca por uma doutrina cristã unívoca e ortodoxa durante a Antiguidade Tardia. / This dissertation comprehends the translation, analysis, and critical annotation of the letters that compose the correspondence of Aurelius Augustine (Thagast, modern day Souk Ahras, 354 - Hippo Regius, modern day Annaba, 430/431), presbyter and then bishop of Hippo, with Eusebius Jerome (Stridon, modern day Ljubliana, 331 - Bethlehem, 419/420), a monk then living in Bethlehem, and which were changed between the years of ca. 394/395 and 419. This dissertation also comprehends an introductory study, in two parts, of the correspondence: first, an interpretation of elements from it in light of the Hellenistic epistolary genre, according to its theory and practice, as described both by Greek and Roman, ancient and christian writers, and by contemporary scholars; afterwards, a historical analysis of the text, supported by studies of the correspondence and modern historiographic scholarship, with emphasis on biographies of our authors, who lived in an age marked by important causes to the development of Latin Patristics, such as the correct interpretation and translation of the Holy Scripture, the battle against heresies, and most importantly the political and social role played by the Church, in the search for a unified, catholic and orthodox christian doctrine during Late Antiquity.

Esta dissertação compreende a tradução, descrição, análise e anotação crítica das cartas que compõem a correspondência, produzida de ca. 394/395 a 419, entre Aurélio Agostinho (Tagaste, atual Souk Ahras, 354 - Hipona, atual Annaba, 430/431), presbítero e posteriormente bispo em Hipona, e Eusébio Jerônimo (Estridão, atual Liubliana, 331 - Belém, 419/420), monge então residente em Belém. Esta dissertação também compreende um estudo introdutório dessa correspondência, dividido em duas partes: uma interpretação de elementos nas cartas à luz do gênero epistolar helenístico, sua teoria e prática, conforme estas foram descritas tanto por outros escritores gregos e latinos, antigos e cristãos, quanto por críticos modernos; em seguida, uma contextualização histórica do texto, por sua vez fundamentada nos estudos da correspondência e na historiografia moderna, com enfoque na biografia de nossos autores, os quais viveram em uma época marcada por questões caras ao desenvolvimento da patrística latina como a discussão acerca da interpretação e tradução das Sagradas Escrituras, o combate às heresias, e, mais importante, o papel político e social da Igreja Católica na busca por uma doutrina cristã unívoca e ortodoxa durante a Antiguidade Tardia. / This dissertation comprehends the translation, analysis, and critical annotation of the letters that compose the correspondence of Aurelius Augustine (Thagast, modern day Souk Ahras, 354 - Hippo Regius, modern day Annaba, 430/431), presbyter and then bishop of Hippo, with Eusebius Jerome (Stridon, modern day Ljubliana, 331 - Bethlehem, 419/420), a monk then living in Bethlehem, and which were changed between the years of ca. 394/395 and 419. This dissertation also comprehends an introductory study, in two parts, of the correspondence: first, an interpretation of elements from it in light of the Hellenistic epistolary genre, according to its theory and practice, as described both by Greek and Roman, ancient and christian writers, and by contemporary scholars; afterwards, a historical analysis of the text, supported by studies of the correspondence and modern historiographic scholarship, with emphasis on biographies of our authors, who lived in an age marked by important causes to the development of Latin Patristics, such as the correct interpretation and translation of the Holy Scripture, the battle against heresies, and most importantly the political and social role played by the Church, in the search for a unified, catholic and orthodox christian doctrine during Late Antiquity.

Comment la taille d'un organisme est-elle régulée au cours du développement embryonnaire ? Quels sont les mécanismes génétiques à l'origine de l'arrêt de la prolifération pendant la croissance d'un organisme pluricellulaire ? Afin d'identifier des acteurs de la sortie du cycle cellulaire au cours du développement, mon travail s'est orienté sur l'étude de gènes suppresseurs de tumeurs pendant la croissance du toit optique (TO) du médaka Oryzias latipes. Le TO, structure dorsale du cerveau moyen des Vertébrés, est un modèle particulièrement adapté à l'étude de la régulation de la prolifération. Trois zones de la marge vers le centre du TO sont discernables : une zone périphérique de prolifération, une zone intermédiaire de cellules sortant du cycle cellulaire et une zone centrale de cellules différenciées. Un crible d'expression par hybridation In Situ a été réalisé et a permis d'identifier 28 gènes exprimés dans le TO, suggérant leur implication dans le contrôle de la sortie du cycle cellulaire au cours du développement. Dans le but de caractériser in vivo la fonction de gènes issus de ce crible, le gène BTG1 (B-cell Translocation Gene 1) et les membres de sa famille, ont été étudiés au cours du développement du médaka. J'ai mené des expériences fonctionnelles sur BTG1, permettant de mettre en évidence son rôle central pour la morphogenèse du système nerveux central. De plus, une autre partie de mon travail s'est penchée sur l'étude de l'expression des membres de la voie de signalisation Hippo, bien connue et caractérisée chez la drosophile et les Mammifères pour son rôle dans le contrôle de la taille des organes via une régulation de l'arrêt de la prolifération. A l'issu de notre travail, une fonction de la voie de signalisation Hippo dans la formation du TO et des somites a pu être mise en évidence au cours du développement du médaka.

No description available.

This thesis examines a primary question raised by both Aristotle and Thomas Aquinas: What constitutes the beginning of a human being? Aristotle and Aquinas raise this question for very different reasons. Modern critical commentators revisit it for their own reasons, namely for the purposes of ethical debates surrounding conception and abortion. They frequently attribute the notions of delayed ensoulment and quickening to Aristotle. Through examination of the primary texts, I demonstrate that this attribution is erroneous. Aristotle contends that ensoulment is substantially complete at conception, though subject to gradual actualization throughout the lifespan of a human being; while Thomas suggests that conception is a process, requiring several substantial changes before a human soul is infused. I argue that Aquinas adapts Aristotle in accordance with his Christian theological commitments, and modern commentators follow him to develop their own notions of delayed ensoulment and quickening.