Le présent mémoire étudie le commandement nouveau (Jn 13,34-35) en le situant dans le contexte du premier discours d'adieu (Jn 13,33-14,31). L'analyse structurelle montre que ce discours est composé d'une introduction (13,33-38) comportant deux thèmes: le retour de Jésus vers son Père et l'amour. Ces deux thèmes sont ensuite développés dans un corps central (14,1-24), lui-même subdivisé en deux sous-unités qui traitent l'une du retour (14,1-14) et l'autre de l'amour (14,15-24). Une conclusion (14,25-31) reprend ces deux thèmes. Ce contexte permet de préciser le sens du commandement nouveau en l'inscrivant dans une mission bien particulière: les disciples poursuivent la mission de Jésus pour rendre présente au monde la communauté eschatologique, communauté fondée sur la communauté de vie qui unit le Père, le Fils et les disciples.

L’objectif du présent mémoire est double. D’une part, il cherche à identifier les facteurs qui permettent au gouvernement canadien et aux peuples autochtones de s’entendre sur des politiques publiques, malgré la persistance d’une logique coloniale. Nous verrons que l’atteinte d’une entente est conditionnelle à la légitimité du processus d’élaboration de la politique publique d’un point de vue autochtone. D’autre part, ce travail invite à penser le processus d’élaboration des politiques publiques comme espace potentiel d’autodétermination. Étant donné la malléabilité des règles qui encadrent l’élaboration des politiques publiques en contexte canadien, le gouvernement – s’il en a la volonté - peut modeler le processus d’élaboration de façon à le rendre plus égalitaire et donc plus légitime d’un point de vue autochtone. Il sera démontré que, dans une optique de changements progressifs, un tel processus d’élaboration peut permettre aux peuples autochtones de regagner une certaine autonomie décisionnelle et ainsi atténuer les rapports de pouvoir inégalitaires. Notre cadre théorique a été construit à l’aide de différents courants analytiques, issus notamment des littératures sur le colonialisme, sur les politiques publiques et sur la légitimité. La comparaison de deux études de cas, soit les processus d’élaboration de l’Accord de Kelowna et du projet de loi C-33, Loi sur le contrôle par les Premières Nations de leur système d’éducation, permettra d’illustrer nos arguments et d’en démontrer l’applicabilité pratique. En somme, nous verrons comment la première étude de cas permet de concevoir l’élaboration des politiques publiques comme espace potentiel d’autodétermination, et comment la deuxième, au contraire, démontre que cette sphère peut encore en être une d’oppression. / The purpose of this thesis is twofold. First, it seeks to identify factors that enable the federal government and Aboriginal peoples to agree on public policies despite the persistence of settler colonialism. It demonstrates that such an agreement is conditional upon the legitimacy, from an Aboriginal perspective, of the policy-making process. Second, this thesis uses a pragmatic approach to call for a reflection on the capacity for policy-making processes to become a space for Aboriginal self-determination. Given the flexibility of current rules that govern the policy-making process in Canada, a government – if it has the will - can shape the process in a more egalitarian fashion, thus increasing the process’s legitimacy from an Aboriginal viewpoint. In a perspective of incremental change, such policy-making process could help Aboriginal people regain some decisional autonomy and hence mitigate the unequal power relationship that actually exists between them and the Canadian state. Building on a theoretical framework that blends different approaches, notably from literatures on public policy, colonialism and legitimacy, this thesis explores two case studies : the policy-making process that led to the Kelowna Accord in 2005 and the one that led to Bill C-33, First Nations Control of First Nations Education Act, in 2014. The comparison of both cases illustrates our arguments and demonstrates its practical applicability. In brief, it shows how the policy-making process can be both a self-determination space and a tool of oppression.

La leishmaniose viscérale est une maladie systémique mortelle en l’absence de traitement. Elle est due aux protozoaires Leishmania donovani et L. infantum, parasites des phagocytes mononucléés, capables d’envahir les organes lymphoïdes et le foie. Le contrôle de l’infection hépatique repose sur la mise en place d’une réponse granulomateuse efficace, promue par une réponse immunitaire Th1, dans un environnement tissulaire Th2. L’objectif de ce travail était l'étude du rôle d’une cytokine Th2 récemment décrite, l’IL-33, dans cette réponse hépatique complexe encore partiellement incomprise. Des dosages d’IL-33 sur des sérums de patients et la détection de cellules IL-33+ dans le foie d’un patient rennais ont placé l’IL-33 comme un biomarqueur possible de la maladie active. L’IL-33 étant exprimée dans les cellules étoilées du foie au cours d’hépatites chroniques, ces cellules ont été exposées à L. donovani. Leur permissivité aux leishmanies sans toxicité apparente ni perturbation de leurs propriétés fonctionnelles, ainsi que la persistance des leishmanies sur une culture de plusieurs semaines, nous ont conduit à proposer les cellules étoilées comme cellules sanctuaires possibles pour les leishmanies viscérotropes, contribuant donc potentiellement au portage asymptomatique. En revanche, elles ne sont pas apparues comme une source majeure d'IL-33 au cours de la leishmaniose viscérale. Chez des souris C57BL/6 et BALB/c infectées par L. donovani, l'IL-33 a été observée dans des cellules ne s'apparentant pas à des cellules étoilées, et principalement localisées dans les granulomes. Des cellules exprimant son récepteur ST2 ayant été également observées dans le foie, un rôle de l’axe IL-33/ST2 a été recherché. Les résultats obtenus chez des souris BALB/c déficientes en ST2 ou traitées par de l'IL-33 recombinante suggèrent que l'IL-33 régule négativement l'expression de cytokines Th1 (IL-12, IFN-γ) et l'infiltrat de neutrophiles et monocytes dans le foie, limitant ainsi le contrôle de la charge parasitaire. Ainsi, l'IL-33 semble être un facteur de susceptibilité pour la leishmaniose viscérale. En parallèle, des travaux entrepris sur des souris C57BL/6 infectées par L. donovani suggèrent de possibles rôles différentiels de l'IL-33 en fonction de l'environnement immunitaire inhérent au fond génétique de l'hôte. / Visceral leishmaniasis is a life-threatening systemic disease caused by Leishmania protozoans, L. donovani and L. infantum, which invade mononuclear phagocytes in the lymphoid organs and the liver. The control of the hepatic parasite burden depends on the granuloma formation, which is favored by a Th1 immune response in a Th2 tissue microenvironment. The aim of this work was to study the role of the recently described Th2 cytokine IL-33 in this complex immune response, which remains partially misunderstood. IL-33 dosages in different patient sera and IL-33+ cells detected in the liver of a patient from Rennes suggested that IL-33 could be a biomarker for active visceral leishmaniasis. As IL-33 was described in hepatic stellate cells during chronic hepatitis, these cells were exposed to L. donovani in primary culture. The cell permissivity to L. donovani and the parasite persistence during a long term culture led us to propose hepatic stellate cells as a new type of sanctuary cells, which could partially explain asymptomatic carriage. However, these cells were apparently not the main source of IL-33 during visceral leishmaniasis. In infected BALB/c and C57BL/6 mice, IL-33 was detected in the liver in non stellate cells preferentially localized in granulomas. The presence of cells expressing its specific receptor ST2 in the liver led us to explore the role of the IL-33/ST2 axis. BALB/c mice deficient in ST2 or treated with recombinant IL-33 and infected with L. donovani revealed that IL-33 downregulates the expression of Th1 key cytokines (IL-12, IFN-γ) and the recruitment of neutrophils and monocytes. Finally, IL-33 acts as a susceptibility factor during visceral leishmaniasis. Besides, the model of L. donovani infected C57BL/6 mice deficient in IL-33 or treated with recombinant IL-33 suggests possible differential roles of IL-33 depending on the immune environment related to the host genetic background.

A síntese de peptídeos em fase sólida passo a passo (SPFS) tem sido aplicada com sucesso na preparação de peptídeos curtos, médios e de determinados sequências contendo mais de 30 resíduos. Entretanto, esta apresenta problemas e limitações que podem ser contornados pela síntese convergente de peptídeos em fase sólida (SCPFS) que se baseia na condensação entre fragmentos peptídicos Nα-acilados protegidos em suas cadeias laterais (doadores de acila) a fragmentos protegidos ligados a um suporte polimérico (receptores de acila). Além de desenvolver outros projetos enfocados na síntese de peptídeos ou no uso de sintéticos para o estudo de peptídeos biologicamente ativos ou proteinas, o nosso grupo de pesquisa tem se dedicado a estudar o emprego de temperaturas altas em SPFS. O objetivo final é propor protocolos ágeis alternativos aos empregados classicamente. Neste trabalho nos propusemos a investigar alguns aspectos da SCPFS e a explorar a possibilidade de agilizá-Ia a 60°C. Para tanto, empregamos como modelos a colecistocinina-33 humana (hCCK-33) não sulfatada e o análogo [Gln1]-gomesina. As seqüências destes peptídeos foram divididas em: doadores de acila (fragmentos central e N-terminal da hCCK-33 não sulfatada de 11 e de 5 resíduos, respectivamente, e N-terminal de 8 resíduos do [Gln1]-gomesina) e receptores de acila (fragmentos C-terminais da hCCK-33 não sulfatada de 17 resíduos e do [Gln1]-gomesina de 10 resíduos). As peptidil-resinas correspondentes foram sintetizadas manualmente por SPFS passo a passo e caracterizadas por análise de aminoácidos para determinação de seus graus de substituição. Suas propriedades de solvatação em diferentes sistemas de solventes foram também examinadas. Análises por RP-HPLC e LC/ESI-MS dos peptídeos brutos obtidos após clivagem das resinas e desproteção total permitiram avaliar as sínteses realizadas. Os doadores de acila foram então gerados a partir das peptidil-resinas empregando procedimentos conhecidos (catálise por DBU ou NaOH) e um proposto por nós (assistência por íons metálicos). Finalmente, os acoplamentos entre os doadores e receptores de acila foram realizados a 37 e 60°C empregando sistemas de solventes adequados à solvatação dos receptores de acila e diferentes reagentes acopladores. As peptidil-resinas alongadas foram analisadas em seu conteúdo de aminoácidos e submetidas à clivagem e desproteção total para liberação dos peptídeos brutos correspondentes. Estes foram submetidos à análise comparativa usando RP-HPLC e LC/ESI-MS. Os resultados obtidos neste primeiro trabalho que emprega alta temperatura na SCPFS demonstraram que: 1) o conhecimento do grau de solvatação das peptidil-resinas auxilia na escolha do sistema de solventes a ser empregado na geração dos doadores de acila (desligamento dos peptídeos protegidos correspondentes) e nos seus acoplamentos aos receptores de acila; 2) a geração de doadores de acila a partir de peptidil-KOR não é trivial como sugere a literatura (o fragmerto 6-19 da hCCK-33 na forma protegida não foi obtido) e deve ser melhor estudada. O tamanho e a seqüência peptídica parecem estar diretamente relacionados à eficiência do processo; 3) o uso de alta temperatura agiliza o processo; 4) a geração de doadores de acila a partir de peptidil-2-CI-Trt empregando 1%TFA em DCM e misturas AcOH:TFE:DCM é simples e eficiente; 5) o uso combinado de DMF, do agente acoplador TBTU e de 60°C levou à agilização dos acoplamentos convergentes realizados, fornecendo os peptídeos desejados com boa qualidade em tempos relativamente menores; 6) vantagens e desvantagens da SCPFS em alta temperatura devem ser melhor avaliadas; 7) a SCPFS também apresenta limitações e problemas a serem contornados, o que demanda exploração sistemática empregando seqüências peptídicas e resinas variadas. / Stepwise solid-phase peptide synthesis (SSPPS) has been applied successfully for the preparation of most peptides containing up to 30 residues. However, it presents problems and limitations. Convergent soIid-phase peptide synthesis (CSPPS) can overcome part of them. This methodology is based on the synthesis of peptide segments by SSPPS followed by their condensations: the Nα- acylated protected segments act as acyl donors and the protected segments bound to the resin as acyl receptors. When the sequence is completed this is detached from the resin and fully deprotected to give the crude peptide. Besides developing other projectsfocused on peptide synthesis itself or on the use of synthetics to study biologically active peptides or proteins, we have systematically examined solid-phase peptide synthesis at elevated temperature. The aim of the present work was to investigate different aspects of convergent solid-phase peptide synthesis and examine the possibility to improve it at 60°C. Thus, unsulfated human cholecystokinin-33 and [Gln1]-gomesin were divided in three and two fragments, respectively. In the first case, the acyl donors were built-up by SSPPS on Kaiser oxime resin while in the second peptide elongation was done on 2-CI-Trt resin. The acyl receptor was synthesized and kept on the MBHA resin. The synthetic process was evaluated through characterization of every peptidyl-resin by amino acid analysis and of each crude peptide obtained from resin cleavage/full deprotection by RP-HPLC and LC/ESI-MS. The swelling degrees of the peptidyl-resins were determined in various solvents or mixtures of high boiling points. The peptidyl-KOR and peptidyl-2-CI-Trt were then submitted to peptide detachment under a few experimental conditions in order to release the Nα-acyl protected peptides (the acyl donors). Finally, their couplings with the acyl receptors were carried-out at 37 and 60°C in solvents or mixtures suitable for peptidyl-resin solvation containing specific coupling agents. The resulting peptidyl-resins were isolated, dried and submitted to HF treatment to release the corresponding unprotected crude peptides, which were analysed by RP-HPLC and LC/ESI-MS. The results found indicated that: 1) the knowledge of the swelling properties of the peptidyl-resins in different solvents systems is very useful in SCPFS. Indeed, it may guide the selection of experimental conditions to be used in peptide detachment from KOR and 2-CI-Trt and in segment condensation at elevated temperature, 2) peptide detachment from KOR is not as trivial as described (it was impossible to release hCCK-33 fragment 6-19 in its protected form). Further studies are certainly required to improve it. It seems that the size and the sequence are strictly related to the process efficiency, 3) high temperature can improve it, 4) peptide detachment from 2-CI-Trt is as simple as described, 5) combination of DMF as solvent, TBTU as coupling agent and 60°C was suited for the segment couplings studied: the reactions were completed in relatively short times and crude peptides of good quality were obtained, 6) this is the first attempt to carry-out CSPFS at elevated temperature, thus its advantages and disadvantages must be studied, 7) CSPPS also presents problems and limitations to overcome. Such task requires further investigation using various resins and peptide sequences.

[pt] Os bezerros de Arão e Jeroboão: Uma verificação da relação intertextual entre Ex 32,1-6 e 1 Rs 12,26-33 tem por objetivo tanto verificar a existência das várias relações intertextuais entre as passagens de Ex 32,1-6 e 1 Rs 12,26-33 quanto apresentar e demonstrar como se manifesta essa intertextualidade. Esta tese faz uso do método sincrônico da análise narrativa. A necessidade de trabalhar com o método sincrônico da análise narrativa existe porque a verificação, a apresentação e a demonstração das relações intertextuais precisam considerar o texto na sua forma final. Este trabalho visar contribuir para o estudo das relações intertextuais aplicadas aos textos bíblicos tanto propondo uma clara conceituação de intertextualidade quanto apresentando os critérios de classificação de suas manifestações, bem como deseja verificar que existem relações intertextuais específicas entre Ex 32,1-6 e 1 Rs 12,26-33 e ampliar o horizonte dessas relações intertextuais a todos os versos dos textos de Ex 32,1-6 e 1 Rs 12,26-33. / [en] Aaron s and Jeroboam s Calves: An Intertextuality Verification Analyzing Exodus 32,1-6 and I Kings 12,26-33 has the purpose not only to verify the existence of a broad intertextuality relations between Exodus 32,1-6 and I Kings 12,26-33 but also to present and demonstrate how this intertextuality relation occurs. This thesis is based using the synchronic method of narrative analysis. The reason to use narrative analysis is because the verification in how the text is presented and demonstrated has to consider the text itself in its final form. This work is focused to shad light in the study of intertextuality relations to or deriving meaning applied to the biblical texts not only proposing a clear concept and thesis but also to present the criteria of classification and manifestation as well. Verifying that there are interrelationships in both texts between Exodus 32,1-6 and I Kings 12,26-33 and to broaden the perspective in these intertextuality to every single verses in Exodus 32,1-6 and I Kings 12,26-33. / [it] I vitelli di Aronne e Geroboamo: Una verifica del rapporto intertestuale tra Es 32, 1-6 e 1 Re 12,26-33 ha come oggetto tanto verificare l esistenza dei vari rapporti intertestuali tra i passaggi di Es 32,1-6 e 1 Re 12,26-33 quanto presentare e dimostrare come si manisfesta questa intertestualità. Questa tesi usa il metodo sincronico dell analise narrativa. La necessità di lavorare con il metodo sincronico dell analise esiste perché la verifica, la presentazione e la dimostrazione dei rapporti intertestuali hanno bisogno di considerare il testo nella sua forma finale. Questo lavoro si rivolge a contribuire con lo studio dei rapporti intertestuali applicati ai testi biblichi tanto al proporre un chiaro concetto di intertestualità quanto al presentare i criteri di classificazione delle sue manifestazioni cosí come desidera verificare che ci sono rapporti intertestuali specifichi tra Es 32, 1-6 e Re 12,26-33 e ampliare l orizzonte di questi rapporti intertestuali a tutti i versi dei testi di Es 32,1-6 e 1 Re 12,26-33.

Made available in DSpace on 2016-04-26T20:23:14Z (GMT). No. of bitstreams: 1 Paula Eschholz Ribeiro Brofman.pdf: 1151614 bytes, checksum: a186fd296cea5e452de8a361dae95cb5 (MD5) Previous issue date: 2014-09-16 / Constitutional Amendment No. 33, dated December 12, 2001 changed the wording of art. 155, § 2, section IX, paragraph a, of the Brazilian Federal Constitution of 1988. Unsurprisingly the commitment of the states and the Federal District for all tax and any entry of goods and commodities in the country. They lacked, however, a constitutional approval for this. It was then that the Constitutional Amendment 33 modified the constitutional archetype of ICMS in order to make it focus on any entry of goods or merchandise in the country. These changes resulted in heated debates on the doctrine of the Tax Law, which saw the creation of a new tax, in the guise of ICMS, enter the legal world through an Amendment to the Constitution. Is that musty derived constituent power is not fully free to modify the constitution to their own pleasure, there are parameters set by the original power that must be respected, otherwise it would incur unconstitutional. Thus, this paper intends to perform a syntactic, semantic and pragmatic analysis of the exaction in order to demonstrate the main changes brought about by Constitutional Amendment No. 33, 2001, marginalized original guidelines and the consequent alterations to the unconstitutionality of the import-ICMS / A Emenda Constitucional nº 33, de 12 de dezembro de 2001 alterou a redação do art. 155, § 2º, inciso IX, alínea a, da Constituição Federal de 1988. Não é novidade o empenho dos Estados e Distrito Federal em tributar toda e qualquer entrada de bens e mercadorias no país. Faltava-lhes, no entanto, uma aprovação constitucional para isso. Foi então, que a Emenda Constitucional nº 33 modificou o arquétipo constitucional do ICMS, a fim de fazê-lo incidir sobre toda e qualquer entrada de bens ou mercadorias em território nacional. Tais mudanças trouxeram calorosos debates na doutrina do Direito Tributário, que viu a criação de um novo imposto, sob as vestes do ICMS, ingressar no universo jurídico por meio de Emenda à Constituição. É cediço que o poder constituinte derivado não é totalmente livre para modificar o texto constitucional ao seu bel-prazer, há parâmetros estabelecidos pelo poder originário que devem ser respeitados, sob pena de se incorrer em inconstitucionalidade. Diante disto, este trabalho pretende realizar uma análise sintática, semântica e pragmática da exação, a fim de demonstrar as principais mudanças trazidas pela Emenda Constitucional nº 33, de 2001, as diretrizes originais marginalizadas e a consequência dessas alterações no ICMS-Importação

Made available in DSpace on 2016-04-26T20:23:44Z (GMT). No. of bitstreams: 1 Louise Vilela Leite Filgueiras Borer.pdf: 1049760 bytes, checksum: 38a748ff575e19aac52d4a1fc64921db (MD5) Previous issue date: 2015-08-07 / The present work focuses the interpretation of the penalty reduction cause of the 4th paragraph of the 33th article of the 11.343/06 law, starting from the identification of the exegetical problems contained in its text, reaching to the solution that preserves its concrete application without harming constitutional principles, what´s done throughout the technique of the constitutional conforming interpretation. Basing this conclusion, the analysis begin with the actual modern context of the criminal thought in doctrine, the risks society and it´s influences, that enforce the need of promoting the guarantist constitutionalism proposed by Luigi Ferrajoli, in order to preserve the fundamental rights and of individuals and meet the constitution in all its terms . In this context, we make a criticism of the anti-guarantist practice of basing the penalty dosimetry on judicial discretion, that has been used to enable the application of the rule under consideration / O presente trabalho enfoca a interpretação da causa de diminuição de pena do parágrafo 4º do artigo 33 da Lei nº11.343/06, partindo da identificação dos problemas exegéticos que o texto da lei contém até chegar à solução que preserva a concreta aplicação da norma sem ferir princípios constitucionais, o que é feito através da técnica da interpretação conforme a constituição. Fundamentando essa conclusão, a análise se inicia com o contexto atual do pensamento criminal na doutrina, a sociedade de risco e suas influências, que fomentam a necessidade de se promover o constitucionalismo garantista proposto por Luigi Ferrajoli, de modo a preservar direitos fundamentais e cumprir a Constituição em todos os seus termos. Nesse contexto, fazemos uma crítica à prática antigarantista de basear a dosimetria da pena na discricionariedade judicial, que tem sido utilizada para viabilizar a aplicação da norma em consideração

Le syndrome d'ischémie-reperfusion (IR), inhérent à la transplantation rénale, est caractérisé par un infiltrat leucocytaire important et des lésions tissulaires graves dont les signaux initiateurs restent à ce jour peu décrits. Postulant que la libération d'alarmines par les cellules en nécrose est décisive dans ce processus, l'objectif principal du présent travail a été d'étudier la contribution de l'alarmine IL-33 dans la genèse des lésions tissulaires dans un modèle murin d'IR rénale. Nos résultats montrent que l'IL-33 est rapidement libérée du rein après IR comme protéine circulante, dès une heure de reperfusion. Les souris IL-33gt/gt, déficientes en IL-33, sont moins sensibles aux lésions induites par l’IR, comme l'attestent le maintien de la fonction rénale et des lésions histologiques atténuées avec un recrutement de polynucléaires neutrophiles (PNN) diminué par rapport aux souris contrôles. Ceci est associé à la perte du recrutement de cellules iNKT productrices d'IFN-γ/IL-17A. Parallèlement, les souris Jα18KO, déficientes en cellules iNKT et protégées contre les lésions d'IR, possèdent également des niveaux élevés d'IL-33 circulante. Nous proposons donc que l'IL-33 endogène contribue aux lésions d'IR en favorisant le recrutement de cellules iNKT, conduisant ainsi à un recrutement amplifié de PNN au niveau du rein lésé. Notre étude, en identifiant l'alarmine IL-33 comme un médiateur précoce de la réponse immunitaire innée induite par l'IR rénale, mettant en jeu les cellules iNKT, contribue à la compréhension des mécanismes impliqués dans la genèse des lésions associées à la greffe rénale et permet de proposer de nouvelles stratégies thérapeutiques. / Ischemia-reperfusion (IR) injury in renal transplantation is characterized by leukocyte infiltration and tissue damage. However, the signals that initiate these events remain poorly understood. Assuming that alarmin release by necrotic cells during IRI is critical, the main objective of the present study was to investigate the role of alarmin IL-33 in kidney injury using a mouse model of renal IR. We observed release of IL-33 shortly after kidney IR concomitantly with an increase in plasma levels of IL-33 within one hour of reperfusion. IL-33 deficient mice (IL-33gt/gt) exhibited reduced renal IR-induced injury, as attested by function preservation, reduced histological change and attenuation of neutrophil recruitment compared to control mice. This was associated with the loss of IFN-γ/IL-17A-producing iNKT cell recruitment. In the meantime, iNKT cell-deficient (Jα18KO) mice, also protected against IRI, have increased levels of circulating IL-33.These findings lead us to propose that endogenous IL-33 contributes to kidney IRI by promoting iNKT cell recruitment and cytokine production, thereby promoting amplified neutrophil recruitment to the injured kidney. The present study identifies the nuclear alarmin interleukin (IL)-33 as an important and early mediator of innate immune response, involving iNKT cells, following experimental kidney ischemia-reperfusion in mice. Our findings contribute to a better understanding of IR-induced injury and may lead to new therapeutic insights into renal-induced injury associated with renal transplantation.

A síntese de peptídeos em fase sólida passo a passo (SPFS) tem sido aplicada com sucesso na preparação de peptídeos curtos, médios e de determinados sequências contendo mais de 30 resíduos. Entretanto, esta apresenta problemas e limitações que podem ser contornados pela síntese convergente de peptídeos em fase sólida (SCPFS) que se baseia na condensação entre fragmentos peptídicos Nα-acilados protegidos em suas cadeias laterais (doadores de acila) a fragmentos protegidos ligados a um suporte polimérico (receptores de acila). Além de desenvolver outros projetos enfocados na síntese de peptídeos ou no uso de sintéticos para o estudo de peptídeos biologicamente ativos ou proteinas, o nosso grupo de pesquisa tem se dedicado a estudar o emprego de temperaturas altas em SPFS. O objetivo final é propor protocolos ágeis alternativos aos empregados classicamente. Neste trabalho nos propusemos a investigar alguns aspectos da SCPFS e a explorar a possibilidade de agilizá-Ia a 60°C. Para tanto, empregamos como modelos a colecistocinina-33 humana (hCCK-33) não sulfatada e o análogo [Gln1]-gomesina. As seqüências destes peptídeos foram divididas em: doadores de acila (fragmentos central e N-terminal da hCCK-33 não sulfatada de 11 e de 5 resíduos, respectivamente, e N-terminal de 8 resíduos do [Gln1]-gomesina) e receptores de acila (fragmentos C-terminais da hCCK-33 não sulfatada de 17 resíduos e do [Gln1]-gomesina de 10 resíduos). As peptidil-resinas correspondentes foram sintetizadas manualmente por SPFS passo a passo e caracterizadas por análise de aminoácidos para determinação de seus graus de substituição. Suas propriedades de solvatação em diferentes sistemas de solventes foram também examinadas. Análises por RP-HPLC e LC/ESI-MS dos peptídeos brutos obtidos após clivagem das resinas e desproteção total permitiram avaliar as sínteses realizadas. Os doadores de acila foram então gerados a partir das peptidil-resinas empregando procedimentos conhecidos (catálise por DBU ou NaOH) e um proposto por nós (assistência por íons metálicos). Finalmente, os acoplamentos entre os doadores e receptores de acila foram realizados a 37 e 60°C empregando sistemas de solventes adequados à solvatação dos receptores de acila e diferentes reagentes acopladores. As peptidil-resinas alongadas foram analisadas em seu conteúdo de aminoácidos e submetidas à clivagem e desproteção total para liberação dos peptídeos brutos correspondentes. Estes foram submetidos à análise comparativa usando RP-HPLC e LC/ESI-MS. Os resultados obtidos neste primeiro trabalho que emprega alta temperatura na SCPFS demonstraram que: 1) o conhecimento do grau de solvatação das peptidil-resinas auxilia na escolha do sistema de solventes a ser empregado na geração dos doadores de acila (desligamento dos peptídeos protegidos correspondentes) e nos seus acoplamentos aos receptores de acila; 2) a geração de doadores de acila a partir de peptidil-KOR não é trivial como sugere a literatura (o fragmerto 6-19 da hCCK-33 na forma protegida não foi obtido) e deve ser melhor estudada. O tamanho e a seqüência peptídica parecem estar diretamente relacionados à eficiência do processo; 3) o uso de alta temperatura agiliza o processo; 4) a geração de doadores de acila a partir de peptidil-2-CI-Trt empregando 1%TFA em DCM e misturas AcOH:TFE:DCM é simples e eficiente; 5) o uso combinado de DMF, do agente acoplador TBTU e de 60°C levou à agilização dos acoplamentos convergentes realizados, fornecendo os peptídeos desejados com boa qualidade em tempos relativamente menores; 6) vantagens e desvantagens da SCPFS em alta temperatura devem ser melhor avaliadas; 7) a SCPFS também apresenta limitações e problemas a serem contornados, o que demanda exploração sistemática empregando seqüências peptídicas e resinas variadas. / Stepwise solid-phase peptide synthesis (SSPPS) has been applied successfully for the preparation of most peptides containing up to 30 residues. However, it presents problems and limitations. Convergent soIid-phase peptide synthesis (CSPPS) can overcome part of them. This methodology is based on the synthesis of peptide segments by SSPPS followed by their condensations: the Nα- acylated protected segments act as acyl donors and the protected segments bound to the resin as acyl receptors. When the sequence is completed this is detached from the resin and fully deprotected to give the crude peptide. Besides developing other projectsfocused on peptide synthesis itself or on the use of synthetics to study biologically active peptides or proteins, we have systematically examined solid-phase peptide synthesis at elevated temperature. The aim of the present work was to investigate different aspects of convergent solid-phase peptide synthesis and examine the possibility to improve it at 60°C. Thus, unsulfated human cholecystokinin-33 and [Gln1]-gomesin were divided in three and two fragments, respectively. In the first case, the acyl donors were built-up by SSPPS on Kaiser oxime resin while in the second peptide elongation was done on 2-CI-Trt resin. The acyl receptor was synthesized and kept on the MBHA resin. The synthetic process was evaluated through characterization of every peptidyl-resin by amino acid analysis and of each crude peptide obtained from resin cleavage/full deprotection by RP-HPLC and LC/ESI-MS. The swelling degrees of the peptidyl-resins were determined in various solvents or mixtures of high boiling points. The peptidyl-KOR and peptidyl-2-CI-Trt were then submitted to peptide detachment under a few experimental conditions in order to release the Nα-acyl protected peptides (the acyl donors). Finally, their couplings with the acyl receptors were carried-out at 37 and 60°C in solvents or mixtures suitable for peptidyl-resin solvation containing specific coupling agents. The resulting peptidyl-resins were isolated, dried and submitted to HF treatment to release the corresponding unprotected crude peptides, which were analysed by RP-HPLC and LC/ESI-MS. The results found indicated that: 1) the knowledge of the swelling properties of the peptidyl-resins in different solvents systems is very useful in SCPFS. Indeed, it may guide the selection of experimental conditions to be used in peptide detachment from KOR and 2-CI-Trt and in segment condensation at elevated temperature, 2) peptide detachment from KOR is not as trivial as described (it was impossible to release hCCK-33 fragment 6-19 in its protected form). Further studies are certainly required to improve it. It seems that the size and the sequence are strictly related to the process efficiency, 3) high temperature can improve it, 4) peptide detachment from 2-CI-Trt is as simple as described, 5) combination of DMF as solvent, TBTU as coupling agent and 60°C was suited for the segment couplings studied: the reactions were completed in relatively short times and crude peptides of good quality were obtained, 6) this is the first attempt to carry-out CSPFS at elevated temperature, thus its advantages and disadvantages must be studied, 7) CSPPS also presents problems and limitations to overcome. Such task requires further investigation using various resins and peptide sequences.

Cette thèse s’inscrit dans le débat actuel relatif au monothéisme biblique et au pluralisme religieux. Ces dernières décennies, ce débat a été influencé par des auteurs comme Jan Assmann pour lequel le monothéisme vétérotestamentaire constitue une racine importante de l’intolérance dont les trois religions monothéistes se seraient rendues coupables. Le but de notre thèse n’est pas d’entrer dans ce débat mais d’approfondir un sujet négligé par la recherche : qu’en est-il des tendances inclusives du monothéisme vétérotestamentaire ? Cette thèse ne se veut pas une contribution historique mais son but est d’étudier les principes théologiques permettant de concevoir des rapports positifs entre le Dieu d’Israël et des individus ou des peuples étrangers. En particulier, nous cherchons à analyser trois textes, le Livre de Jonas, le Psaume 33 (TM et LXX) et le roman Joseph et Aséneth. Bien qu’il s’agisse de trois textes différents en ce qui concerne le genre littéraire, l’origine et la datation, ils ont en commun d’aborder le problème du rapport entre le Dieu d’Israël et les non-Israélites. Plus concrètement, chacun de ces trois textes présente le Dieu d’Israël comme un créateur universel qui, en tant créateur, a pitié de toutes ses créatures. / The starting point of this study is the current debate on monotheism and religious pluralism. In recent decades, this debate has been strongly influenced by some authors such as Jan Assmann for whom the monotheism originating in the Old Testament is the root of the intolerance and violence of the three monotheistic religions. Rather than participating at this debate, the intention of this study is to answer the following questions: what about inclusive tendencies in Old Testament monotheism? Thus, this thesis is aimed at looking into the theological principles motivating and supporting the possibility of an approach by individuals and peoples to the God of Israel. With this aim, our objective is to analyse three texts where the relationship between YHWH, Israel and the non-Israelites is examined: the book of Jonah, Psalm 33 (MT and LXX), and the novel, Joseph and Aseneth. Although these three texts are different concerning their genre, period and provenance, they have the following ideas in common: the relationship between the God of Israel and non-Israelites as well as the concept of God as an universal creator who has pity of all his creatures.