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Submitted by Jhosep Victorino Beltrán Ramirez (jhosep@ift.unesp.br) on 2018-04-30T23:53:58Z No. of bitstreams: 1 Thesis final version.pdf: 1232865 bytes, checksum: 9c45a7f2b11fb5626fc2289be640684d (MD5) / Rejected by Hellen Sayuri Sato null (hellen@ift.unesp.br), reason: Solicitamos que realize correções na submissão seguindo as orientações abaixo - Incluir Resumo no PDF Agradecemos a compreensão on 2018-05-02T17:34:18Z (GMT) / Submitted by Jhosep Victorino Beltrán Ramirez (jhosep@ift.unesp.br) on 2018-05-03T02:49:03Z No. of bitstreams: 1 TesisDKP.pdf: 952544 bytes, checksum: 7ba12d74da05e9e6a1834ff32937078d (MD5) / Rejected by Hellen Sayuri Sato null (hellen@ift.unesp.br), reason: Solicitamos que realize correções na submissão seguindo as orientações abaixo: - incluir palavras-chave no PDF após o resumo - incluir Key words no PDF após o abstract Agradecemos a compreensão on 2018-05-03T17:25:11Z (GMT) / Submitted by Jhosep Victorino Beltrán Ramirez (jhosep@ift.unesp.br) on 2018-05-04T01:04:35Z No. of bitstreams: 1 TesisDKP.pdf: 952865 bytes, checksum: 283f93ab15503686eccf06947a681380 (MD5) / Approved for entry into archive by Hellen Sayuri Sato null (hellen@ift.unesp.br) on 2018-05-04T18:33:41Z (GMT) No. of bitstreams: 1 beltranramirez_jv_dr_ift.pdf: 952865 bytes, checksum: 283f93ab15503686eccf06947a681380 (MD5) / Made available in DSpace on 2018-05-04T18:33:41Z (GMT). No. of bitstreams: 1 beltranramirez_jv_dr_ift.pdf: 952865 bytes, checksum: 283f93ab15503686eccf06947a681380 (MD5) Previous issue date: 2018-03-02 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Nesta tese utilizamos a teoria de perturbação causal para estudar a eletrodinâmica quântica escalar com os campos de Duffin-Kemmer-Petiau. Determinamos as seções de choque diferenciais no nível da árvore, o tensor de polarização do vácuo, a função de auto energia e a renormalizabilidade da teoria. Depois disso, comparamos nossos resultados com os obtidos através dos campos de Klein-Gordon-Fock, determinando que eles não são completamente equivalentes / In this Thesis we use causal perturbation theory to study scalar quantum electrodynamics with Du n-Kemmer-Petiau elds. We determine the differential cross sections at the tree level, the vacuum polarization tensor, self energy function and the normalizability of the theory. After that, we compare our results with those ones obtained via Klein-Gordon-Fock elds determining that they are not completely equivalenttf

Les cyclodipeptides et leurs dérivés, les dicétopipérazines (DKP), constituent une large classe de métabolites secondaires aux activités biologiques remarquables qui sont essentiellement synthétisés par des microorganismes. Les voies de biosynthèse de certaines DKP contiennent des synthases de cyclodipeptides (CDPS), une famille d’enzymes récemment identifiée. Les CDPS ont la particularité de détourner les ARNt aminoacylés de leur rôle essentiel dans la synthèse protéique ribosomale pour les utiliser comme substrats et ainsi catalyser la formation des deux liaisons peptidiques de différents cyclodipeptides. Le travail de thèse présenté dans ce manuscrit a pour objectif de caractériser la nouvelle famille des CDPS. Dans un premier temps, la caractérisation tant structurale que mécanistique de la première CDPS identifiée, AlbC de Streptomyces noursei, est présentée. Puis, les résultats obtenus avec trois autres CDPS, chacune de ces enzymes ayant des caractéristiques adéquates pour approfondir l’étude de la famille des CDPS, sont décrits. Ainsi, la CDPS Ndas_1148 de Nocardiopsis dassonvillei a permis d’étendre nos connaissances sur les bases moléculaires de la spécificité des CDPS. La CDPS AlbC-IMI de S. sp. IMI 351155 est un bon modèle pour analyser l’interaction de chacun des deux substrats nécessaires à la formation d’un cyclodipeptide. Enfin, la caractérisation de la CDPS Nvec-CDPS2 chez l’animal Nematostella vectensis a permis de fournir le premier exemple d’enzyme d’origine animale impliquée dans la synthèse peptidique non ribosomale. / Cyclodipeptides and their derivatives, the diketopiperazines (DKPs), constitute a large class of secondary metabolites with noteworthy biological activities that are mainly synthesized by microorganisms. The biosynthetic pathways of some DKPs contain cyclodipeptide synthases (CDPSs), a newly defined family of enzymes. CDPSs hijack aminoacyl-tRNAs from their essential role in ribosomal protein synthesis to catalyze the formation of the two peptide bonds of various cyclodipeptides. The aim of the work presented in this thesis manuscript is to characterize the CDPS family. At first, the structural and mechanistic characterization of the first identified CDPS, AlbC of Streptomyces noursei, is presented. Then, the results obtained with three other CDPSs, each of which having suitable properties to increase our understanding of the CDPS family, are described. The CDPS Ndas_1148 of Nocardiopsis dassonvillei extends our knowledge of the molecular bases of the CDPS specificity. The CDPS AlbC-IMI of S. sp. IMI 351155 is a good model to analyze the interaction of each of the two substrates required for the formation of a cyclodipeptide. Finally, the characterization of the CDPS Nvec-CDPS2 from Nematostella vectensis provides the first example of enzymes of animal origin involved in nonribosomal peptide synthesis.

Malgré l’intérêt et la diversité des propriétés pharmacologiques des 2,5-dicétopipérazines (DKP), les voies de biosynthèse de ces molécules d’origine microbienne sont très peu connues. L’objectif de mes travaux de thèse a été i) de documenter de nouvelles voies de biosynthèse de DKP qui se caractérisent par la présence d’une synthase de cyclodipeptides (CDPS) travaillant souvent de concert avec une ou plusieurs enzymes de modification des cyclodipeptides et ii) d’explorer la diversité chimique codée par ces voies. Dans un premier temps, je me suis intéressée aux CDPS. Après la sélection par bioinformatique de candidats dans les bases de données génomiques, j’ai pu identifier 51 nouvelles CDPS actives et montrer que ces enzymes peuvent incorporer 17 des 20 acides aminés naturels. Par ailleurs, ce travail a permis de mieux caractériser la famille des CDPS, de définir l’existence de plusieurs sous-familles aux signatures fonctionnelles spécifiques et d’établir les premiers éléments d’un code de spécificité pour la synthèse de cyclodipeptides. Dans un second temps, je me suis attachée à caractériser les enzymes de modification associées aux nouvelles CDPS et, en particulier, les dioxygénases dépendant du Fe(II) et du 2-oxoglutarate (OG) qui sont très représentées dans ces voies. J’ai ainsi pu détecter une activité in vivo pour 11 OG et poursuivre la caractérisation in vitro pour l’une de ces OG, ce qui a permis de caractériser les DKP qu’elle synthétise et d’ainsi montrer la complexité des modifications chimiques introduites. L’ensemble de ces travaux a donc permis d’identifier et de caractériser de nouvelles voies de biosynthèse qui donnent accès à une diversité accrue de DKP. / Despite the interest and diversity of the pharmacological properties of 2,5-diketopiperazines (DKPs), the biosynthetic pathways of these microbial molecules are poorly documented. The aim of my doctoral work was i) to identify new DKP biosynthetic pathways that are characterized by the presence of a cyclodipeptide synthase (CDPS) often associated with one or more cyclodipeptide-tailoring enzymes and ii) to explore the chemical diversity encoded by these pathways. First of all, my study focused on CDPSs. After the bioinformatics-based selection of candidates, 51 novel CDPS were characterized, revealing the incorporation of 17 of the 20 proteinogenic amino acids. Moreover, this work has allowed a better characterization of the CDPS family, by showing the existence of several subfamilies with specific functional signatures and laying the foundations of a specificity conferring code for the synthesis of cyclodipeptides. Second, I characterized the tailoring enzymes associated with the newly identified CDPSs and, in particular, the Fe(II) and oxoglutarate dependent dioxygenases (OGs) that are highly represented in these pathways. I detected the in vivo activity for 11 OGs and characterized the in vitro activity for one of them, showing the complexity of the chemical modifications introduced into the cyclodipeptide. This work has led to identify and characterize novel biosynthetic pathways that provide access to a greater diversity of DKPs.

Cyclodipeptides and their derivatives, the diketopiperazines (DKPs), constitute a large class of secondary metabolites with noteworthy biological activities that are mainly synthesized by microorganisms. The biosynthetic pathways of some DKPs contain cyclodipeptide synthases (CDPSs), a newly defined family of enzymes. CDPSs hijack aminoacyl-tRNAs from their essential role in ribosomal protein synthesis to catalyze the formation of the two peptide bonds of various cyclodipeptides. The aim of the work presented in this thesis manuscript is to characterize the CDPS family. At first, the structural and mechanistic characterization of the first identified CDPS, AlbC of Streptomyces noursei, is presented. Then, the results obtained with three other CDPSs, each of which having suitable properties to increase our understanding of the CDPS family, are described. The CDPS Ndas_1148 of Nocardiopsis dassonvillei extends our knowledge of the molecular bases of the CDPS specificity. The CDPS AlbC-IMI of S. sp. IMI 351155 is a good model to analyze the interaction of each of the two substrates required for the formation of a cyclodipeptide. Finally, the characterization of the CDPS Nvec-CDPS2 from Nematostella vectensis provides the first example of enzymes of animal origin involved in nonribosomal peptide synthesis.

This thesis deals with design and implementation of programming structure of game web portal. The web portal will serve as a communication and information center to simplify coordination among players and allow them to gain new experience. In the thesis are analyzed the needs of players, existing solutions and their drawbacks. The results of this analysis are used to design individual functions of the portal. Implementation of the most important parts of the website has been described, the implementation of these parts were evaluated and some enhancemets were eventually suggested. In the end of this thesis several functionalities were suggested, which could extend the portal in the future.