Texte remanié de: Habilitationsschrift--Theologische Fakultät--Basel--Universität, 2007. / Bibliogr. p. 337-362.

Diss.--München--Ludwig Maximilian Universität, 1989. / Bibliogr. p. 177-186.

O gene SLC45A2 codifica a proteína MATP, envolvida na síntese de melanina através do processamento e transporte intracelular da tirosinase e transporte de prótons para o melanossomo. Por sua vez, a tirosinase, codificada pelo gene TYR, catalisa os dois primeiros passos da conversão de tirosina em melanina, além de atuar em uma etapa final da biossíntese de eumelanina. Considerando que polimorfismos nestes genes influenciam a variação de características normais de pigmentação, que somente recentemente mais informações sobre a função do gene SLC45A2 foram descobertas e que diversas questões sobre o envolvimento da tirosinase nos fenótipos normais de pigmentação ainda permanecem sem total compreensão, é necessário o melhor entendimento das interações entre as variantes desses genes de pigmentação e moléculas regulatórias, assim como o conhecimento sobre a diversidade de tais genes em uma população miscigenada como a brasileira. Dessa forma, o presente trabalho teve como objetivo analisar a diversidade genética das regiões, promotora, codificante e 3\'UTR dos genes SLC45A2 e TYR em uma amostra da população brasileira. As regiões regulatórias e codificadoras dos genes SLC45A2 e TYR foram analisadas por sequenciamento de nova geração em uma amostra de 340 indivíduos, estratificados de acordo com a pigmentação dos olhos, cabelos e pele, bem como quanto à presença ou ausência de sardas. Bibliotecas de DNA foram preparadas utilizando o Haloplex Target Enrichment System (Agilent Technologies) e sequenciadas por meio da plataforma MiSeq (Illumina). Os softwares cutadapt, BWA e GATK/VCFx foram utilizados para trimagem dos adaptadores, alinhamento e chamada de variantes, respectivamente. O programa PHASE foi utilizado para a reconstrução dos haplótipos. Um total de 58 variantes foram identificadas no gene SLC45A2. Destas, 28 foram associadas a pelo menos uma das características de pigmentação avaliadas. Embora as regiões nãocodificadoras tenham apresentado maior diversidade genética, associações significativas também foram encontradas em regiões exônicas. Dentre estas, destaca-se a associação do alelo rs16891982*G (exon 5, Leu374Phe) com pele clara (p = 9,54 x 10-35, OR = 22,66) e cabelos loiros (p = 1,59 x 10-26, OR = 31,72). Quando observamos os haplótipos inferidos para as regiões codificantes das isoformas 1 e 2 que possuem esse SNP e as associações encontradas, podemos notar que os únicos haplótipos associados com fenótipos de pigmentação claros para ambas isoformas [\"Iso2cds1\": pele clara (p = 3,65 x 10-29, OR =22,63) e cabelos loiros (p = 6,34 x 10-23, OR = 26,19); \"Iso1cds1\": pele clara (p = 1,08 x 10-24, OR = 17,38) e cabelos loiros (p = 1,94 x 10-22, OR = 22,93)] possuem como diferença em relação a todos os outros haplótipos associados com pigmentação escura o alelo rs16891982*G. Para o gene TYR foram identificadas 42 variantes e 15 se mostraram associadas a algum dos fenótipos de pigmentação avaliados. A maior parte da diversidade desse gene foi encontrada na região intrônica, com ênfase para a associação do genótipo rs1393350*A/A com olhos azuis (p = 0,0253, OR = 13,06) e cabelos castanho-claros (p = 0,0019, OR = 16,07). Ao analisarmos as associações encontradas para os haplótipos inferidos para essa região, podemos notar que os haplótipos \"cds5\" (p = 1,71 x 10-05, OR = 21,26), \"cds7\" (p = 0,0061, OR = 23,70) e \"cds9\" (p = 0,0017, OR = 29,25) estão associados a pele escura e o haplótipo \"cds12\" (p = 0,015, OR = 21,61) a ausência de sardas. Quando nos atentamos a composição desses haplótipos em relação ao SNP rs1393350, podemos perceber que todos os haplótipos possuem o alelo referência (rs1393350*G), o que é consistente com a associação entre o genótipo (rs1393350*A/A) e fenótipos de pigmentação claros. Os resultados aqui encontrados reafirmam a importância desempenhada pelos genes SLC45A2 e TYR na geração da diversidade de fenótipos de pigmentação. / The SLC45A2 gene encodes the Membrane-Associated Transporter Protein, which mediates melanin synthesis by tyrosinase trafficking and proton transportation to melanosomes. On the other hand, the tyrosinase protein, encoded by the TYR gene, catalyzes the first two steps of tyrosine to melanin conversion in addition to acting in a final stage of eumelanin biosynthesis. Considering that polymorphisms in these genes influence normal pigmentation variation, that only recently more information about SLC45A2 gene function were discovered and that many questions about the tyrosinase involvement in normal pigmentation phenotypes are still not fully understood, it is necessary to better understand the interactions between variants in these pigmentation genes and regulatory molecules, as well as to improve knowledge about their diversity in a mixed population like the Brazilian one. Thus, the present study aimed at analyzing the genetic diversity of the promoter, coding and 3\'UTR regions from the SLC45A2 and TYR genes in a Brazilian admixed population sample (n=340). The regulatory and coding regions were analyzed by next-generation sequencing procedures. The individuals were stratified according to eye, hair and skin pigmentation, as well as to the presence or absence of freckles. DNA libraries were prepared using the Haloplex Target Enrichment System (Agilent Technologies) and sequenced at the MiSeq platform (Illumina). cutadapt, BWA and GATK/VCFx software packages were used for trimming adaptor sequences, alignment and genotype calling, respectively. The PHASE program was used for haplotypes reconstruction. A total of 58 variation sites were identified in the SLC45A2 gene. Of these, 28 were found in association with at least one of the analyzed pigmentation characteristics. Although the non-coding regions were more diverse, the exonic region also showed significant associations. Among them, the association of the rs16891982*G allele (exon 5, Leu374Phe) with light skin (p = 9.54 x 10-35, OR = 22.66) and blond hair (p = 1.59 x 10-26, OR = 31.72) stands out. When we observe the inferred haplotypes for the isoforms 1 and 2 coding regions that have this SNP and the associations found, we can recognize that haplotypes associated with light pigmentation phenotypes [\"Iso2cds1\": light skin (p = 3.65 x 10-29, OR = 22.63) and blond hair (p = 6.34 x 10-23, OR = 26.19); \"Iso1cds1\": light skin (p = 1.08 x 10-24, OR = 17.38) and blond hair (p = 1.94 x 10-22, OR = 22.93)] have the rs16891982*G allele, while haplotypes associated with dark pigmentation harbors the other one. Forty-two variation sites wereidentified for the TYR gene and 15 of them were associated with one of the evaluated pigmentation phenotypes. Most of the diversity of this gene was found in the intronic region, with emphasis on the association of genotype rs1393350*A/A with blue eyes (p = 0.0253, OR = 13.06) and light brown hair (p = 0.0019, OR = 16.07). When we analyze the associations found for the inferred haplotypes for this region, we can note that the haplotypes \"cds5\" (p = 1.71 x 10-05, OR = 21.25), \"cds7\" (p = 0.0061, OR = 23.70) and \"cds9\" (p = 0.0017, OR = 29.25) were associated with dark skin and the haplotype \"cds12\" (p = 0.015, OR = 21.61) with absence of freckles. When the composition of the haplotypes concerning this SNP (rs1393350) is taken into account, we can see that all haplotypes have the reference allele (rs1393350*G), which is consistent with the association between the rs1393350*A/A genotype and lighter pigmentation phenotypes. These findings provide additional support to the role played by SLC45A2 and TYR in the generation of pigmentation phenotypes diversity

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

E-rosette formation by human lymphocytes incubated with sheep red blood cells (sRBC) is inhibited by morphine. We studied the ability of the opiate antagonists naloxone and Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2) to block this action. Active E-rosette formation by lymphocytes incubated with morphine was reduced from the control of 35.7±1.7% to 23.7±1.5% (p<0.001). Similarly, total E-rosette formation was reduced by morphine from the control of 65.8±1.3% to 53.2±2.9% (p<0.001). These effects were blocked by co-incubation of the lymphocytes with either Tyr-MIF-1 or naloxone (p<0.05). Tyr-MIF-1 was active (p<0.05) at concentrations as dilute as 10-13M. These results indicate that the neuropeptide Tyr-MIF-1 exerts an antiopiate effect at the human T-lymphocyte.

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2017-2018 / Les Dialexeis de Maxime de Tyr (seconde moitié du IIe siècle ap. J.-C.) sont de courts textes abordant des questions philosophiques avec clarté et élégance. Ce mémoire présente la traduction et le commentaire littéraire de quatre d’entre eux, qui discutent de grands philosophes du passé : le procès de Socrate (Dialexis 3), la querelle d’Homère et de Platon sur la poésie (Dialexis 17), la réconciliation de ces derniers en faisant d’Homère le premier des philosophes (Dialexis 26) et enfin l’éloge de Diogène (Dialexis 36). À la suite d’une traduction annotée, le commentaire cherche à dégager les principaux aspects de la construction d’un idéal du philosophe à partir de micro-analyses textuelles. Le premier chapitre pose le cadre conceptuel de ces portraits : une rhétorique proche de la Seconde Sophistique, marquée par les procédés de l’éloge ; et une définition de la philosophie comme sagesse et vertu poussées à leur paroxysme, s’incarnant au long des siècles dans la succession des sages. Le deuxième chapitre examine les traits caractéristiques de ces philosophes. Socrate et Diogène, tout comme Homère et Platon – les premiers traités comme exempla d’action vertueuse et les derniers comme des enseignants de la sagesse par leurs œuvres – voient leur ethos grandi par la présence de comparants divers. Enfin, le dernier chapitre s’intéresse de plus près à la situation d’énonciation interne et externe des Dialexeis, qui se reflète dans la stratégie pédagogique d’une part, et d’autre part dans la confrontation des différentes figures philosophiques – Maxime compris – avec leurs rivaux dans le domaine littéraire et esthétique, sophistes, orateurs, poètes et artistes. Le mémoire conclut sur le caractère protéiforme de la figure du philosophe dans les Dialexeis. / Maximus of Tyre’s Dialexeis (second half of the 2nd century BC) are short lectures dealing with style and clarity with philosophical questions. This study aims at translating and analysing four of them, in which Maximus portrays some famous philosophers of the Greek past. He thus pictures Socrates’ trial (Dialexis 3), Homer and Plato’s quarrelling about poetry (Dialexis 17), tries to reconcile both of them by showing how great a philosopher Homer is (Dialexis 26) and praises Diogenes’ lifestyle (Dialexis 36). The literary comment is based on close readings of the annotated translation, in order to show the author’s ideal picture of the philosopher. The first chapter qualifies Maximus’ style as mainly epidictic, close to the Second Sophistic’s standards, and defines philosophy as virtue and wisdom embodied in the wisemen who succeed in cultivating them along centuries. The second chapter explores the philosopher’s main features. Whereas Socrates and Diogenes are pictured as virtuous exempla, Homer and Plato are rather dealt with as authors and teachers of wisdom. All of them are compared with diverse characters, who add to their ethos. Eventually, the third chapter is a closer look at the Dialexeis’ internal and external enunciative situation: Maximus’ and his philosophical characters’ self-display as wise and virtuous teachers leads them to confront their fellow enemies – sophists, orators, poets and artists – in the literary and aesthetic field. This study concludes on the portray of the philosopher as a man with many turns and faces.

Afin de déjouer les défenses immunitaires de l’hôte et créer les niches nécessaires à leur survie, les bactéries pathogènes mettent on œuvre de nombreux mécanismes ciblant les voies de signalisation de la cellule hôte. L’un de ces mécanismes repose sur la sécrétion de protéines bactériennes dans les cellules cibles afin de moduler directement leurs réseaux de signalisation. Cependant, les signaux, les senseurs et les effecteurs impliqués dans ces régulations sont encore peu ou mal connus. La détection de l’environnement dans la cellule hôte lors de l'infection est l’élément clé d’une réponse adaptée, et les systèmes de signalisation basés sur les mécanismes de phosphorylation sont indispensables à l'adaptation hôte-pathogène. L’aspect innovant de ce projet repose sur l’étude du rôle des Ser/Thr kinases et phosphatases sécrétées lors des interactions hôte-pathogène, modifiant ainsi la réponse globale de l’hôte durant l’infection. Pendant ma thèse, j’ai tout d’abord étudié le rôle d’une nouvelle protéine kinase bactérienne identifiée chez Coxiella burnetii, nommée CstK (Coxiella serine threonine Kinase). C. burnetii, l’agent étiologique de la zoonose appelée fièvre Q, modifie les défenses de la cellule hôte, permettant sa réplication dans des vacuoles spécifiques à l’intérieur de la cellule hôte. Par ailleurs, la sécrétion d’un grand nombre d’effecteurs bactériens est indispensable au détournement du phagosome par Coxiella. Nous ainsi avons démontré que cette potentielle protéine kinase, identifiée in silico dans le génome de C. burnetii, est capable de s’autophosphoryler et par conséquent possède une activité kinase. De plus, nous avons identifié différentes protéines spécifiques de la cellule hôte interagissant avec CstK à l'aide du modèle amibe Dictyostelium discoideum, un phagocyte professionnel eucaryote, permettant des études génétiques et biochimiques. Dans la deuxième partie de mon projet, je me suis intéressée au rôle d’une probable protéine sécrétée, la tyrosine phosphatase PtpA, durant l’infection par Staphylococcus aureus. Bien connue dans les hôpitaux, où elle est responsable de nombreuses maladies nosocomiales, cette bactérie possède un grand nombre de facteurs de virulence, responsables d’infections variées, et l’apparition exponentielle de souches multi-résistantes en font un problème majeur. Ce pathogène est capable d’envahir et de persister dans un grand nombre de types cellulaires différents chez l’Homme, en sécrétant des protéines effectrices qui vont moduler les réponses cellulaires. Nous avons démontré que PtpA était sécrétée durant la phase de croissance bactérienne, et pu déterminer que PtpA possédait une activité tyrosine phosphatase, régulée par la tyrosine kinase CapA1B2 de S. aureus. Enfin, en utilisant le modèle D. discoideum, nous avons pu identifier des protéines de l’hôte qui interagissent avec PtpA, mais leur rôle dans l’infection n’est pas encore connu. / Bacterial pathogens have developed diverse strategies towards host signalling pathways, in order to subvert the immune response and/or create permissive niches for their survival. One such strategy is based on the secretion of bacterial signalling proteins into the target host cells, thereby directly modulating the status of host signalling networks. Because the mechanisms involved are largely intractable to most in vivo analyses, very little is known about the signals, sensors, and effectors mediating these adaptations. Sensing the host environment is a key component to execute appropriate developmental programs, and the eukaryotic-like phosphosignaling systems in prokaryotes are emerging as equally important regulatory systems as the well-known eukaryotic systems, but the study of their functions is still in its infancy. The innovative aspect of this project resides in the study of the emerging role of secreted Ser/Thr kinases and phosphatases in the control of host-pathogen interactions thus modifying the global host response during infection. During my thesis, I first investigated the role of a novel bacterial protein kinase identified in Coxiella burnetii that we named CstK (Coxiella serine threonine Kinase). C. burnetii, the etiological agent of the emerging zoonosis Q fever, subverts host cell defenses, permitting its intracellular replication in specialized vacuoles within host cells. Secretion of a large number of bacterial effectors into host cell is absolutely required for rerouting the Coxiella phagosome. We demonstrated that this putative protein kinase identified by in silico analysis of the C. burnetii genome is able to autophosphorylate and undergoes in vitro phosphorylation. Moreover, we identified specific host cell proteins interacting with CstK, by the use of the model amoeba Dictyostelium discoideum, an eukaryotic professional phagocyte amenable to genetic and biochemical studies. In the second part of my project, I was interested in the role of a putative secreted protein tyrosine phosphatase (PtpA) during Staphylococcus aureus infection. Well-known in hospital-acquired diseases, this bacteria produces multiple virulence factors that lead to various severe diseases, and the increase of multi-resistant strains is a major concern. This pathogen has the ability to invade and persist in a number of different human host cell types, secreting effector proteins to modulate cellular responses. Here we demonstrated that PtpA is secreted during the bacterial growth. We also determined that PtpA presents a tyrosine phosphatase activity that is regulated by the tyrosine protein kinase CapA1B2 of S. aureus. At last, using the D. discoideum model, we identified some host proteins that interact with PtpA, but their link with infection still remain to be studied.

This thesis compares four excavated ritual places that have been connected through place names to the two Norse gods Týr and Ullr. The purpose is to contribute to the discussion about the nature of Týr and Ullr and their relationship. Excavation reports, primary sources and other publications are used as material to achieve this purpose. A qualitative method is used in the comparison between the ritual places. The conclusion is that Ullr probably were a sun god and law god with connections to aristocracy, war, rings and possibly horses, but that he also changed through time. The relationship with Týr remains obscure though, partly because of the limited material, but the two gods seems to have had similar connections to aristocracy and war. Both gods may also have survived into the Viking age. The presence of other gods such as Freyr and Odin makes the tracing of Týr and Ullr more complicated.

The work in this thesis mainly focuses on the assessment of density functional methods for computing structures and energies of organic and bioorganic molecules. Previous studies found dramatic conformational and stability changes from B3LYP to MP2 geometry optimization for some Tyr-Gly conformers. Possible reasons could be large intramolecular basis set superposition errors (BSSEs) in the MP2 calculations and the lack of dispersion in the B3LYP calculations. The fragmentation method and three kinds of rotation methods were used to investigate intramolecular BSSE. It is concluded that the rotation method cannot be used to correct intramolecular BSSE along a rotation profile. Another methodology is to employ modern density functionals. We focused on M06-L with the Tyr-Gly conformer ‘book6’. Potential energy profiles were determined by computing the energy for geometries optimized at various fixed values of a distance that controls the degree of foldedness of the structure. M06-L manifested itself as a very promising method to investigate the potential energy surface of small peptides containing aromatic residues. To predict Tyr-Gly structures, 108 potential conformers were created with a Fortran program. The geometry optimizations were done using M06-L/6-31G(d) and M05-2X/6-31+G(d). Two schemes were employed and the most stable conformers were compared to the 20 stable conformers found by B3LYP. Both schemes found 10 conformers similar to one of the B3LYP stable conformers, as well as several newly found conformers. The study of a missing B3LYP stable conformer showed that the possible reason of missing conformers may be the lack in dispersion in B3LYP theory. To study the hydration effect, we studied the conformations of neutral and zwitterionic 3-fluoro-γ-aminobutyric acid (3F-GABA) in solution using different solvation models, mainly the explicit water molecule models. Zwitterionic forms of 3F-GABA are preferred in solution. M06-2X performs better in calculating transition energy profiles than MP2.

Le retour à la littérature classique et l'héritage culturel sont omniprésents dans les œuvres littéraires, rhétoriques ou philosophiques de l'époque de Maxime de Tyr. Maxime suit cette tradition puisque dans ses Dialexeis sont éparpillées des références aux auteurs qui le précèdent. Maxime est influencé surtout par Homère et Platon comme on constate en lisant ses Dialexeis, où il montre sa prédilection pour les deux grands maîtres. Quant à Homère on trouve des citations utilisées pour illustrer ou pour compléter le sens d'un ensemble des phrases du texte de Maxime. Quelquefois Maxime procède à un léger changement dans les vers homériques afin de les adapter à l'entité syntaxique de son propre texte. Il y aussi des références aux noms ou aux épisodes pris dans les épopées homériques. Maxime utilise aussi l'allégorie homérique pour véhiculer des idées ou développer sa pensée philosophique.L'influence de Platon est profonde et s'étend à tous les domaines de la pensée de Maxime : politique, religieux, artistique, mais surtout philosophique. L'auteur des Dialexeis se trouve devant le problème épineux de la réconciliation de la philosophie avec la poésie. C'est en utilisant les citations des épopées homériques que Maxime trouve une manière de parler des conceptions philosophiques. Autrement dit, les exemples pris dans le texte d'Homère sont surtout utilisés afin que Maxime rende plus claire et explicite sa parole chaque fois qu'il expose ses idées philosophiques. Maxime prouve dans l'œuvre même, qu'un poète peut être aussi un grand philosophe, scellant ainsi la coexistence et arrivant à la réconciliation entre Homère et Platon. / The return to the classical literature and the evocation of cultural heritage are ubiquitous in the works of literature or those related to rhetoric and philosophy during the first centuries of the Roman Empire. Maximus of Tyr, who lived in the time of Commodus', follows this trend, as his Orations are full of citations or references to the works of his predecessors. However, he shows his preference for Homer and Plato, as their influence is evident in the Orations. As far as Homer is concerned, we mostly find citations that illustrate Maximus' text or complete the meaning of a series of phrases. Sometimes Maximus intervenes in Homer's text in order to adapt it to his own. Moreover, we can find references to names or to precise moments of the Iliad or the Odyssey, which are dispersed in the Orations. Maximus uses, also, the Homeric allegory in order to convey his thoughts about some philosophical issues such as the harmonious style of life, the pursuit of human felicity and the cultivation of a virtuous character. Plato's influence is also profound and it is extended to a wide range of Maximus' interests: politics, religion, art and mainly philosophy. Furthermore, in an effort to reconcile poetry and philosophy, Maximus uses the Homeric citations so as to develop more explicitly his philosophical conceptions, which, otherwise, would have stayed obscure. In this way he proves that a poet can be at the same time a great philosopher sealing the coexistence and bridging the differences between Homeric poetry and Platonic philosophy.