Blood-sucking louse Polyplax serrata harbor two phylogenetically distinct symbiotic bacteria from the orders Legionellales (Gammaproteobacteria) and Neisseriales (Betaproteobacteria). Based on rigorous phylogenetic analyses, the first bacteria was confirmed as member of genus Legionella, and the name Candidatus Legionella polyplacis, sp. n. was proposed. Vertical transgeneration transmission was proved by visualisation of the symbiont in host tissues. Improved genome of latter symbiont is considerably larger and possesses more metabolic functions. In the genome, I found horizontally transferred operon, which encode synthesis of enzymes involved in urea cleavage.

Dans le contexte actuel, il devient nécessaire de rendre les alternatives au pétrole, tel que le bioéthanol 2G, disponibles à grande échelle. Cependant, l’étape d’hydrolyse par les enzymes de Trichoderma reesei reste un verrou à un procédé économiquement stable et rentable. Ces travaux de thèse, s'intègrent dans le cadre du projet Futurol et ont pour objectifs d'identifier et de caractériser de nouvelles enzymes fongiques pour améliorer l'hydrolyse de la biomasse lignocellulosique. A partir des données protéomiques disponibles pour Podospora anserina et Fusarium verticillioides, une douzaine d'enzymes candidates ont été identifiées dans leurs sécrétomes. Ce travail de thèse s'est plus particulièrement focalisé sur les AA9s « Lytic Polysaccharide Monooxygenases » (LPMOs) de P. anserina. Parmi les LPMOs étudiées, PaLPMO9A, PaLPMO9E et PaLPMO9H, qui possèdent un CBM1, sont les plus actives sur la cellulose. La détermination de la régiosélectivité d'action a mis en évidence que PaLPMO9A et PaLPMO9H clivent la cellulose en position C1 et C4 alors que la PaLPMO9E génère uniquement des produits oxydés en C1. La PaLPMO9H est la plus versatile puisqu’elle est active sur les cello-oligosaccharides solubles et sur les polysaccharides hémicellulosiques liés en β-(1,4) (i.e., xyloglucane, glucomannane). La supplémentation du cocktail de T. reesei avec PaLPMO9E ou PaLPMO9H a permis de doubler les rendements d'hydrolyse du miscanthus prétraité. Les travaux réalisés au cours de cette thèse ont permis de démontrer l'importance de ces enzymes oxydatives dans les phénomènes de déconstruction de la lignocellulose chez les champignons filamenteux. / In the current context, it becomes essential to make alternative to oil, such as the 2G bioethanol, available at large scale. However, the hydrolysis step by Trichoderma reesei enzymes remains the major bottleneck for an economically sustainable process. The present work is part of the Futurol project, and aims at identifying and characterizing new fungal enzymes to improve the hydrolysis of lignocellulosic biomass. From the proteomic data available for Podospora anserina and Fusarium verticillioides, a dozen of interesting enzymes were identified in their secretomes. This work focuses, mainly, on the AA9s « Lytic Polysaccharide Monooxygenases » (LPMOs) from P. anserina. Among all the LPMOs studied, PaLPMO9A, PaLPMO9E and PaLPMO9H that harbored a CBM1 were the most active on cellulose. Investigation of their regioselective mode of action revealed that PaLPMO9A and PaLPMO9H oxidatively cleaved at both C1 and C4 positions while PaLPMO9E released only C1-oxidized products. PaLPMO9H that was the most versatile in terms of substrate specificity as it also displayed activity on cello-oligosaccharides and β-(1,4)-linked hemicellulose polysaccharides (e.g., xyloglucan, glucomannan). The hydrolysis yield of the pretreated miscanthus was significantly improved up to 2 fold, when the PaLPMO9E, or PaLPMO9H were supplemented to the T. reesei cocktail. This work demonstrated the importance of these oxidative enzymes for lignocellulose deconstruction by fungi. These biocatalysts open new prospects to improve the enzymatic conversion of plant biomass for 2G bioethanol production.

Ferrocene is an important molecule in the field of chemical biology due to its stability, unique redox property and significant lipophilicity for better cellular delivery. The medicinal importance of ferrocene is well recognized after its successful incorporation into breast cancer drug tamoxifen and antimalarial drug chloroquin. Designing ferrocene conjugated transition metal complexes is an interesting area of research in the field of photodynamic therapy, a new modality of light activated cancer treatment. The objective of the present thesis work is to develop photoactive ferrocene conjugates showing DNA photocleavage and photocytotoxic activity. We have synthesized the ferrocene conjugated imidazophenanthroline derivative which exhibits visible light induced DNA photocleavage activity and photocytotoxicity in HeLa cell line. The corresponding phenyl analogue is found to be inactive. Polypyridyl platinum(II) complexes of ferrocenyl as well as phenyl moiety are prepared and studied their interactions with calf thymus DNA. The cytotoxicity of the complexes enhance significantly upon irradiation of UV-A light of 365 nm. To enhance the photodynamic potential and to understand the role of organometallic ferrocenyl moiety, ferrocene conjugated terpyridyl copper(II) complexes having planar phenanthroline bases are prepared. The interaction of these complexes with duplex DNA and their photo-induced DNA cleavage and anticancer activity in HeLa cancer cells are studied. The complexes are able to generate ROS in the presence of visible light which causes DNA damage as well as cell death. The importance of ferrocenyl moiety is evidenced from the less activity of the corresponding phenyl analogues complex. We have prepared copper(II) complexes of ferrocenyl methyl dipicolylamine ligand to understand the role of terpyridyl moiety. These complexes lacking any conjugation between the copper(II) and the ferrocenyl moiety are found to be less active compared to the terpyridyl conjugated system. The copper(II) complexes are found to show undesirable dark cytotoxicity in the presence of cellular thiols like GSH. To overcome the dark toxicity problem and to understand the mechanistic aspects of DNA photocleavage and photocytotoxicity, a series of binary ferrocene conjugated terpyridyl complexes of Fe(II), Co(II), Cu(II) and Zn(II) are prepared and their DNA photocleavage and anticancer activity studied. The zinc(II) complex having redox-active ferrocenyl moiety and redox-inactive zinc(II) center exhibits significant PDT effect with low dark toxicity compared to its copper(II) analogue. The ferrocenyl moiety plays an important role towards showing photocytotoxic activity since its phenyl analogue is inactive in nature. Finally, the present thesis work opens up a new strategy for designing and developing new ferrocene based metal complexes as novel photosensitizers for PDT applications.

This thesis work deals with different aspects of the chemistry of La(III) and Gd(III) complexes, their interaction with DNA and proteins, photo-induced cleavage of double-stranded DNA, photocytotoxic effect on cancer cells, cell death mechanism and cellular localization behaviour. Chapter I gives an introduction to the metal-based anticancer agents with special emphasis on clinically used drugs and the growing field of lanthanide therapeutics. An overview of the current strategies of cancer treatment, especially photodynamic therapy (PDT), is presented. Mode of small molecule-DNA interactions and the mechanistic aspects associated with DNA photodamage reactions and PDT effect are discussed with selected examples of compounds that are known to photocleave DNA on exposure to light of different wavelengths. A brief discussion on the various therapeutic applications of the lanthanide compounds is also made. Chapter II presents the synthesis, characterization, DNA binding, BSA binding, photo-induced DNA cleavage activity and photocytotoxicity of La(III) and Gd(III) complexes of phenanthroline bases to explore the UV-A light-induced DNA cleavage activity and photocytotoxicity of the complexes. Chapter III describes the synthesis, characterization, DNA binding, photo-induced DNA cleavage activity and photocytotoxicity of La(III) and Gd(III) complexes of phenanthroline bases with an aim to improve the design of the complexes to achieve better solution stability and DNA binding of the complexes. Chapter IV presents the synthesis, characterization, DNA binding, and UV-A light-induced DNA photocleavage activity and photocytotoxicity of La(III) and Gd(III) complexes of pyridyl phenanthroline bases with an objective to improve the photoactivity of the complexes by introducing an additional pyridyl group. Cell death mechanism and confocal microscopic studies are also carried out to gain more insight into the PDT effect caused by light in the presence of the complex. Chapter V describes the synthesis and characterization of La(III) and Gd(III) complexes of terpyridine bases and acetylacetonate to study the complexes as a new class of photosensitizers to explore their DNA photocleavage activity and photocytotoxicity in HeLa cells. Effect of attaching a glucose moiety to the acetyl acetone (Hacac) ligand has been studied. The cellular uptake behaviour of the La(III) pyrenyl-terpyridine complexes has also been investigated. Finally, Chapter VI presents the synthesis and characterization of curcumin and glycosylated curcumin La(III) and Gd(III) complexes having terpyridine base with an objective to study the photoactivated anticancer activity of the complexes in visible light. This chapter describes the visible light-induced DNA cleavage activity and photocytotoxicity of the complexes by exploiting curcumin and glycosylated curcumin as the photosensitizer ligands. Study on the cellular uptake behavior of curcumin La(III) complexes having pyrenyl terpyridine ligand is also presented. The references have been assembled at the end of each chapter and indicated as superscript numbers in the text. The complexes presented in this thesis are represented by bold-faced numbers. Crystallographic data of the complexes which are characterized structurally by single crystal X-ray crystallography are provided in CIF format in the enclosed CD (Appendix-I). Due acknowledgements have been made wherever the work described is based on the findings of other investigators. Any unintentional omission that might have happened due to oversight or mistake is sincerely regretted.

Cotutelle internationale de thèse réalisée entre l'Université de Montréal et l'Université de Lille / Résumé Victoire inattendue de Donald Trump aux États-Unis lors de la campagne présidentielle de 2016 ; succès du camp du Brexit au Royaume-Uni la même année ; disparition des deux partis de gouvernement au deuxième tour de la campagne présidentielle en France lors de l’élection de 2017 ; victoire majoritaire d’un tiers-parti, la Coalition Avenir Québec, lors de l’élection provinciale de 2018 au Québec : des deux bords de l’Atlantique, d’importantes recompositions des scènes partisanes et des résultats électoraux inopinés agitent les analyses politiques, médiatiques et pour partie universitaires. Ces phénomènes sont parfois interprétés au travers du prisme de la « montée des populismes ». Certains travaux pointent du doigt le « peuple » et sa propension à se laisser séduire, voire berner, par des leaders « populistes ». L’explication, souvent sur la base d’enquêtes de sondage, serait à trouver dans le vote, pêlemêle, des « perdants de la mondialisation », des classes populaires ou encore du monde ordinaire des zones rurales. Le constat d’un champ politique apparemment chamboulé par les franges dominées du monde social s’accompagne du paradoxe de pauvres votant contre leurs intérêts supposés. En France, ces questionnements s’inscrivent en partie dans des débats autour du vote des classes populaires dans un contexte d’effacement du clivage gauche-droite comme référent politique. Au contraire, au Québec, la scène partisane est présentée comme de plus en plus polarisée autour de ce clivage en raison du moindre attrait de la cause souverainiste tandis que la notion de classes populaires n’est pas aussi centralement mobilisée par les analyses politiques. En comparant ces deux cas distincts, ce travail de recherche vise à éclairer sous un jour qualitatif les rapports à la politique et au politique des classes populaires en France et au Québec. Sur la base d’une enquête ethnographique dans deux campings populaires dans le Pas-de-Calais et dans la partie sud de la région de Québec, ce travail étudie par le bas et dans une perspective comparée les représentations et les attitudes politiques de campeuses et de campeurs saisonniers dans des contextes de loisirs. Je mobilise comme données d’enquête une campagne d’une cinquantaine d’entretiens, des observations ethnographiques réalisées pendant deux saisons estivales dans ces deux campings et dans d’autres espaces de loisirs. En analysant les représentations ordinaires des sphères partisanes et les sens sociaux du vote auprès des enquêté-e-s rencontré-e-s, ce travail souligne une même distance soupçonneuse vis-à-vis du champ politique auprès de groupes sociaux aux propriétés sociales comparables. Le vote y apparait comme une information politique équivoque et parfois difficilement interprétable. A rebours des seuls schèmes savants de compréhension du jeu politique, ce travail souligne la mobilisation parmi les classes populaires françaises et québécoises d’outils profanes comparables, les indices et les rumeurs, qui observés in situ illustrent la pluralité des modes d’appréhension de la politique. Pour partie faiblement connectées aux enjeux du champ politique, souvent en écho à des expériences personnelles, les attitudes politiques des classes populaires nécessitent d’être étudiées dans une perspective plus large. Ces rapports au politique se comprennent davantage en réinscrivant ces représentations politiques et du monde social dans les relations qu’entretiennent ces enquêté-e-s à l’État et dans les frontières identitaires et de classe qu’ils et elles mobilisent pour se situer socialement. Cette recherche souligne ainsi les divergences et les effets de trajectoires sociales et de lieu dans les visions du monde que mobilisent les classes populaires dans ces deux espaces nationaux. Ma contribution vise donc à éclairer sous un autre jour les recompositions des scènes partisanes en France et au Québec en abordant la question au travers des rapports ordinaires à la politique des classes populaires. Elle esquisse une sociologie politique des classes populaires au Québec et prend position dans les débats portant sur la droitisation des classes populaires et sur la « montée des populismes » en France et au Québec en proposant une contribution méthodologique à l’ethnographie du politique. / Abstract Donald Trump’s unforeseen victory in the U.S’s 2016 presidential campaign. The unexpected Brexit in the U.K. the same year. The disappearance of the two governing political parties in France at the 2017 elections. The electoral success of a third party, the Coalition Avenir Québec, during the provincial elections in 2018 in Quebec. On both sides of the Atlantic, unpredicted electoral results and a large reshuffling of partisan scenes are upsetting political, media and academic analyses. These phenomena are sometimes summed up as part of the “rise of populism”. Some works single out the “people” and their habit of being seduced, sometimes of being fooled, by “populist” leaders. The (jumbled) causes – built through statistical explications – are usually found with the “losers of the globalization”, the popular social classes or with ordinary people of rural regions. The observation of a political world turned upside down by the more dominated margins of society is usually brought up with the paradox of poor people voting against their supposed interests. In France, these reflections are part of the larger debate concerning the voting habits of the popular classes in the context of the slow demise of the right-left divide as the main political reference. On the contrary, in Quebec, the partisan sphere is seen as being more and more polarized around this divide, as the question of sovereignty loses its significance. At the same time, the notion of popular social classes is not as centrally used by analysts in Quebec. Comparing these two cases allows this research to shed – a qualitative – light on the popular classes’ relations to politics and political sides in France and in Quebec. This work is based on an ethnographic fieldwork in two lower class campgrounds in Pas-de-Calais (in France) and in the south of the “ region of Québec ”. It is a study, from the bottom-up and in a comparative perspective, of the representations and political attitudes of seasonal campers in a leisurely context. My analysis is based on around fifty interviews and a set of ethnographic observation made during two summer seasons in two campgrounds and in other spaces of leisure. In my analysis of the research participants, ordinary representations of the political parties and of the social significance of voting underlines a suspicious distance from the political realm that is common to socially comparable groups. Voting habits appear to give ambiguous political information that is often difficult to interpret. Far from the erudite patterns of understanding the political game, my work emphasizes common secular tools used by popular classes in France and in Quebec. When such tools, like the use of clues or of rumors for instance, are observed on site, they illustrate the plurality of the participants’ understanding of and relationship to the political. The political attitudes of the popular classes are very loosely connected to the issues of the political realm and are usually rooted in personal experiences. They thus need to be studied in a larger perspective. These relationships to the political are better understood when they are connected to the participants’ relationship to the State and to their own mobilization of identities which allows them to situate themselves socially. My work therefore underscores the divergences and effects of diverse social and spatial trajectories on the social representations and world visions that the popular social classes muster in these two distinct national spaces. My work consequently aims at shedding a different light on the reshuffling of the partisan scenes in France and in Quebec by orienting the debate towards the ordinary relationships of the popular classes to the political. This thesis points at a political sociology of popular classes in Quebec. It also takes a stand in the debates on the shift to the right of these lower classes and on the “rise of populism” in France and in Quebec. This stand is rooted in a methodological contribution to the ethnography of the political.

The Masters thesis deals with dependence of quality parameters of malt on the temperature of mashing at sweet wort preparation. The theoretical part focuses on the technology of malt production including description of ingredients, production parts, some kinds of malt and the quality parameters. There is also described the technology of sweet wort preparation and the methods of determination of the malt quality parameters in the sweet wort there. The experimental part focuses on determination of malt extract, viscosity, haze, colour, time of starch cleavage, pH, degree of fermentation and beta-glucans content. Based on temperature dependence of parameters, the individual samples were compared and the effects of temperature were discussed. The biggest extract of light and caramel malts was explored at 70 °C, of coloured malt at 50 °C. The lowest viscosity of light and coloured malts was explored at 65 °C, of caramel malt at 50 °C. The lowest haze of wort was at 65 °C. Ideal colour of all malts was at all mashing temperatures. Ideal pH of all malts was explored at 70 °C. Ideal time of starch cleavage was explored at 70-85 °C. The biggest achievable degree of fermentation and the hugest increase of beta-glucans content were explored at 65 °C.

Les ribosomes sont des complexes nucléoproétiques responsables de la traduction. Chez les eucaryotes, la biogenèse du ribosome est un processus complexe très régulé qui fait intervenir un nombre important de facteurs d’assemblages (~200). La construction d’un ribosome est initiée dans le nucléole puis continue dans le nucléoplasme et se termine dans le cytoplasme. La maturation cytoplasmique de la petite sous-unité ribosomale implique la dissociation séquentielle des facteurs d’assemblage tardifs et la maturation finale de l’ARNr 18S. Ce processus est catalysé par l’endonucléase Nob1 qui assure la coupure de l’extrémité 3’ du précurseur de l’ARNr 18S (pré-18S) aboutissant à sa forme mature. Ce mécanisme est coordonné par la protéine Pno1 qui est le partenaire de Nob1. Des informations détaillées sur l’architecture des particules pré-ribosomiques nous ont permis de mieux comprendre les différents intermédiaires de la biogenèse. Cependant, certains aspects fonctionnels comme la conformation adoptée par Nob1 pour assurer la coupure du site D du pre-18S reste encore flou. L’objectif de mon travail a été de mieux comprendre les aspects très tardifs de la maturation cytoplasmique du ribosome. Pour ce faire, nous avons redéfini l’organisation modulaire de l’endonucléase Nob1 chez les eucaryotes pour ensuite étudier son mode d’interaction avec son partenaire Pno1. Des tests fonctionnels in vitro ont été effectués pour étudier le rôle de Pno1 dans la régulation de la coupure par Nob1.Nos résultats nous ont permis de montrer que le domaine catalytique de Nob1 adopte une conformation atypique. En effet le domaine PIN est composé de deux fragments (res 1-104 and 230-255) séparé par une boucle interne qui est importante pour la reconnaissance avec son partenaire Pno1. Nos études nous ont également montré que Pno1 inhibe l’activité de Nob1 probablement en reconnaissant directement l’ARNr substrat, masquant ainsi le site de coupure de l’endonucléase. Ces résultats sont complémentaires et cohérents avec les données structurales de cryo-EM de la particule pré-40S humaine récemment publiées. En effet, Nob1 est dans une conformation incapable de couper le pré-ARNr puisque son domaine catalytique se retrouve à une distance d’environ 30Å de son ARN substrat. Ce phénomène implique donc des changements de conformations ou encore la nécessité de protéine accessoire pour déplacer certains facteurs. La protéine Cinap est impliqué dans la maturation de l’ARNr 18S. Nos études d’interaction avec les protéines localisées au niveau de la plateforme (à savoir RPS14, RPS26, le complexe Nob1/Pno1) ont permis de montrer que Cinap pouvait former un complexe tripartite avec l’endonucléase Nob1 et son partenaire Pno1. De plus, Cinap est capable de reconnaitre RPS26 dans un complexe RPS14-dépendant. Il est important de noter que RPS26 est un composant de la petite sous-unité qui remplace Pno1 dans le ribosome mature. De ce fait le recrutement de RPS26 au sein du pré-ribosome nécessite la dissociation de Pno1 et cet échange serait assurée par Cinap. Sur la base des travaux effectués, nous pouvons proposer un modèle de maturation où la formation du complexe Cinap/Pno1 induirait un changement de conformation permettant à Nob1 de reconnaitre son substrat et donc de catalyser la coupure du site D qui aboutit à la maturation de l’ARNr 18S et donc à la production de la sous-unité 40S mature. / Ribosomes are translational machineries universally responsible of protein synthesis. In eukaryote, ribosome assembly is a complex and highly regulated process that requires coordinated action of more than 200 biogenesis factors. Ribosome assembly is initiated in the nucleolus, continues in the nucleoplasm and terminates in the cytoplasm. The cytoplasmic maturation events of the small ribosomal subunit are associated with sequential release of the late assembly factors and concomitant maturation of the pre-rRNA. During final maturation of the small subunit, the pre-18S rRNA is cleaved off by the endonuclease Nob1, which activity is coordinated by its binding partner Pno1. Detailed information on pre-ribosomal particle architectures have been provided by structural snapshots of maturation events. However, key functional aspects such as the architecture required for pre-rRNA cleavage have remained elusive. In order to better understand these late steps of cytoplasmic pre-40S maturation, we first redefine the domain organization of Nob1, then study its binding mode with Pno1 using different tools such as sequence analysis, structure prediction and biochemical experiments and, we then performed functional assay to elucidate the role played by Pno1 during the pre-18S rRNA maturation.Our results have shown that eukaryotic Nob1 adopts an atypical PIN domain conformation: two fragments (res 1-104 and 230-255) separated by an internal loop, which is essential for Pno1 recognition. We also found out that Pno1 inhibits Nob1 activity likely by masking the cleavage site. Our findings further support the recently published cryo-EM structure of the pre-40S, where Nob1 displays an inactive conformation. Moreover, 18S rRNA 3’-end cleavage has to happen and this implies structural rearrangement or requirement of some accessory proteins such as Cinap, an atypical kinase involved in pre-18S processing. Studying the interplay between proteins localized in the pre-40S platform (RPS14, RPS26, Nob1/Pno1 complex) has shown that Cinap is able to form a trimeric complex with Nob1 and its binding partner Pno1. Furthermore, Cinap can recognize RPS26 in a RPS14-dependent manner, which had already been studied with its yeast counterpart. It is important to note that RPS26 is the ribosomal protein replacing Pno1 in the mature ribosome. Our finding clearly suggests a mechanism where RPS26 recruitment to the ribosome requires Pno1 dissociation. This exchange would be carried out by Cinap. Therefore, we can suggest a simplified model as follow: upon binding with Pno1, the newly formed complex (Cinap/Pno1) will trigger a conformational change, which will allow the endonuclease Nob1 to reach its substrate (D-site) and perform its cleavage resulting in mature 18 rRNA generation.

Systematic variation of membrane anchor, spacer and pharmacophore building blocks leads to an optimisation of the inhibitory effect of tripartite structures towards BACE1-induced cleavage of the amyloid precursor protein (APP). / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Cette thèse est destinée à appréhender le phénomène Taliban d'un autre point de vue, c'est-à-dire en tantqu'État, durant la période 1996-2001. À cet égard, nous avons utilisé la théorie d'Alain Touraine relative auxmouvements sociaux, distinguant trois grands principes caractérisant un mouvement social : l'identité, l'oppositionet la totalité, ces trois éléments étant interdépendants. Le premier chapitre de cette thèse est destiné à analysercomment les Talibans, en tant que sujet historique, ont été créés dans un contexte de guerre et d'opposition. Sontainsi successivement abordés la guerre avec l'Union soviétique, les Moudjahidins, les guerres civiles, les oppositionsrégionales et le clivage essentiel entre sunnites et chiites. Ensuite, il a été tenté de clarifier la façon dont le caractèretotalitaire de l'identité de l'Etat Taliban est renforcé par ses deux dimensions organisationnelles : l'islamisme et lepachtounisme, ce qui a conduit à confronter le régime des Talibans à la définition du modèle classique de régimetotalitaire concernant les institutions et la domination. La dernière partie aborde la question de la chute de l'EtatTaliban. La contradiction entre l'universalisme idéologique et l'existence des Talibans en tant qu'Etat a conduit àl'isolement sur la scène internationale. Les Talibans échouent par ailleurs à établir une domination intégrale enAfghanistan et se trouvent confrontés à une crise de légitimité interne ouvrant la voie à leur chute. En conclusion, ilest souligné la façon dont les Talibans ont mis en place une centralisation politique, en dépit de la profondeur desclivages tribaux et idéologiques. Pour atteindre leurs buts, ils se sont concentrés principalement sur trois éléments :l'islam fondamentaliste, la conscience nationale et tribale et l'honneur du guerrier. Finalement par le moyen de lathéorie de George Bataille, l'auteur de la présente thèse tente de préciser que les Talibans ont échoué à établir leuremprise totalitaire dans le climat hétérogène de la société afghane, malgré leurs efforts pour imposer les troiséléments d'homogénéisation susmentionnés. / In the present thesis, it is intended to survey Taliban phenomenon, as a State, during 1996-2001 from another pointof view. In this regard, it is benefitted from Alain Touraine’s theory on the function of social movements. Hedescribes the function of each movement based on three major principles: Identity, Opposition and Totality, andconsiders the three of them as being interrelated. The first chapter of the present thesis is intended to indicate howTaliban, as a historical subject, is created in the context of war and opposition. For instance, the conflict between theSoviet Union and Mujahidin, civil wars, regional oppositions, as the important cleavage of Sunni-Shiite. Afterwards,it is tried to clarify how the totalitarian aspect of Taliban’s identity is reinforced by its two significant organizingdimensions: Islamism and Pashtunism. Subsequently, we proceed to Taliban’s endeavor to establish an Islamictotalitarian state and also it is tried to reveal the assimilation between the Taliban regime and a classical model oftotalitarian regime regarding institution and domination. Dealing with the fall of Taliban state is done within the lastchapter. It is analyzed how the Taliban’s ideology of universalism confronts the national interests such as any othertotalitarian Stat. The confrontation of ideological universalism and the national interests leads to isolation and fall ofTaliban, in the international stage. Taliban even fails to establish an integral domination within Afghanistan.Therefore, Taliban is dragged into the crisis of internal legitimacy which paved the way to its fall. As a conclusion,it is dealt with how Taliban tried to create political centralization, despite the existence of effective tribal andideological cleavage. To fulfill their aim, they concentrated mainly on three elements of fundamentalist Islam, thenational and tribal consciousness and the honor of the warrior. Eventually, by the means of George Bataille’s theory,the writer of the present thesis tries to clarify that Taliban failed to establish its expected totalitarism in theheterogeneous climate of Afghan society, despite its efforts in imposing the three aforementioned homogenizingelements.

While the molecular defect that cause sickle cell disease has well been established, the cause of vaso-occlusive crisis remains elusive and largely debated upon. Majority of studies have linked the painful episodes to polymerization of sickle hemoglobin following its deoxygenation. The variability of the disease symptoms among patients, compounds efforts for a holistic therapy. Hydroxyurea, a stimulator of Hb F induction and a widely used treatment, has ameliorated the complication of SCD but it is only effective in 50% of the patients. Expression of Hb F lowers the content of Hb S in blood and hence reduces oxidative stress caused by Hb S denaturation. Sickle cell disease severity depends on several factors. Most importantly, the ability of red cell to sickle dominates all other determinants. While deoxygenation of sickle hemoglobin may be inevitable, the duration with which the red cell remains in the deoxygenated state can be manipulated. Deoxygenation is a transient process that when compared to the time taken to develop the long filaments of deoxyhemoglobin to causes severe sickling, the red cell would have been cycled back to the lungs and re-oxygenated to restore the healthy conditions of the cell. In fact, if sickle cells would flow as fast as healthy erythrocytes, the detrimental impacts of sickling such as vaso-occlusive crisis, would not be a concern for this disease. Unfortunately, the unstable sickle hemoglobin undergoes denaturation through auto-oxidation, which imposes oxidative stress to the cells. The oxidative stress inhibits erythrocytes tyrosine phosphatases, a course which subsequently impair their constitutive action against the tyrosine kinases. In the end, a net tyrosine phosphorylation state in the red cell membrane proteins, most notably the transmembrane protein band 3, succeeds. Band 3 tyrosine phosphorylation abrogates the protein’s interaction with ankyrin and spectrin-actin cytoskeleton, hence the cytoskeleton loses its major anchorage to the membrane thus engendering membrane destabilization. A destabilized erythrocyte sheds membrane fragments in form of microvesicles/microparticles and discharges free hemoglobin into the extra cellular matrix. In consequence, the microparticles power initiation of coagulation cascade through activation of thrombin, while free Hb inflicts inflammation, scavenges nitric oxide which is necessary for vasodilation and induces further oxidative stress within the microvasculature, and activates expression of adhesion receptors on the endothelium. Taken together, these events culminate in entrapment of red cells (not naming leucocytes and platelets) in the microvasculature, blockade of blood vessels and further damage of erythrocytes through prolonged deoxygenated state thus terminating in tissue injury, strokes, and organ damage, amid vaso-occlusive episodes which always require hospitalization and extensive medical care for survival. Band 3 tyrosine phosphorylation and membrane weakening is not unique just to SCD, but also a druggable target for malaria. Malaria, a disease that is touted as the evolutionary cause of sickle cell disease, surprisingly thrives through the same mechanism. Briefly, malaria parasite consumes hemoglobin for its DNA synthesis, and in the process generate reactive oxygen species from denatured hemoglobin that feeds into the oxidative stress which triggers band 3 tyrosine phosphorylation. In this case however, a destabilized membrane offers perfect conditions for merozoites’ (malaria daughter parasites) egress/exit out of the cell to begin infecting other red cells. Ultimately, the ensuing anemia and organ dysfunction leads to patient’s death. Treatment of diseased cells with imatinib and other Syk inhibitors effectively reversed membrane weakening. A stabilized membrane not only survives longer in circulation to alleviate SCD symptoms but also traps and starves malaria parasite leading to termination of the parasitic infection. With band 3 tyrosine phosphorylation at center stage, this dissertation explores the above events in an effort to unveil a novel therapy for sickle cell and malaria diseases. First, the therapeutic strategy regarding SCD is discussed in detail beginning with non-transfused patients and ending in additional mechanistic study on inactivation of the principal erythrocyte’s protein tyrosine phosphatase 1 B, PTP1B. The dissertation then provides an initial proof of concept on efficacy of imatinib in treatment of malaria as a monotherapy and its efficacy when used in a triple combination therapy with the standard of care treatment. Finally, I outline an alternative possible mechanism of action of quinine against malaria.