La question de la mémoire et de l’identité est au centre des débats contemporains. La guerre d’Algérie représente l’un des cas où cette question est encore particulièrement brûlante, d’où la nécessité d’y revenir. La confrontation entre les mémoires plurielles des communautés impliquées par le conflit algérien a opposé une mémoire à l’autre, une identité à l’autre. Comment la littérature a-t-elle traduit ces conflits mémoriels et identitaires? À travers l’analyse de la production littéraire de trois écrivains d’origine algérienne exilés en France, ce travail étudie l’inscription du sujet identitaire et mémoriel à l’intérieur de la littérature algérienne francophone des années 70 et 80. Cette littérature, loin de constituer l’apanage exclusif des auteurs arabo-berbères, s’est enrichie grâce aux apports pluriels des auteurs pieds-noirs et juifs d’Algérie. Mettre en comparaison les ouvrages d’auteurs issus de milieux algériens différents permet de s’interroger sur la pluralité de cette littérature. Si le premier chapitre introduit théoriquement le sujet de l’identité, le deuxième illustre la manière dont les enjeux identitaires déterminent les questions mémorielles et historiques concernant l’Algérie contemporaine. Le troisième chapitre analyse la genèse et le développement de la littérature algérienne francophone, surtout de la littérature judéo-maghrébine et de la littérature pied-noir. Le dernier chapitre présente une analyse comparative des textes du corpus: Dieu en barbarie (1971) et Le maître de chasse (1973) de Mohammed Dib; Frimaldjézar (1976) et L’échelle de Mesrod (1984) d’Albert Bensoussan; Maman la Blanche (1981) et Alger l’amour (1982) d’Alain Vircondelet / The main aim of this research is to study the evolution of Algerian Francophone literature after independence proposing a new classification criterion which goes beyond the concept that North African literature in French language only consists of authors whose mother tongue is Arabic or Berber. The panorama of Algerian Francophone literature is indeed characterized by an extremely heterogeneous variety of productions: it is not only Arab and Berber authors who produce a remarkable literature, but Jewish and Pieds-Noirs writers as well. This study focuses on the plurality of the Algerian Francophone literature, highlighting the characteristics of every single cultural-specific production, i.e. the Arab-Berber, the Jewish and the Pied-Noir one, and asserting that each one has an overall consistency. The analysis is actually based on the hypothesis that every literary production presents specific thematic and stylistic levels, so that no one is reducible to another. The examined corpus consists of six novels written in French by writers born in Algeria during the colonization and exiled in France after 1962, each of them belonging to a specific cultural group: the Jewish writer Albert Bensoussan (Frimaldjézar, 1976, and L’échelle de Mesrod, 1984), the Pied-Noir novelist Alain Vircondelet (Maman la blanche, 1981, and Alger l’amour, 1982) and the Arab writer Mohammed Dib (Dieu en barbarie, 1971, and Le maître de chasse, 1973)

La lombalgie liée à la dégénérescence du disque intervertébral (DIV) est un problème majeur de santé publique touchant une large proportion de nos populations vieillissantes. Actuellement, la prise en charge de cette maladie est essentiellement symptomatique mais grâce à de récentes découvertes, les processus de dégénérescence discale sont aujourd'hui mieux compris. Ces nouvelles connaissances permettent d'envisager de nouvelles stratégies thérapeutiques. Parmi ces stratégies et afin de répondre aux stades précoces de cette maladie, une attention particulière est portée sur les stratégies impliquant l’injection intradiscale de facteurs de croissance tels que le GDF-5 ou le TGF-β1, ciblant les processus de dégénérescence du DIV. En dépit de résultats encourageants concernant la sécurité d’utilisation et la tolérance clinique de ces facteurs de croissance, leur efficacité clinique doit encore être amélioré. Pour cela, l’utilisation de biomateriaux permettant une libération prolongée et la protection des facteurs de croissance, présente un intérêt majeur. Ce travail de thèse a donc pour objectif le développement de systèmes à libération prolongée de ces deux facteurs de croissance. Pour ce faire, deux biomatériaux ont été étudiés : les nanofibres de silice et les microbilles de pullulane. Pour ces deux matériaux, leurs synthèses et caractérisations ont été réalisées avant de s'intéresser à leur potentiel d'adsorption et de libération des facteurs de croissance. Les résultats obtenus sont tres encourageants puisqu’ils montrent une libération prolongée jusqu’a 28 jours in vitro avec un maintien de l’activité biologique des facteurs de croissance libérés. L’ensemble des données de cette thèse suggère le potentiel prometteur des systèmes présentés pour le développement de stratégies innovantes pour la médecine régénératrice DIV. / Low back pain caused by the intervertebral disc (IVD) degeneration is a major health concern affecting a large proportion of our aging populations. While current treatments of this disease are mainly symptomatic, recent discoveries have allowed a better understanding of the degenerative processes and new therapeutic strategies have been envisioned. Among these strategies, there is a growing interest for approaches aiming a tackling early stages of this disease, involving the intradiscal injection of growth factors such as GDF-5 or TGF-β1, able to target IVD degenerative processes. However, despite encouraging results regarding the safety and clinical tolerance of these growth factors, their clinical efficacy has to be further improved. To this end, the use of biomaterials allowing the sustained release and the protection of growth factors is of particular interest. The objective of this thesis is thus to develop systems able to deliver these two growth factors in a long period of time. Therefore, two biomaterials were studied: silica nanofibers and pullulan microbeads. For both materials, their syntheses and characterizations were studied, as well as their potential use for growth factors adsorption and release. Promising results were obtained demonstrating a sustained release for up to 28 days in vitro, while maintaining the released growth factors biological activity. Altogether, these data suggest that these newly designed systems may be promising candidates for the development of innovative strategies for the IVD regenerative medicine.

The neurotransmitters serotonin (5-HT) and dopamine (DA) play roles in eating disorders, mood disorders, such as depression and anxiety, and in the regulation of locomotion. The 5-HT2C receptor is one of fourteen 5-HT receptor subtypes that is expressed in regions of the brain including the hippocampus, amygdala, dorsal striatum, nucleus accumbens (NA) and substantia nigra, and is therefore implicated in behaviours and disorders associated with these regions. 5-HT has been shown to exert both a tonic and phasic inhibitory control, through the 5-HT2C receptor, on the firing rate and bursting activity of DA-containing neurones in the ventral tegmental area which enhances DA release in the NA and prefrontal cortex. In addition, the 5-HT2C receptor is under the control of a monophasic diurnal rhythm and is in a position to alter circadian regulation and behaviour due to its expression in the suprachiasmatic nucleus (the light entrainable oscillator (LEO)). It was hypothesised that elevating expression of the 5-HT2C receptor would have a detrimental effect on mood and cause hypolocomotion while reducing 5-HT2C receptor expression would improve mood, cause hyperphagia, obesity and hyperlocomotion. In order to investigate these hypotheses mouse models that either over- or under-expressed the 5-HT2C receptor were implemented. The 5-HT2C receptor expression pattern and levels were confirmed in all mouse lines. A behavioural phenotype of hypolocomotion and increased anxiety in the 5-HT2C receptor over-expressing mice and hyperphagia, obesity and hyperlocomotion in the 5-HT2C receptor under-expressing mice were found the latter is conistent with current literature. During backcrossing of the mouse lines onto the C57Bl/6 genetic background the abnormal behavioural phenotypes were lost suggesting that 5-HT2C receptor function is particulary sensitive to the genetic background on which it is being expressed. In response to altered expression levels of 5-HT2C receptor, compensatory alterations were found in the 5-HT system, with an inverse relationship existing between both the 5-HT1A receptor mRNA expression levels and 5-HT release in the hippocampus with the expression levels of the 5-HT2C receptor. Over-expression of 5-HT2C receptor appears to inhibit DA release in the cortex. The circadian experiments showed that under-expressing the 5-HT2C receptor did not alter the regulation of the food entrainable oscillator and there was a suggestion that the regulation of the LEO was affected. In summary, these results demonstrate that altered expression of 5-HT2C receptors results in abnormal behaviours consistent with its role in psychiatric disorders, but that the outcome is dependent on the genetic background.

This thesis is focused on the development and utilisation of chemical and biological tools to probe the function of modified bases in DNA with specific exploration of the less well-studied T-modifications: 5-hmU, 5-fU and Base J. LCMS/MS techniques are first utilised to enable the accurate global quantification of T-modifications (5-hmU, 5-fU and Base J) in both trypanosomatids and mammalian DNA. A chemical affinity-enrichment sequencing method for the T-modifications is next described, which allows their chemoselective tagging over their C-modification counterparts. DNA fragments containing 5-fU are selectively tagged and enriched via oxime, hydrazine or benzimidazole formation using a biotinylated probe, and DNA fragments containing 5-hmU can be first chemically oxidised to 5-fU using KRuO4. .Proof-of-principle T-modification enrichment is demonstrated by DNA sequencing. In the following chapter, sequencing methods are employed to investigate the role of T-modifications in both trypanosomatids and mammalian samples. In T.Brucei, Base J formation is probed by artificial incorporation of 5-hmU and subsequent Base J chemical sequencing. Base J is preferentially formed or depleted at certain genomic loci; suggesting that Base J formation is sequence-specific. This may imply a distinct role for the 5-hmU sites which are not further glucosylated. Next, 5-hmU enrichment sequencing is performed in SMUG1 knockdown HEK293T cells to determine the genomic location of 5-hmU in mammals. An increase in 5-hmU loci is observed upon SMUG1 knockdown. 5-hmU enriched regions are found to be T-rich and depleted in exons and promoters. Furthermore, 5-hmU sites show poor overlap with known TET-enzyme binding sites, indicating that 5-hmU is formed via a TET-independent mechanism in HEK293T cells. Next, mass spectrometry-based proteomics studies are utilised to determine 5-fU protein-binders in mammals. Pulldown of proteins using biotinylated baits enables the identification of proteins which are enriched or suppressed in the presence of the 5-fU modification compared to a non-modified control. Enriched proteins include those associated with DNA-damage, consistent with the current understanding that 5-fU is a product of oxidative damage in mammalian DNA. Finally, a mechanistic insight into the effect of formylated bases on nucleosomal structure is described. Schiff base formation between formylated nucleobases and histone protein lysine side-chains is demonstrated. This provides a molecular mechanism for the association of 5-fC with increased nucleosomal occupancy in vivo.

Lors du sommet extraordinaire qui s’est déroulé à Barcelone en novembre 1995, vingt-cinq pays de l’Union Européenne et douze pays méditerranéens ont décidé de lancer un partenariat global euro-méditerranéen, l’idée des partenaires étant d’arriver à tourner une page de rupture qui a marqué les relations entre les deux rives pendant plusieurs années. En effet, ce pont, érigé sur une mer où, de part et d’autre, on assiste à un nombre croissant de tensions et de conflits, a constitué l’unique enceinte de dialogue et d’échanges entre les États du bassin méditerranéen. Malgré la domination des Européens en matière de décisions, ce choix demeure inéluctable pour le bon voisinage dans la région.Toute fois, sans un réel engagement de la part des deux partenaires méditerranéens, notamment la forte implication de l’Union Européenne pour construire un véritable projet d’intégration régionale, le processus euro-méditerranéen risque de se trouver dans la corbeille de l’histoire humaine. / At the time of the extraordinary summit which proceeded in Barcelona in November 1995, twenty-five countries of the European Union and twelve Mediterranean countries decided to launch a euro-Mediterranean total partnership, the idea of the partners being to manage to turn a page of rupture which marked the relations between two banks during several years. Indeed, this bridge, set up on a sea where, on both sides, one attends a growing number of tensions and conflicts, constituted the single enclosure of dialogue and exchanges between the States of the Mediterranean basin. In spite of the domination of Europeans as regards decisions, this choice remains inescapable for the good neighborhood in the area. Any time, without a real engagement on behalf of the two Mediterranean partners, in particular the strong implication of the European Union to build a true project of regional integration, the euro-Mediterranean process is likely to be in the basket of the human history.

The 5-hydroxytryptamine (5-HT) system modulates numerous physiological and behavioural processes, and dysfunction within this system underlies many behavioural disorders, such as major depression. The 5-HT1A receptor is the primary somatodendritic autoreceptor that controls the firing rate of 5-HT neurons, but is also coupled to numerous signalling pathways. An understanding of 5-HT1A receptor signalling may lead to the development of antidepressant drugs that selectively target therapeutic pathways in treating depression. The 5-HT1A receptor is coupled to inhibitory G-proteins via its intracellular loops 2 and 3. Point mutations within these loops selectively uncouple receptor signalling pathways. In this thesis, I addressed whether mutant receptors’ uncoupling from signalling pathways is associated with alteration in G-protein interaction and coupling. Using bioluminescence resonance energy transfer (BRET) to monitor receptor-G-protein interactions, we show that both wild-type and mutant receptors demonstrate a saturable interaction with Gαi protein in unstimulated conditions. Addition of 5-HT increased the BRET signal for the wild-type 5-HT1A receptor, and this increase was blocked by a 5-HT1A receptor antagonist and G-protein blocker (pertussis toxin). Mutant receptors that were deficient in Gαi signalling, but not those that still signalled to Gαi, failed to respond to receptor activation with increased receptor-Gαi interaction. Pull down studies verified the basal and agonist-induced interaction of 5-HT1A receptors with Gαi proteins. In conclusion, we have shown that the 5-HT1A receptor interacts with Gαi consistent with a pre-coupled model and that 5-HT-induced activation enhances this interaction and requires specific residues in the intracellular loops.

The 5-hydroxytryptamine (5-HT) system modulates numerous physiological and behavioural processes, and dysfunction within this system underlies many behavioural disorders, such as major depression. The 5-HT1A receptor is the primary somatodendritic autoreceptor that controls the firing rate of 5-HT neurons, but is also coupled to numerous signalling pathways. An understanding of 5-HT1A receptor signalling may lead to the development of antidepressant drugs that selectively target therapeutic pathways in treating depression. The 5-HT1A receptor is coupled to inhibitory G-proteins via its intracellular loops 2 and 3. Point mutations within these loops selectively uncouple receptor signalling pathways. In this thesis, I addressed whether mutant receptors’ uncoupling from signalling pathways is associated with alteration in G-protein interaction and coupling. Using bioluminescence resonance energy transfer (BRET) to monitor receptor-G-protein interactions, we show that both wild-type and mutant receptors demonstrate a saturable interaction with Gαi protein in unstimulated conditions. Addition of 5-HT increased the BRET signal for the wild-type 5-HT1A receptor, and this increase was blocked by a 5-HT1A receptor antagonist and G-protein blocker (pertussis toxin). Mutant receptors that were deficient in Gαi signalling, but not those that still signalled to Gαi, failed to respond to receptor activation with increased receptor-Gαi interaction. Pull down studies verified the basal and agonist-induced interaction of 5-HT1A receptors with Gαi proteins. In conclusion, we have shown that the 5-HT1A receptor interacts with Gαi consistent with a pre-coupled model and that 5-HT-induced activation enhances this interaction and requires specific residues in the intracellular loops.

The 5-hydroxytryptamine (5-HT) system modulates numerous physiological and behavioural processes, and dysfunction within this system underlies many behavioural disorders, such as major depression. The 5-HT1A receptor is the primary somatodendritic autoreceptor that controls the firing rate of 5-HT neurons, but is also coupled to numerous signalling pathways. An understanding of 5-HT1A receptor signalling may lead to the development of antidepressant drugs that selectively target therapeutic pathways in treating depression. The 5-HT1A receptor is coupled to inhibitory G-proteins via its intracellular loops 2 and 3. Point mutations within these loops selectively uncouple receptor signalling pathways. In this thesis, I addressed whether mutant receptors’ uncoupling from signalling pathways is associated with alteration in G-protein interaction and coupling. Using bioluminescence resonance energy transfer (BRET) to monitor receptor-G-protein interactions, we show that both wild-type and mutant receptors demonstrate a saturable interaction with Gαi protein in unstimulated conditions. Addition of 5-HT increased the BRET signal for the wild-type 5-HT1A receptor, and this increase was blocked by a 5-HT1A receptor antagonist and G-protein blocker (pertussis toxin). Mutant receptors that were deficient in Gαi signalling, but not those that still signalled to Gαi, failed to respond to receptor activation with increased receptor-Gαi interaction. Pull down studies verified the basal and agonist-induced interaction of 5-HT1A receptors with Gαi proteins. In conclusion, we have shown that the 5-HT1A receptor interacts with Gαi consistent with a pre-coupled model and that 5-HT-induced activation enhances this interaction and requires specific residues in the intracellular loops.

Zugl.: Berlin, Freie Universiẗat, Diss., 2008.

The 5-hydroxytryptamine (5-HT) system modulates numerous physiological and behavioural processes, and dysfunction within this system underlies many behavioural disorders, such as major depression. The 5-HT1A receptor is the primary somatodendritic autoreceptor that controls the firing rate of 5-HT neurons, but is also coupled to numerous signalling pathways. An understanding of 5-HT1A receptor signalling may lead to the development of antidepressant drugs that selectively target therapeutic pathways in treating depression. The 5-HT1A receptor is coupled to inhibitory G-proteins via its intracellular loops 2 and 3. Point mutations within these loops selectively uncouple receptor signalling pathways. In this thesis, I addressed whether mutant receptors’ uncoupling from signalling pathways is associated with alteration in G-protein interaction and coupling. Using bioluminescence resonance energy transfer (BRET) to monitor receptor-G-protein interactions, we show that both wild-type and mutant receptors demonstrate a saturable interaction with Gαi protein in unstimulated conditions. Addition of 5-HT increased the BRET signal for the wild-type 5-HT1A receptor, and this increase was blocked by a 5-HT1A receptor antagonist and G-protein blocker (pertussis toxin). Mutant receptors that were deficient in Gαi signalling, but not those that still signalled to Gαi, failed to respond to receptor activation with increased receptor-Gαi interaction. Pull down studies verified the basal and agonist-induced interaction of 5-HT1A receptors with Gαi proteins. In conclusion, we have shown that the 5-HT1A receptor interacts with Gαi consistent with a pre-coupled model and that 5-HT-induced activation enhances this interaction and requires specific residues in the intracellular loops.