Short summary: Background: High cardiovascular risk in patients with chronic kidney disease is partly due to mineral dysbalance, microinflammation and oxidative stress. CKD patients accumulate traditional and non-traditional CV risk factors. FGF23, MMPs and PlGF belong among these non-traditional biomarkers of CV risk. FGF23 is a phosphaturic hormone and inhibitor of calcitriol synthesis. It is associated with vascular calcifications. Matrix-metalloproteinases (e.g. MMP-2, MMP-9) are proteolytic, proinflammatory enzymes, contributing to myocardial remodelation. Placental growth factor (PlGF) is a proangiogenic cytokine that is associated with LV hypertrophy in animal model. Plasmatic FGF23, MMPs and PlGF are elevated in CKD. Aim: We aimed to describe dynamic changes between several novel biomarkers of CV risk (FGF23, MMP-2, MMP-9 and PlGF) in CKD stages 1-5, to describe their mutual correlations and possible association with traditional CV risk markers. We studied possible association of laboratory and echocardiographic parameters in patients with CKD stages 2-4. Methods: In a cross-sectional study we evaluated 80 patiens with CKD 1-5 and 44 healthy controls. In a prospective study we evaluated echocardiographic and laboratory parameters in 62 patients with CKD 2-4 for an average study period of 36±10...

Type II diabetes mellitus is associated with many detrimental health situations including heart complications. The purpose of this study was to identify a role for PKA-dependent Rap1a signaling in the AGE-RAGE cascade. My hypothesis was Rap1a GTPase increased the downstream effects of AGE-RAGE signaling in diabetes via a PKA-dependent pathway leading to elevated ECM remodeling in the heart. Cardiac fibroblasts were isolated from heterozygous (Het) and diabetic (db/db) mice. To test the hypothesis, gain-ofunction and loss-ofunction treatments were used. PKC-Zeta is known as a major signaling hub that potentially links PKA-dependent and AGE-RAGE signaling cascades so PKC-Zeta inhibition to downregulate PKA-dependent cascade at PKC-Zeta was also used. Results showed a downregulation of signaling markers in the AGE-RAGE cascade when disrupting Rap1a crosstalk at PKC-Zeta. By understanding where the PKA-dependent and AGE-RAGE signaling cascades crosstalk, a new molecular mechanism is understood possibly leading to decreasing remodeling in a diabetic heart.

Tableau d'honneur de la Faculté des études supérieures et postdoctorales, 2006-2007 / La sociocritique issue des travaux de Claude Duchet relève d'un certain paradoxe, dans la mesure où elle tente à la fois de voir comment le texte littéraire est immergé dans son contexte de production et comment il peut intervenir sur celui-ci en opérant une transformation du discours par le biais d'un travail esthétique. La théorie du discours social de Marc Angenot et la socio-poétique de Régine Robin, deux approches qui relèvent de la sociocritique, incarnent bien ce dilemme. C'est par l'analyse d'une œuvre littéraire québécoise contemporaine, La rage de Louis Hamelin, que nous désirons examiner les facettes de cette confrontation. Lui-même profondément ambivalent, le premier roman de Hamelin se révèle une œuvre de choix pour explorer cette problématique qui a déjà alimenté bon nombre de débats chez les sociocriticiens.

This study followed a qualitative research approach, and semi-structured interviews regarding the subject matter were conducted with the knowledgeable and experienced respondents in the Gauteng traffic-related departments. A literature review was also conducted to provide a comprehensive understanding of the research problem in both local and international context. The research stresses the fact that motorists are continuing to lose their lives on Gauteng province, as a result of violent traffic disputes, therefore people suffer financial, physical, psychological as well as social effects as a consequence of such actions. The findings revealed that all the traffic stakeholders are working cooperatively towards implementing the crime prevention strategic plans, but for policing road rage in particular there is no specific strategy in action. In addition, this study reveals that it is impossible for the traffic police to curb road rage incidents because the latter occur as a result of unpredictable human behavior. / Police Practice / M. Tech. (Policing)

This study followed a qualitative research approach, and semi-structured interviews regarding the subject matter were conducted with the knowledgeable and experienced respondents in the Gauteng traffic-related departments. A literature review was also conducted to provide a comprehensive understanding of the research problem in both local and international context. The research stresses the fact that motorists are continuing to lose their lives on Gauteng province, as a result of violent traffic disputes, therefore people suffer financial, physical, psychological as well as social effects as a consequence of such actions. The findings revealed that all the traffic stakeholders are working cooperatively towards implementing the crime prevention strategic plans, but for policing road rage in particular there is no specific strategy in action. In addition, this study reveals that it is impossible for the traffic police to curb road rage incidents because the latter occur as a result of unpredictable human behavior. / Police Practice / M. Tech. (Policing)

Amyloid beta (Aβ) has been postulated to be the principle initiator of the pathogenesis of Alzheimer’s disease (AD). Therefore, understanding the underlying mechanisms of Aβ induced neurotoxicity in the early stages of AD would be essential for finding potential therapeutic targets of AD. Aβ-binding alcohol dehydrogenase (ABAD) has been shown to be a mitochondrial binding site for Aβ. Expression of ABAD has been found to be increased in brains of AD sufferers. Two dimensional electrophoresis studies have revealed that endophilin 1 was upregulated in Tg mAPP/ABAD mice brains as compared to Tg mAPP, Tg ABAD and non-Tg mice brains. Increased expression of endophilin 1 has also been found in brains of AD patients as compared to non-demented control brain tissues. Endophilin1 has been reported to regulate c-Jun N-terminal kinase (JNK) activation. In this study, expression of dominant negative forms of endophilin 1 (DN-endophilin 1) in mouse cortical neurons exhibited a significant reduction of Aβ induced JNK activation. Furthermore, using cell counting methods, it was shown that the transfection of DN-endophilin 1 increased neuron survival after Aβ treatment. Aβ has also been proposed to disrupt the interaction of ABAD and Cyclophilin D (CypD), which would trigger mitochondrial permeable transition, thereby leading to neurotoxicity. For fluorescence resonance energy transfer (FRET) analysis of the interaction of ABAD and CypD, a mitochondria targeted, EYFP tagged ABAD plasmid (pMito-ABAD-EYFP) and an ECFP tagged CypD (pCypD-ECFP) plasmid were developed. Positive FRET signals in SK-N-SH cells co-expressing pMito-ABAD-EYFP and pCypD-ECFP indicated that ABAD interacts with CypD in the mitochondria of mammalian cells. RAGE (receptor for advanced glycation end products) has been reported to bind to Aβ and mediate the toxic effects of Aβ peptides on neurons and microglia. It has been shown previously that Tg mAPP/DN-RAGE mice display preserved cognitive function as compared to Tg mAPP mice. To investigate possible mechanisms involved in rescuing cognitive function by RAGE blockage, two dimensional electrophoresis was used to analyze differential protein expression between Tg mAPP and Tg mAPP/DN-RAGE mice cortex. Altered expression of four proteins, including NADH dehydrogenase flavoprotein 2 (NDUFV2), glyoxalase 1 (GLO1), proteasome subunit beta type 4 (PSMB4, or β7 subunit of proteasome) and nitrilase family, member 2 (Nit2) have been observed between Tg mAPP/DN-RAGE mice cortex and Tg mAPP mice cortex. NDUFV2 is a 24kDa subunit of complex 1 which is involved in ATP synthesis. GLO1 is a cytosolic enzyme that plays a role the glutathione-dependent detoxification of α-oxoaldehydes, such as methylglyoxal. PSMB4 is a subunit of the 26s proteosome which is in the degradation of ubiquitinylated proteins. The function of Nit2 is still unclear.

This dissertation assesses rage and its utility for fictional Black girls and adolescents in asserting their humanity, accessing their voices, and developing strategies of resistance that contribute to their identity formation. Through analyses of six novels: 1) God Bless the Child, 2) Breath, Eyes, Memory, 3) The Hate U Give, 4) The Bluest Eye, 5) Daddy Was a Number Runner, and 6) The Poet X, this research presents rage as a canonical theme in Black women’s coming-of-age narratives and presents connections between rage, rights, and resistance. The connections, revealed through stimuli and adaptations associated with rage, frame an argument for North Americas as an arbiter of anger. The novels construct an “arc of anger” that places them in conversation about Black girl rage and presents a tradition of Black women crafting Black girl protagonists who are conduits for counternarratives of rage. This dissertation also examines how history, memory, and culture contribute to Black girls’ frustrations and knowledge bases. By looking to works published between the angry decade (the 1960s) and the age of rage (the 2010s), the research presents ways Black women novelists and their characters return to rage to combat social institutions and critique social constructions of Black girlhood and womanhood.

This dissertation addresses the phenomenon of 'radical commodities'-commercial products which advance an oppositional politics. Examples of such include the products of Rage Against The Machine, a 'revolutionary' rock band; Michael Moore, a best-selling author and award-winning documentary filmmaker; Naomi Klein, a journalist and author of the international bestseller No Logo; The Body Shop, a multinational manufacturer and retailer of 'natural' cosmetics and toiletries; Freitag, a company which manufactures bags, wallets and other fashionable accessories from recycled materials, and; the Adbusters Media Foundation, publisher of Adbusters magazine and producer of Blackspot shoes. Radical commodities are fundamentally paradoxical objects whose apparent ethic would appear to be at odds with the fact that they are commodities. This dissertation asks: can a commodity-object legitimately serve as a vehicle for social and political critique? It is reasoned that the problem of radical commodities is principally structural. Marx's seminal writings on the commodity accordingly represent the logical point of departure. The Marxian analysis illuminates not only the commodity-structure, but also the political problematic which emerges from that structure-for Marx, the commodity is a mechanism of exploitation. From an orthodox Marxist perspective, the idea of a radical commodity would therefore be most contradictory, or indeed impossible. It is argued, however, that the Marxian analysis is inconclusive. This dissertation traces a genealogy of analyses of the commodity, which variously advance or diverge from the orthodox Marxist position. From a perspective of the consumption of commodity-objects, the radical commodity would appear to be possible. Yet, the relationship between the commodity-structure and the capitalist ideology runs deep. The question of the radical commodity is therefore markedly more complex than it might initially appear. With regard to the ideological consequence of the commodity-structure, however, certain streams of post-Marxist analysis are themselves problematic, for they ultimately short-circuit historical critique and destabilise the very possibility of politics. In contrast, this dissertation seeks to reaffirm a place for politics and, in so doing, to establish the theoretical possibility of radical commodities. To contend that the idea of a radical commodity is not fundamentally contradictory, however, says nothing of the political potency of such objects. These are undoubtedly complex objects, whose peculiarities cannot be ascertained by abstract theorisation alone. For this reason, this dissertation also employs empirical analyses of a number of radical commodities. In sum, it is argued that the sphere of commodities should be admitted as a possible site for the expression or implementation of a radical politics, and thus that radical commodities should be understood as a legitimate vehicle for social and political critique, but that such objects are by no means free from contradiction, and that the political efficacy of these products is anything but guaranteed.

Les vaisseaux sanguins sont composés de cellules enchâssées dans la matrice extracellulaire (MEC). Certaines interactions entre les cellules et les composés de la MEC sont impliquées dans plusieurs changements pathologiques et physiologiques au niveau de la paroi artérielle. L'hypertension systolo-diastolique provoque deux formes de remodelage vasculaire : hypertrophique dans les artères de conductance et eutrophique dans les artères de résistance. Les mécanismes régissant le remodelage eutrophique ne sont pas encore bien éclaircis. Afin de les étudier, nous avons utilisé un modèle d'hypertension systolodiastolique induite par l'inhibition de la synthèse de monoxyde d'azote. Nous avons démontré que la contribution des protéines de désadhésion semblait différer d'un type de remodelage à l'autre et que les métalloprotéinases matricielles (MMPs) ne jouaient pas un rôle crucial dans le développement du remodelage eutrophique, contrairement au remodelage hypertrophique. Au cours du vieillissement, on observe des modifications de la paroi vasculaire des artères de conductance, augmentant leur rigidité : une fragmentation des fibres élastiques, leur calcification (élastocalcinose), une augmentation des liens covalents entre les protéines de la MEC et une fibrose. Cette rigidité conduit au développement de l'hypertension systolique isolée. Afin d'évaluer l'implication des MMPs dans la fragmentation de l'élastine et leur rôle dans le développement de l'élastocalcinose, nous avons utilisé un modèle animal d'élastocalcinose basé sur l'inhibition de la maturation de la matrix Gla protein (MGP), une protéine anti-calcifiante, par la warfarine. Nous avons observé une augmentation rapide et transitoire de l'activité de la MMP-9, suivie de l'activation du transforming growth factor-ß (TGF-ß). L'inhibition de l'activité des métalloprotéinases et de TGF-ß a permis de prévenir l'élastocalcinose. Par ailleurs, l'élastocalcinose est accélérée par le diabète. Cette accélération est reliée à la durée et à la sévérité du diabète. Or, ce dernier est associé à une augmentation de la synthèse des produits avancés de glycation (AGEs) pouvant former des liens covalents iv entre les protéines de la MEC. Ne disposant pas de modèle animal pour étudier l'implication des AGEs dans l'élastocalcinose associée au diabète, nous en avons créé un. Dans ce modèle, le diabète est induit par une diète riche en lipides et une injection de streptozotocine (30 mg/kg/jr). L'élastocalcinose est provoquée par l'inhibition de la maturation de la MGP. Nous avons observé une accélération de l'élastocalcinose, liée à la durée du diabète, et une accumulation de AGEs dans la paroi des artères fémorales. L'utilisation de pyridoxamine, un inhibiteur de la formation des AGEs, et de l'ALT711, un briseur des liaisons covalentes formées par les AGEs, a permis de prévenir et de limiter, respectivement, la calcification dans ce modèle. En outre, nous avons montré que la stimulation du récepteur des AGEs (RAGE), pouvait être impliquée dans l'élastocalcinose et élucidé certains éléments de signalisation dans ce processus. Ces travaux ont fait émerger le rôle des MMPs, de TGF-ß et des produits avancés de glycation dans le remodelage hypertrophique et l'élastocalcinose associée ou non au diabète. Ceux-ci sont reliés à l'apparition de l'hypertension systolo-diastolique et systolique isolée, respectivement. L'inhibition de ces acteurs pourrait constituer de nouvelles thérapies anti-hypertensives.

Le virus de la rage appartient à l'ordre des Mononegavirales. Ces virus sont enveloppés, et leur génome est<br />composé d'une seule molécule d'ARN de polarité négative. Dans le cas du virus de la rage, cet ARN encode<br />cinq protéines virales dont la nucléoprotéine (N) qui est fortement impliquée dans la réplication et la<br />transcription du virus. L'objectif de mon travail de thèse consistait à obtenir des informations structurales à<br />la meilleure résolution possible sur la nucléoprotéine (N) du virus de la rage, ceci afin de mieux comprendre<br />les mécanismes impliqués dans la multiplication virale. La nucléoprotéine existe sous deux formes : en<br />complexe « soluble » avec la phosphoprotéine (P), ou associée à l'ARN viral. Le complexe N-ARN viral est<br />la matrice utilisée par l'ARN-polymérase pour effectuer la transcription et la réplication. Il est possible de<br />produire de manière recombinante des complexes N-ARN en forme d'anneaux composés d'un nombre de<br />nucléoprotéines allant de 9 à 15 sous-unités par complexe. La mise au point d'une technique biochimique<br />pour purifier ces différentes espèces suivie d'études en microscopie électronique et en cristallographie aux<br />rayons X ont conduit à l'obtention d'un modèle atomique à une résolution de 3.5 Å. L'ultrastructure du<br />complexe dont la structure a été résolue est formée par l'association entre 11 nucléoprotéines et un brin<br />d'ARN de 99 bases. Il s'agit de la première structure de nucléoprotéine d'un virus à ARN négatif associée à<br />son substrat, l'ARN. Cette structure permet de constater que la nucléoprotéine séquestre étroitement l'ARN<br />limitant ainsi la formation d'ARN double brin et le protégeant de la réponse immunitaire innée. Pour devenir<br />accessible à la polymérase virale, l'ARN génomique du virus de la rage doit être dissocié localement de<br />quelques protomères de nucléoprotéine. Ce mode de fonctionnement spécifique existe probablement pour<br />d'autres virus comme celui de la rougeole, Ebola ou la grippe, responsables eux aussi de pathologies<br />humaines graves. La nucléoprotéine est une cible antivirale intéressante puisqu'elle n'existe qu'au sein des<br />virus.