O RAGE é um receptor transmembrana, imunoglobulina-like que existe em múltiplas isoformas e interage com um amplo repertório de ligantes extracelulares. O RAGE é expresso em níveis baixos na maioria das células, porém o aumento da presença de seus ligantes no domínio extracelular faz com que o RAGE inicie uma cascata de sinalização intracelular complexa, resultando em estresse oxidativo, ativação do fator de transcrição NF-B, aumento da expressão de citocinas, além da indução de sua própria expressão. O envolvimento do RAGE neste amplo espectro de sinalização vincula este receptor a diversas condições patológicas. Nesta tese utilizamos 3 modelos experimentais que induzem inflamação sistêmica (Leishmania amazonensis, Lipopolissacarídeo e sepse) e 1 modelo experimental que mimetiza a denervação neuronal (modelos experimentais in vivo). Além disso utilizamos diferentes abordagens de bloqueio do RAGE a fim de elucidar a função deste receptor. Com base em nossos resultados os modelos experimentais foram eficientes em induzir o aumento do RAGE e sua sinalização no sistema nervoso central, desencadeando a síntese e liberação de moléculas pró-inflamatórias e o aumento do estresse oxidativo, culminando em neuroinflamação e neurodegeneração. As intervenções de bloqueio do RAGE foram eficientes em inibir as vias de sinalização intracelular mediadas pelo receptor, comprovando a via de ação. Levando em conta nossos principais resultados concluímos que: a) RAGE atua como mediador da perda neuronal em resposta ao insulto inflamatório em diversas estruturas do SNC, b) está presente no corpo dos neurônios dopaminérgicos e envolvido na morte destes neurônios; c) o aumento do RAGE é tempo-dependente e a morte dos neurônios está vinculada a ação deste receptor. / RAGE is a transmembrane, immunoglobulin-like receptor that exists in multiple isoforms and interacts with a broad repertoire of extracellular ligands. RAGE is expressed at low levels in most cells, but the increased presence of its ligands initiates a complex intracellular signaling cascade resulting in oxidative stress, activation of transcription factor NF-B, increased expression of cytokines in addition to concomitant upregulation of RAGE itself. In this thesis we used 3 experimental models which induce systemic inflammation (Leishmania amazonensis, Lipopolysaccharide and sepsis) and 1 experimental model that mimics neuronal denervation (experimental models in vivo). In addition, different approaches to block RAGE were used to elucidate the function of this receptor. Based on our results the experimental models were efficient in inducing the increase of RAGE and its signaling in the central nervous system, triggering the synthesis and release of proinflammatory molecules and the increase of oxidative stress, culminating in neuroinflammation and neurodegeneration. The RAGE blocking interventions were effective in inhibiting receptor-mediated signaling, proving the signaling pathway. Considering our main results, we conclude that: a) RAGE acts as a mediator of neuronal loss triggered by inflammatory insults in various CNS structures; b) RAGE is present in the body of dopaminergic neurons and is involved in the death of these neurons; c) the increase of RAGE is time-dependent, and the neuronal death is dependent on the action of this receptor.

A presente pesquisa teve como objetivo geral considerar os processos sociais envolvidos na situação do adolescente em conflito com a lei no Brasil, suas implicações na transformação de histórias de vidas e consequente demandas nos programas de atendimento. De forma mais específica, objetivou trazer conhecimentos concretos para o campo de trabalho socioeducativo, e investigar aquilo que se apresenta como propiciador da reincidência. Como forma de alcançar esses objetivos, foi considerada a seguinte questão norteadora: o que leva o adolescente a infracionar novamente? A metodologia foi baseada na Teoria do Vínculo de Pichon-Riviere, propondo-se como procedimento grupos operativos, os quais foram realizados com adolescentes do meio fechado (Internação) e meio aberto (Liberdade Assistida). O principal instrumento de coleta de dados consistiu no conteúdo das entrevistas, sendo a análise complementada com outras pesquisas realizadas na temática. Os dados coletados, considerando as medidas socioeducativas, demonstram que elas não dão conta do objeto ao qual se propõem: o rompimento com o ciclo da delinquência, com a repetição do ato de delinquir. A forma como as medidas estão sendo propostas são reguladoras muito externas, e não estão entrando no cerne do problema. Nesse sentido, devem considerar os sentimentos de raiva e ódio que movem o adolescente. No subtexto dessa raiva existem situações de humilhação e sentimentos de vergonha que, por não serem elaborados, criam o ciclo humilhação-vergonha-ódio. Entra-se em círculo odioso, retroalimentado, que supõe a raiva, a dimensão que o prazer de delinquir tem, ao que os adolescentes denominam adrenalina. Algo que os deixa aficionados como se fosse vício / The current research had as general purpose consider the social processes involved at the condition of adolescents in conflict with the law in Brazil, their implications at the process of changing of life histories and resultant demand in the service programs. More specifically, it intended bring real knowledge to the social educational field of work, and inquire into that present itself as reincidence propitiating. To achieve that objectives, it was considered the follow leading question: what does the adolescent commit an infraction again? The methology was based on the Theory of Bond by PICHON_RIVIERE, proposes as procedure operative groups, that was achieved with adolescents of closed system (internment) and opened system (Assisted Freedom). The main instrument to data collection was consisted in the interviews\'s content, being the analysis complemented with other researches achieved in the same area. The collected data, considering the social educational measures, demonstrate they can\'t handle of the object of their purpose: the break-up of deliquence cycle, with the recurrense of deliquence act. The way how these measures are being purpose are very external regulatories, and they are not moving into the heart of the matter. In this sense, they have to consider rage and hate feelings, that moves the adolescent. In the subtext of that hate there are abasement situations and feelings of shame that, because they are not elaborate, create a cycle of humiliation - shame - hate. Entering a hateful and feedback cycle, that suppose rage, the dimension of the pleasure of commit a crime, what they call of adrenaline. Which makes them excited, like an addiction

Cyclooxygenase (COX) is the rate limiting enzyme that catalyses the production of prostanoids, which are crucial to vascular homeostasis. Evidence suggests that endothelial dysfunction and inflammation play a role in vascular complications in aging and diabetes. Previous animal studies by our laboratory at RMIT University reported enhanced COX expression with aging in rat aortas, platelets and monocytes. Potentially, alteration in COX expression may result in an imbalanced prostanoid production favoring the synthesis of vasoconstrictors and hence increase the risk of cardiovascular events in the aging population. The regulation of altered COX expression in aging, however, is not clear. It has been suggested that histone hyperacetylation may be an important mechanism that regulates COX levels during the aging process as increased histone acetylation has been shown to occur with aging. Thus, we hypothesized that COX expression is modulated by histone hyperacetylati on. This was investigated by measuring COX expression in histone hyperacetylated cultured endothelial cells. In the case of diabetes, studies have reported that the development of diabetes and its complications is associated with persistent inflammatory activity, evident with increased inflammatory markers in the circulation. COX-mediated pathways may be involved in this inflammatory process in diabetes. Furthermore, the formation of advanced glycation end products (AGEs) is accelerated in diabetes. AGEs can bind to receptors for AGEs (RAGE), which has also been suggested to play a role in inflammation in diabetes. We hypothesized that COX- and RAGE-mediated pathways contribute to increased inflammation in diabetes and potentiate the development of diabetic vascular complications. This was investigated by measuring changes in COX-mediated pathways in both rat and human diabetic models. The current thesis reports: 1) in cultured endothelial cells, histone hyperacetylation was associated with increased COX expression; 2) an overall increase in inflammation was observed in diabetes involving COX- and RAGE-mediated pathways. This was supported by increased platelet COX-1 and monocyte COX-2 levels in Zucker rats, increased monocyte COX-2 in human Type 1 diabetes and elevated plasma TXB2 and PGE2 levels in both human Type 1 and Type 2 diabetic subjects. Up-regulation of RAGE expression was further found in platelets and monocytes in both human diabetes types. When treated with NSAIDs, plasma prostanoid levels, COX and RAGE expression were reduced significantly in both platelets and monocytes in human diabetic subjects. 3) It is unclear how COX and RAGE expression was regulated, but histone modifications may be one of the mechanisms. Data from cultured cells indicated that increased COX expression was associated with increased histone acetylation levels induced by TSA. Concurrent increases in histone acetylation and COX-2 levels were also observed in human Type 1 diabetes, but similar findings were not observed in human Type 2 diabetes. In addition, we failed to find an age-dependent increase in monocyte histone H4 acetylation in human Type 2 diabetes despite an age-dependent increase in monocyte COX-2 expression. Thus, whether histone hyperacetylation modulates COX expression and in what conditions require further investigation.

La mucoviscidose est une maladie à transmission autosomique récessive, due à des mutations du gène CFTR. Les patients, partageant de mêmes mutations de CFTR et un même environnement, ont une expression phénotypique variable, suggérant l'influence d'autres gènes modifiant la sévérité de la maladie, appelés gènes modificateurs. L'atteinte respiratoire, caractérisée par une inflammation exacerbée, est un facteur principal de morbimortalité. L'haplotype ancestral AH8.1, impliqué dans la réponse inflammatoire, est constitué de 4 variants : LTa +252A/G, TNF -308G/A, HSPA1B +1267A/G et AGER -429T/C. Ainsi, l'objectif était de rechercher une association entre l'haplotype AH8.1 et la sévérité de l'atteinte respiratoire. Nous avons montré dans une cohorte de 404 patients européens, porteurs de différentes mutations de CFTR, que AH8.1 était associé au déclin de la fonction respiratoire. Nous avons taché de répliquer nos résultats dans une cohorte homogène de 1089 patients français, F508del homozygotes, sans succès à ce jour. Nous poursuivons cette étude chez des patients porteurs d'autres mutations de CFTR. Les variants de cet haplotype ont également été étudié séparément. Nous avons ainsi montré que AGER-429T/C, non seulement modulait la sévérité de l'atteinte respiratoire, mais, était également associé in vitro à une plus grande production de la protéine RAGE. L'ensemble de ces résultats suggère à ce jour que l'haplotype AH8.1 pourrait moduler la sévérité de l'atteinte respiratoire des patients non homozygotes pour la mutation CFTR F508del. De plus, le variant AGER-429T/C seul, modulant la sévérité de l'atteinte respiratoire, la protéine RAGE pourrait être envisagée comme biomarqueur dans la mucoviscidose. Mots clés : mucoviscidose - gène modificateur - haplotype ancestral AH8.1 - RAGE

In the present study possible associations between driver characteristics and aggressive driving were examined. 210 participants responded to a questionnaire consisting of self-report measures of emotion regulation ability, personality traits, and attitudes towards traffic behaviours in a Swedish translation of the Propensity for Angry Driving Scale (PADS). The main results showed that females, older age, agreeableness, openness, and social desirability were negatively correlated with angry driving behaviour as measured by the PADS. Impulsivity, attention seeking, trait irritability, verbal trait aggression, positive attitude towards speeding, and a high self-reported car manoeuvring ability were positively correlated with angry driving. Partial correlations showed that social desirability, trait irritability, and a positive attitude towards speeding explained most of the unique variance. Multiple regression analysis showed that trait irritability, positive attitude towards speeding, and a high self-reported car manoeuvring ability were the most important predictors of angry driving.

Pre-gestational diabetes increases the risk of congenital malformation in the offspring and both morbidity and mortality in the diabetic mother and her offspring. During pregnancy, high glucose levels act as a teratogen through several cellular and biochemical pathways and increased production of reactive oxygen species (ROS) has a central role in diabetic embryopathy. The aim of this work was to investigate the importance of genetic predisposition for congenital malformations and to study the genes involved in the teratogenic process of diabetic pregnancy. The crossbreeding of two rat strains, with both low and high incidence of diabetes-induced malformations, indicated that strain-specific maternal factors, such as disturbed serum levels of amino acids, triglycerides, and β-hydroxybutyrate, were associated with malformation. In addition, disturbed fetal expression of genes involved in ROS defense and development (Shh, Bmp4, Ret and Gdnf) in mandible and heart, and decreased activity of Gapdh and Aldose Reductase were associated with the teratogenic process, and the trans-generational heredity of the mother determined the type of malformations induced by maternal diabetes. In rat embryos, a diabetic environment in utero changed the expression of genes involved in ROS defense (Nrf2, Gpx1 and Cat), development of mandible and heart (Msx2, Shh, Bmp4, Ret and Gdnf), and neural tube closure and apoptosis (Pax3 and p53). The changes were divergent with tissue-specific alterations of gene expression in developing mandible, heart anlage, and whole embryo. Disruption of the Receptor for Advanced Glycation End products (RAGE) had a protective effect against diabetic embryopathy in mice, and the blockage of RAGE diminished ROS production in the offspring: this supported oxidative stress being a necessary etiological component in diabetic embryopathy. Maternal metabolic state and genetic susceptibility influence fetal outcome in experimental diabetic pregnancy. Disturbed protection against oxidative stress and tissue-specific derangements in the expression of developmental genes play pivotal roles in the teratogenic mechanism, and enhanced levels of Advanced Glycation End products (AGE) and RAGE-induced oxidative stress are involved in diabetic dysmorphogenesis.

Research has suggested that affective states have critical effects on various cognitive processes and performance. Evidence from driving studies has also emphasized the importance of driver situation awareness (Endsley, 1995b) for driving performance and safety. However, to date, no research has investigated the relationship between affective effects and driver situation awareness. Two studies examined the relationship between a driver's affective states and situation awareness. In Experiment 1, 30 undergraduates drove in a simulator after either anger or neutral affect induction. Results suggested that an induced angry state can degrade driver situation awareness and driving performance more than the neutral state. Interestingly, the angry state did not influence participants' perceived workload. Experiment 2 explored the possibilities of using an "attention deployment" emotion regulation strategy as an intervention for mitigating angry effects on driving, via an adaptive speech-based system. 60 undergraduates drove the same scenario as in Experiment 1 after affect induction with different intervention conditions: anger with no sound; anger with the ER system: directive/ command style emotion regulation messages; anger with the SA system: suggestive/ notification style situation awareness prompts; or neutral with no sound. Results showed that both speech-based systems can not only enhance driver situation awareness and driving performance, but also reduce the anger level and perceived workload. Participants rated the ER system as more effective, but they rated the SA system as less annoying and less authoritative than the ER system. Based on the results of Experiment 2, regression models were constructed between a driver's affective states and driving performance, being mediated by situation awareness (full mediation for speeding and partial mediation for collision). These results allow researchers to construct a more detailed driver behavior model by showing how an affective state can influence driver situation awareness and performance. The practical implications of this research include the use of situation awareness prompts as a possible strategy for mitigating affective effects, for the design of an affect detection and mitigation system for drivers.

Le détournement de la machinerie cellulaire par un pathogène est souvent essentiel à sa propagation dans l'organisme de l'hôte. Les voies de signalisation qui contrôlent l'homéostasie cellulaire constituent une cible stratégique de nombreux virus lors d'une infection. Le virus de la rage possède la particularité d'induire la survie des neurones qu'il infecte. Le site de fixation à des domaines PDZ (PDZ-BS) de la glycoprotéine du virus de la rage a été identifié comme étant un élément clef dans le contrôle des voies de survie et d'apoptose. Ce PDZ-BS reconnaît uniquement deux isoformes de la famille des " Microtubule Associated Serine/Threonine kinase " (MAST1 et MAST2). La kinase MAST2 possède une fonction inhibitrice de survie en contrôlant l'élongation des neurites et interagit, par ailleurs, avec le PDZ-BS de la phosphatase PTEN, autre inhibiteur essentiel de la survie neuronale. Nous avons montré in vitro que les domaines C-terminaux de PTEN (PTEN13-Cter) et de la glycoprotéine (Cyto13-vir) entrent en compétition pour la fixation domaine PDZ de MAST2. La résolution de la structure du domaine PDZ de MAST2 et PTEN13-Cter, son ligand endogène, révèle un mode d'interaction original avec une large surface d'interaction. Ce réseau d'interaction est conservé dans la structure du domaine PDZ de MAST2 complexé au ligand viral Cyto13-vir. En parallèle, nous avons démontré que le PDZ-BS de la glycoprotéine est nécessaire pour induire la survie des cellules infectées et qu'il module la distribution spatiale de PTEN in cellulo. Cette localisation est dépendante de la phosphorylation de PTEN-Cter.

Rheumatoid arthritis is a chronic inflammatory autoimmune disease. Measurement of the level of serum markers (sRAGE, S100A9, S100A8 and S100A12) and genetic testing for the presence of the PTPN22 genetic polymorphism could help elucidate the underlying cause of inflammation and complications in RA, such as atherosclerosis. Therefore, serum levels of sRAGE, S100A9, S100A8 and S100A12 were measured by ELISA in patients with established RA (n=138). The associations between the serum levels of these molecules; and inflammatory markers and RA complications were analysed by multiple linear regression modelling. Established RA patients (n=192) were investigated for the PTPN22 C1858T genetic polymorphism by PCR-RFLP. Multiple logistic regression modelling was used to examine the association between PTPN22 C1858T genetic polymorphism and inflammatory markers and RA complications. In RA patients, we found that serum levels of S100A9 were associated with the body mass index (BMI); and the presence of S100A8 and S100A12. The serum levels of S100A8 in RA patients were associated with the presence of anti-citrullinated peptide antibodies, rheumatoid factor and S100A9. The serum levels of S100A12 in RA patients were associated with the presence of anti-citrullinated peptide antibodies and S100A9; and a history of diabetes. Inflammatory markers and RA complications were not associated with the PTPN22 genetic polymorphism in established RA patients; serum level of triglyceride was the only variable associated with PTPN22 C1858T in multiple logistic regression analysis. Taken together, these data suggest that serum levels of sRAGE, S100A9 and S100A12 protein may be useful correlates of inflammation and autoantibody production in RA patients. Further studies are recommended to determine whether these markers predict clinical outcomes when measured at the onset of RA.

Thesis (M.A.)--Miami University, Dept. of Communication, 2006. / Title from first page of PDF document. Includes bibliographical references (p. 58-59).