Esta tese é composta por cinco estudos que tiveram como objetivo geral investigar a exposição à violência direta (ser a vítima) e indireta (ser testemunha) e suas relações com bem-estar subjetivo e sintomas de depressão, ansiedade e estresse em adolescentes de escolas públicas da cidade de Porto Alegre - RS. O primeiro capítulo apresenta uma revisão sistemática de literatura sobre exposição à violência na adolescência e suas relações com saúde mental. O segundo capítulo é um estudo de adaptação e validação da Escala de Depressão, Ansiedade e Estresse para Adolescentes (EDAE-A). O terceiro capítulo, estudo empírico, teve como objetivo investigar a prevalência de exposição de adolescentes à violência direta e indireta e sua associação com idade, sexo, reprovação escolar e configuração familiar. Já o quarto estudo, também empírico, investigou as relações entre exposição à violência direta e indireta, bem-estar subjetivo e sintomas de depressão, ansiedade e estresse. Por fim, o quinto capítulo apresenta o relato da experiência de devolução dos dados da pesquisa que teve como objetivo discutir violências(s) cotidianas. Participaram 426 adolescentes de escolas públicas, de 12 a 18 anos, que responderam a uma ficha de dados sociodemográficos e aos instrumentos Triagem de Exposição à Violência de Crianças na Comunidade, Escala de Depressão, Ansiedade e Estresse para Adolescentes (EDAE-A), Escala de Afetos Positivos (AP) e Afetos Negativos (AN) e a Escala Multidimensional de Satisfação de Vida para Adolescentes (EMSVA). Análises descritivas e inferenciais foram realizadas. Os resultados desta tese indicaram a alta prevalência de exposição direta e indireta dos adolescentes à violência e a associação com sintomas internalizantes. A adaptação e validação do instrumento EDAE-A possibilitaram a avaliação conjunta das variáveis depressão, ansiedade e estresse, demonstrando boas propriedades psicométricas. A construção do Índice de Bem-Estar Subjetivo, englobando a satisfação de vida e afetos positivos e negativos, deve ser mais bem explorada em pesquisas futuras. Finalmente, a intervenção focal realizada com os adolescentes demonstrou o quanto a violência é naturalizada no contexto escolar, indicando a necessidade de trabalhos preventivos e interventivos para essa população. Limitações e sugestões para novos estudos são descritas. / This thesis is comprised of five studies that had as main objective to investigate the exposure to direct violence (being victim) and indirect (being witness) and their relationship with subjective well-being and symptoms of depression, anxiety and stress in adolescents from public schools of the city of Porto Alegre - RS. The first chapter presents a systematic review of literature on exposure to violence in adolescence and its relationship with mental health. The second chapter is a study of adaptation and validation of the Depression, Anxiety and Stress Scale for Adolescents (DASS-A). The third chapter (a empirical study) aimed to investigate the prevalence of adolescent exposure to direct and indirect violence and its association with age, sex, school failure and family configuration. The fourth study (which is also empirical) investigated the relationship between exposure to direct and indirect violence, subjective well-being and symptoms of depression, anxiety and stress. Finally, the fifth chapter presents a report about the experience of informing the participants about the results of the research with the aim of discussing violence(s) in the daily life. The participants were 426 adolescents from public schools, 12-18 years old, who responded the sociodemographic form and the following instruments Screening of Exposure to Violence of Children in the Community; Depression, Anxiety and Stress Scale for Adolescents (DASS-A); Positive Affects (PA) and Negative Affects (NA) and the Multidimensional Life Satisfaction Scale for Adolescents (MLSSA). Descriptive and inferential analyses were performed. The results of this thesis indicated a high prevalence of direct and indirect exposure of adolescents to violence and the association with internalizing symptoms. The adaptation and validation of instrument DASS-A allowed the joint assessment of the variables depression, anxiety and stress, demonstrating good psychometric properties. The construction of the Subjective Well-being Index, encompassing life satisfaction besides positive and negative affects, should be further explored in future research. Finally, the focal intervention realized with the adolescents demonstrated how much the violence is naturalized in the school context, indicating the necessity of preventive and interventional actions for this population. Limitations and suggestions for further research are described.

Submitted by Josiane ribeiro (josiane.caic@gmail.com) on 2015-04-10T16:26:20Z No. of bitstreams: 1 niuza vieira correa.pdf: 1263833 bytes, checksum: cf8ea09aa09e02c4718ef045562745bb (MD5) / Rejected by Vitor de Carvalho (vitor_carvalho_im@hotmail.com), reason: - Citação incorreta; - Palavras-chave em caixa baixa on 2015-04-10T18:34:24Z (GMT) / Submitted by Josiane ribeiro (josiane.caic@gmail.com) on 2015-04-10T18:46:33Z No. of bitstreams: 1 niuza vieira correa.pdf: 1263833 bytes, checksum: cf8ea09aa09e02c4718ef045562745bb (MD5) / Approved for entry into archive by Vitor de Carvalho (vitor_carvalho_im@hotmail.com) on 2015-05-08T17:52:47Z (GMT) No. of bitstreams: 1 niuza vieira correa.pdf: 1263833 bytes, checksum: cf8ea09aa09e02c4718ef045562745bb (MD5) / Made available in DSpace on 2015-05-08T17:52:47Z (GMT). No. of bitstreams: 1 niuza vieira correa.pdf: 1263833 bytes, checksum: cf8ea09aa09e02c4718ef045562745bb (MD5) Previous issue date: 2013 / O presente estudo tem como escopo a avaliação das estratégias de gestão dos programas de pós-graduação da Área das Ciências Biológicas II, que obtiveram notas 6 e 7 em duas avaliações trienais consecutivas que aderiram ao Programa de Excelência Acadêmica (PROEX), criado pela Capes em 2004, com a finalidade de apoiar e manter o nível de desempenho dos programas de pós-graduação. O principal objetivo desta pesquisa é identificar as dimensões e atividades que norteiam o diferencial nível de excelência acadêmica, definido pela Capes para atribuição de notas 6 e 7 aos programas de pós-graduação stricto sensu, estimulando iniciativas voltadas aos rumos e significados da internacionalização. A metodologia utilizada foi de natureza exploratória, qualitativa e descritiva, por meio da analise de relatórios financeiros dos programas de pós-graduação stricto sensu da Área das Ciências Biológicas II inseridos no PROEX, relatórios esses, fornecidos pela Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) e, ainda, por meio de informações fornidas (disponibilizadas) pelos programas de pós-graduação, no aplicativo Coleta de Dados, ano base 2011, disponíveis no sítio da CAPES, no caderno de indicador “Proposta do Programa”. A delimitação do estudo na Área das Ciências Biológicas II justifica-se por concentrar o maior número de programas atendidos pelo PROEX. A fundamentação teórica do estudo, além de articular-se com a análise dos dados, contemplou três eixos temáticos mutuamente integrados: o Sistema Nacional da Pós-Graduação (SNPG), o Sistema de avaliação da pós-graduação da Capes e, finalmente, a inserção internacional/internacionalização da pós-graduação brasileira. Assim, concluímos que são predominantes as ações de internacionalização Sul-Norte e a internacionalização passiva junto aos programas analisados. Concluímos, ainda, que o PROEX vem atingindo seus objetivos, pois manteve o nível de qualidade de 95% dos programas de pós-graduação participantes. / The present study has as an aim the valuation of the management strategies of the post-graduation programs of the Biological Sciences II Area, which have gotten the grades 6 and 7 in two consecutives triennial valuations that have adhered to the PROEX ( Academic Excellence Program) created by Capes in 2004, whith the purpose of supporting and maintaining the level of performance of the Post-Graduation programs. The main goal of this research is to identify the extent and the activities that guide the differential level of academic excellence, which is defined by Capes to the assignment of the grades 6 and 7 to the Stricto Sensu Post-graduation, inciting some enterprises turned to the directions and meanings of the internationalization. It has been used the exploratory, qualitative and descriptive nature methodology through analysis of the financial reports of the Stricto Sensu Post-graduation programs of Biological Sciences II Area, which were provided by the Brazilian Federal Agency for Support and Evaluation of Graduate Education (Capes). Still, through analysis of some information given by the Post-graduation programs in the Data Collection application, base year 2011, available in the Capes’ site – notebook display “Program Proposal”. The study delimitation in the Area of biological sciences II is legitimated by concentrating the largest number of programs attended by PROEX. Besides jointing to the data analysis, the theoretical basis for this study looked on three thematic axes mutually integrated: The Post-Graduation National System (SNPG), The CAPES’ Valuation System of Post-Graduation and finally, the international insertion/ internationalization of the Brazilian post-graduation. Thus, we can conclude that the actions of internalization South-North and the passive internalization, added to the analized programs are predominant. Still, we conclude that PROEX has been achieving its goals, since such program has sustained the level of quality of 95% ( percent) of the participating programs.

In a rapidly growing global economy businesses must effectively manage their assets to remain competitive and promote company growth. Many companies are only now beginning to realize that employee knowledge is a valuable asset to their business and also needs to be managed. Organizations are exploring different ways to improve the sharing of knowledge within a business and how to keep employee’s with key knowledge within the business. This study investigates social media and the impact of business hierarchy on knowledge sharing within an organization. The use of social media, in our particular case, wikis, within an organization is investigated as part of the broader term Enterprise 2.0. This study is based on the theoretical understanding of wikis as tools that enable internalization, externalization and objectification of knowledge. This study investigates what may be the contributing factors that affect an employee’s use of a centralized wiki for knowledge sharing. This study focuses on the employees of a British software development and training company, SoftX, and used a mixed method research strategy based on the use of online surveys and face-to-face interviews. We used an online tool, SurveyMonkey, to register and correlate responses to our survey. In total, 99 responses were received and semi-structured, face-to-face interviews were conducted with five employees.   Correlations were used in establishing foundation for the analysis of the variables. Finally, the causality between the assumed factors affecting the use of the SoftX wiki is tested using multiple linear regression analysis. Several important factors presented themselves as a result of our study at SoftX which could explain the apparent lack of use of their wiki as a means of knowledge sharing within the business. The analysis demonstrates that the use of the SoftX's wiki by employees was influenced by organizational, personal and technological factors.

La transformation des cellules normales de l’organisme en un phénotype malin est souvent accompagnée de changements dans leur antigénicité. L’antigène Tn (GalNac-O-Ser/Thréo) est un antigène (Ag) glycopeptidique spécifique des tumeurs et exprimé à la membrane plasmique des cellules cancéreuses dans la majorité des carcinomes humains ainsi que dans certaines tumeurs hématologiques, tandis qu’il n’est pas détecté dans les cellules normales. Il représente donc une cible potentielle très intéressante pour l’immunothérapie passive par anticorps, car il n’est pas détectable dans les cellules normales, mais est démasqué dans environ 90% des cancers épithéliaux du fait d’une dérégulation des processus de glycosylation. Les anticorps monoclonaux (AcM) spécifiques d’antigènes exprimés à la membrane des cellules tumorales ont une efficacité prouvée dans le traitement de certains cancers. Ces AcM thérapeutiques sont particulièrement intéressants pour le traitement des cancers du fait de leur forte spécificité pour les cellules tumorales et de leur faible toxicité pour les cellules normales, contrairement aux chimiothérapies conventionnelles, mais leur mécanisme d’action est encore mal connu. L’AcM Chi-Tn est un anticorps chimérique homme/souris capable de se fixer de façon spécifique à l’antigène tumoral Tn, alors qu’il ne se fixe pas sur les cellules normales. Cet AcM pourrait donc être envisagé comme agent thérapeutique dans le traitement des cancers épithéliaux par immunothérapie passive.Nous nous sommes intéressés à l’AcM Chi-Tn non couplé en vue d’analyser son mécanisme d’action et d’évaluer son efficacité thérapeutique in vivo. Nous avons montré que l’AcM Chi-Tn seul ne possède pas d’effet toxique direct sur les lignées de cellules tumorales Tn-positives in vitro. Cependant, en présence de macrophages, cet AcM est capable d’induire la lyse de ces cellules par un mécanisme d’ADCC. In vivo, l’AcM Chi-Tn, associé à la cyclophosphamide, induit le rejet d'une tumeur du sein dans plus de 80% des souris. Cette inhibition de la croissance tumorale est abolie chez les souris déficientes pour la chaine associée aux récepteurs RFc activateurs, suggérant in vivo un mécanisme d’ADCC. Par l’étude microscopique du microenvironnement tumoral, nous avons observé que les cellules tumorales forment in vivo des synapses avec des macrophages, des neutrophiles, mais aussi des lymphocytes B. Des expériences de survie in vivo chez des souris déficientes pour différentes populations cellulaires montrent que les lymphocytes T semblent nécessaires à la protection des souris par Chi-Tn contre la tumeur. Ainsi, ces résultats confirment le rôle des effecteurs exprimant des RFc activateurs, mais aussi le rôle indispensable de la réponse immune adaptative pour assurer l'effet thérapeutique des AcM.Nous nous sommes également intéressés à l’utilisation potentielle de l’AcM Chi-Tn comme vecteur d’agents cytotoxiques. In vivo, dans un modèle de tumeurs solides chez la souris, des expériences de biodistribution montrent que l’AcM Chi-Tn est capable de cibler spécifiquement les zones tumorales, ce qui en fait un anticorps potentiellement utilisable comme vecteur de molécules toxiques. L’internalisation du complexe anticorps/antigène cible est un pré-requis nécessaire à l’utilisation de l’anticorps conjugué. Nous avons montré in vitro que l’AcM Chi-Tn est internalisé dans les endosomes précoces et de recyclage pendant un temps relativement long, faisant de cet AcM un bon candidat pour être couplé à des agents cytotoxiques. Durant ma thèse, nous avons couplé l’AcM Chi-Tn à la toxine saporine ou à la molécule cytotoxique auristatine F, et nous avons montré in vitro que ces conjugués sont cytotoxiques sur des lignées cellulaires Tn-positives. / Pas de résumé en anglais

L'internalisation et le trafic intracellulaire sont des mécanismes cruciaux dans la régulation de la signalisation des récepteurs couplés aux protéines G (RCPG) dans lesquels les -arrestines jouent un rôle central. Des agonistes biaisés qui sont capables d'activer sélectivement les voies de signalisation dépendantes des protéines G ou dépendantes des -arrestines ont été récemment identifiés. D'autre part, le concept selon lequel la signalisation des RCPG serait limitée à la membrane cellulaire a été contesté sur la base des données qui démontrent que de nombreux RCPG induisent du signal aussi bien à partir d'endosomes qu'au niveau de la surface cellulaire. Le glucose-dependent insulinotropic polypeptide (GIP) est une hormone incrétine essentielle dans l'homéostasie glucidique postprandiale. Elle exerce ses fonctions en se liant à un récepteur couplé aux protéines G, le RGIP qui est impliquée dans divers processus physiologiques et physiopathologiques. À ce jour, l'internalisation et le trafic intracellulaire du RGIP ainsi que leurs mécanismes moléculaires sous-jacents n'ont pas été étudié en détail. Dans ce contexte, le but de notre travail était d'abord d'étudier ces mécanismes et ensuite de caractériser le profil d'internalisation du N-acétyl-GIP, un analogue du GIP connu pour être résistant à la dégradation par le DPP-IV. Enfin, nous avons étudié si, en plus de sa signalisation à la membrane cellulaire, le RGIP est capable d'induire une signalisation à partir d'endosomes. Dans cette étude, nous montrons d'abord que l'internalisation du RGIP est un processus impliquant la clathrine, le complexe AP-2 et la dynamine, mais pas la région C-terminale du récepteur, ni les -arrestines1/2. Nous avons également montré que le N-acétyl-GIP, qui présente une activité agoniste pleine sur la production d'AMPc et sur la sécrétion d'insuline dans les cellules MIN-6-B1, n'est pas capable de stimuler l'internalisation du RGIP. Cela suggère que le N-acétyl-GIP pourrait être un agoniste biaisé du RGIP induisant préférentiellement la voie d'activation de Gs comparativement à un adressage du récepteur vers des puits recouverts de clathrine. Nous avons également réussi à observer une persistance au cours du temps de la production d'AMPc induite par le GIP. Le signal persistant dépend de l'internalisation du RGIP et est irréversible après lavage du GIP de la membrane cellulaire. De plus, nous avons détecté d'une manière directe la forme active de Gs au niveau d'endosomes contenant le RGIP en utilisant des plasmides codant pour des Nanobodies fusionnés à la GFP. Enfin, en utilisant un biosenseur FRET d'AMPc dirigé à la surface des endosomes précoces, nous avons également pu détecter d'une manière directe la production d'AMPc spécifiquement à la surface des endosomes contenant le RGIP internalisé. À notre connaissance, cette dernière observation est la première de ce genre, prouvant le concept de signalisation à partir d'endosomes par une approche de détection directe. Les résultats de cette étude apportent des informations quant à la régulation pharmacologique de l'internalisation et de la signalisation du RGIP, ouvrant des perspectives prometteuses dans le domaine du GIP. / Internalization and trafficking are crucial mechanisms regulating G-protein coupled receptors (GPCRs) signaling in which -arrestins play a central role. Biased agonists which selectively activate either G protein or -arrestin signaling pathway were identified. On the other hand, the concept of GPCR signaling being restricted to cell membrane has been contested on the basis of data demonstrating GPCR signaling from endosomes as well as from the cell surface. Glucose insulinotropic polypeptide (GIP) is an incretin hormone essential in post-prandial glucose homeostasis. It exerts its functions through binding to a G protein-coupled receptor, GIPR which is involved in various physiological and pathological processes. To date, GIPR internalization and trafficking and the underlying molecular mechanisms have not been investigated in detail. In this context, the aim of our work was to study these mechanisms and to characterize the internalization profile of N-Acetyl-GIP, a GIP analogue resistant to DPP-IV degradation. Finally, we investigated if GIPR signaling can occur from endosomes alongside its signaling at the cell membrane. In this study, we first report that GIPR internalization involves clatherin, AP-2 and dynamin but not C-terminal region of the GIPR nor -arrestin1/2. Moreover, N-Acetyl-GIP, which fully stimulated cAMP production and insulin secretion from MIN-6-B1 cells, did not stimulate internalization of the GIPR. This suggests that N-Acetyl-GIP could be a biased GIPR agonist preferentially inducing Gs activation pathway over directing the receptor to clathrin-coated pits. We have also succeeded to witness a sustainability in GIP-induced cAMP production. The sustained signal was dependent on GIPR internalization and unreversed by GIP removal from the cell membrane. Moreover, we directly detected the active form of Gas in early endosomes containing GIPR using a genetically encoded GFP tagged nanobody. Finally, using a FRET sensor of cAMP targeted to the surface of early endosomes, we also directly detected cAMP production specifically at the surface of endosomes containing internalized GIPR. The latter observation is the first of this kind, proving the endosomal signaling concept by a direct detection approach. This study brings new insights into the pharmacological regulation of GIPR internalization and signaling, opening promising perspectives in GIP field.

Contrairement aux autres chimiokine, CX3CL1 a la particularité d'exister sous deux formes protéiques fonctionnelles : une forme soluble chimio-attractante impliquée dans le recrutement leucocytaire comme toutes les chimiokines et une forme membranaire qui confère au couple CX3CL1/CX3CR1, une propriété surprenante de molécule d'adhésion participant à l'arrêt et à la transmigration des leucocytes circulants. Le CX3CR1 appartient à la famille des Récepteurs Couplés aux Protéines Gi, c'est-à-dire qu'il inhibe l'enzyme de synthèse de l'AMP cyclique (AMPc), l'adénylate cyclase. L'étude de la cinétique et du rôle du signal AMPc déclenché en aval du CX3CR1, activé par la forme soluble ou membranaire du CX3CL1 font l'objet de ce travail de thèse. La réponse à la forme membranaire est de même amplitude que celle induite par la forme soluble, mais présente une cinétique considérablement ralentie. Ce ralentissement corrèle avec une moindre internalisation du CX3CR1, qui semble être retenu en surface par le ligand membranaire. Un recrutement plus lent des ? arrestines sur le CX3CR1 activé par le CX3CL1 membranaire renforce cette hypothèse d'une internalisation plus tardive du CX3CR1 comparé à une activation par la forme soluble. Le rôle physiologique de l'AMPc a été également exploré sur les deux fonctions principales du couple CX3CL1/CX3CR1 : le chimiotactisme et l'adhésion. Le rôle inhibiteur de l'AMPc sur ces deux fonctions, confirme une action immunosuppressive de ce messager secondaire. Ces résultats indiqueraient que, grâce à leurs réponses AMPc inhibitrices, les cellules activées par les chimiokines seraient sélectionnées pour une réponse efficace en milieu inflammatoire. / CX3CL1 is a particular chemokine which, in contrast to other chemokines exists in two physiological forms: a soluble form is implicated in chemotaxis and cellular migration like all chemokines; whereas a membranous form confers to the CX3CL1/CX3CR1 couple an adhesive role, contributing in particular to the arrest of circulating leukocytes and their migration to the site of inflammation. The CX3CR1 belongs to the family of Receptor Coupled with Proteins Gi (RCPG), which inhibits the enzyme that syntheses cyclic AMP (cAMP), the adenylyl cyclase. The study of the kinetics and the role of the cAMP signal triggered downstream of CX3CR1, activated by soluble or membranous form of the CX3CL1 are the aims of this work of thesis. The response induced by the membranous form has the same amplitude as the one induced by the soluble form, but has a significantly slowed kinetic. This slowdown correlates with less internalization of CX3CR1, which seems to be retained on the surface by the membranous ligand. A slower recruitment of β-arrestin on the CX3CR1-activated by membranous CX3CL1 strengthens the hypothesis of a later internalization of CX3CR1 compared to activation by the soluble form. The physiological role of cAMP was also explored in the two principal functions of the couple CX3CL1 / CX3CR1: chemotaxis and adhesion. The inhibiting effect of cAMP in these two functions confirms an immunosuppressive action of this second messenger. These results indicate that through their inhibitory cAMP responses, cells activated by chemokines are selected for an effective response in the inflammatory conditions.

This thesis answers the question how big is the negative externality associated with driving under the influence of alcohol in crowns per kilometer driven by the driver with alcohol in blood. The calculation includes the economic consequences of accidents, specifically, loss of production, the cost of health care, administration and social expenditures, included are also the values of lost human lives and values for heavy and light injuries. Calculation of externality is used to determine the fine that internalizes this externality.

The internalization of external costs is a prioritized task of the European Union, aiming for an implementation until 2020. This study wants to provide an estimate of the expected reactions of the freight traffic market in Germany. For this purpose, the earnings from and expenses for the traffic system in Germany including external costs are analyzed to obtain a valid financial balance for each means of transport. In case of missing cost coverage, adequate internalization measures are defined to counteract the different causes of external costs. With this data, a computational model is created to assess the resulting effects on modal shift, traffic avoidance and efficiency gains in the transport market. Using prices of transport services, average transport distances and attributes of the means of transport and the transported goods, a detailed estimation of the expected market reactions is given. The results are then evaluated considering both risks and chances for the transport market as well as the national economy. Consequently, advice for politics and research is presented to facilitate the execution of the chosen internalization measures. Eventually, a SWOT analysis is conducted to judge the validity of the found results.

Body dissatisfaction and disordered eating behaviors are significant public health concerns, especially among college-age women. Despite extensive research, the complex nature of disordered eating and its etiology has prevented a satisfactory predictive model from being developed and validated and has therefore hindered the development of effective prevention and intervention strategies. This study aimed to integrate four of the most common etiological theories into a model to predict disordered eating behaviors. Bivariate correlations and moderation analyses were conducted to determine the strength of relationships between variables and to determine whether a protective factor (i.e., self-compassion) moderates the effects of risk factors (i.e., media exposure, thin-ideal internalization, negative affect) on body dissatisfaction, drive for thinness, and bulimic behaviors. Results indicated that there were correlations between negative affect, thin-ideal internalization, and disordered eating behaviors. Contrary to hypotheses, media exposure had significant relationships with both bulimia and body dissatisfaction but was not significantly associated with thin-ideal internalization. Broadly, negative affect and thin-ideal internalization predicted disordered eating behaviors. Finally, self-compassion did not emerge as a consistent moderator of the relationship between the three risk factors and disordered eating behaviors – except with drive for thinness. Findings have potential implications for mental and physical healthcare interventions to reduce symptom experiences and increase well-being.

Eine Einführung in die Weight Bias Internalization Scale (WBIS) ist ein Selbstbeurteilungsfragebogen zur Erfassung negativer gewichtsbezogener Selbststereotypisierung, inklusive der deutschen Version der Skala.