The studies presented in this thesis focus on human and canine models for autoimmune disease, with the main aim to gain new knowledge about disease mechanisms and to further evaluate the dog as a model for autoimmune disease. Autoimmune Polyendocrine Syndrome type 1 (APS-1) is a hereditary human multiorgan disease caused by mutations in the autoimmune regulator (AIRE) gene. Hallmarks of APS-1 are chronic mucocutaneous candidiasis caused by Candida albicans, together with the autoimmune endocrine disorders hypoparathyroidism and adrenocortical failure. Many human diseases have an equivalent disease in dogs. Because humans share environment, and in part life style with the dogs they provide an interesting model for further genetic studies. Immune responses to Candida albicans in APS-1 patients displayed an increased secretion of the proinflammatory cytokine IL-17A and similar results were also found in AIRE deficient mice. Anticytokine autoantibodies to IL-17A, IL-17F and IL-22 were detected in APS-1 patients, and a radioligand binding assay for measuring these autoantibodies was developed and evaluated. In the canine studies we investigated whether canine diabetes mellitus could serve as a model for human autoimmune diabetes mellitus. Furthermore, we investigated type I IFN responses in Nova Scotia duck tolling retriever dogs with a systemic autoimmune disease resembling human SLE. Four assays were used in search for signs of humoral autoimmunity in diabetic dogs. However, no evidence for a type 1 diabetes-like phenotype in dogs was found. Sera from Nova Scotia duck tolling retrievers suffering from steroid-responsive meningitis arteritis elicited an increased expression of IFN-inducible genes in the canine MDCK cell line. This suggests that these dogs have an IFN signature, as seen in human SLE.

La liaison de l’insuline à son récepteur permet le recrutement de protéines adaptatrices, ce qui conduit notamment à l’activation de la voie mitogénique des MAPK et des voies impliquées dans le métabolisme du glucose. Deux voies complémentaires contribuent au recrutement du transporteur de glucose, GLUT4, à la membrane ;la voie de la PI3-kinase qui implique la formation du messager secondaire PtdIns(3,4,5)P3 conduisant à l’activation de la PKB et la voie de la petite protéine G, TC10, qui implique les protéines APS, CAP et c-Cbl. <p><p>La phosphatidylinositol 5-phosphatase 2 (SHIP2) contrôle négativement la voie des MAPK par interaction avec des acteurs de la cascade et la voie de la PI3-kinase en hydrolysant le PtIns(3,4,5)P3 en PtIns(3,4)P2. De plus, il a été montré dans notre laboratoire que SHIP2 peut interagir directement avec la protéine CAP ainsi que co-immunoprécipiter avec le récepteur de l’insuline et c-Cbl, participant ainsi à un complexe multiprotéique formé des protéines CAP et c-Cbl et du récepteur. Au cours de ce travail, nous avons tenté de mieux comprendre l’implication moléculaire de SHIP2 dans la cascade TC10. Comme APS est la première protéine de la cascade à être recrutée au récepteur suite à une stimulation par l’insuline et qu’elle peut interagir directement avec le récepteur et les protéines CAP et c-Cbl, nous avons étudié dans un premier temps le lien potentiel entre APS et SHIP2.<p><p>Nous avons montré que SHIP2 interagit de manière directe avec la protéine adaptatrice APS tant dans un système de sur-expression (CHO-IR) que dans un système endogène (3T3-L1). Bien qu’une stimulation par l’insuline ne semble pas modifier cette interaction, elle induit néanmoins le recrutement d’une fraction des protéines APS et SHIP2 du cytoplasme vers la membrane plasmique. L’étude des domaines d’interaction a montré que la région centrale de SHIP2 qui comprend le domaine catalytique est nécessaire pour cette association. <p><p>Nous avons ensuite montré que cette association entre APS et SHIP2 peut moduler certaines de leurs propriétés biochimiques. D’une part, bien que la sur-expression de SHIP2 n’influence pas le recrutement d’APS au récepteur, SHIP2 diminue, indépendamment de son activité enzymatique, la phosphorylation sur tyrosine d’APS induite par l’insuline et l’interaction entre APS et c-Cbl, qui sont deux étapes cruciales dans la cascade TC10. Ainsi, SHIP2 pourrait non seulement influencer la cascade de l’insuline par son activité enzymatique, mais également par interaction avec des acteurs de la cascade. D’autre part, APS augmente l’activité 5-phosphatase de SHIP2 dans un test in vitro. Elle pourrait ainsi, outre son rôle positif dans la cascade, participer au rétrocontrôle négatif de la voie de signalisation à l’insuline. Finalement, nous avons déterminé comment ces deux protéines influencent les cascades de l’insuline. Alors qu’APS n’influence pas l’activation de la PKB, ni le taux de PtdIns(3,4,5)P3, la sur-expression d’APS et de SHIP2 induit une inhibition plus forte de l’activation de la PKB comparée à celle provoquée par SHIP2 seul. De plus, une sur-expression de SHIP2 abolit l’augmentation induite par APS de la phosphorylation des MAPK. Cette activation des MAPK par APS semble dépendre de sa liaison au récepteur car les domaines PH et essentiellement SH2 sont indispensables pour cet effet positif.<p><p>En conclusion, nous avons mis en évidence l’existence d’une association entre APS et SHIP2. Cette interaction modifie certaines de leurs propriétés biochimiques et fournit un nouveau mécanisme d’action pour ces protéines dans le contrôle négatif de la voie de signalisation à l’insuline. <p><p> / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

Det aktiebolagsrättsliga kapitalkravet har från det att kravet blev lagstadgat syftat till att säkerställa att det alltid föreligger ett ekonomiskt utrymme mellan aktiebolagets tillgångar och skulder. Därtill ska kravet fungera som en seriositetsspärr och borgenärsskydd. Kravet på en lägsta aktiekapitalgräns har historiskt sett utgjort ett betydande skydd för borgenärerna. Aktiekapitalkravet har betraktats som nödvändigt för borgenärerna bl.a. av den anledning att säkerställa att det finns en tillräcklig ekonomisk marginal som ska svara för bolagets förpliktelser. I denna uppsats utreds aktiekapitalet och det bakomliggande syftet att tillförsäkra borgenärerna säkerhet såväl det nationella kravet som två andra nordiska rättsordningars krav.Kapitalkraven i Europa har genomgått många reformeringar, majoriteten av länderna har reducerat deras kapitalkrav för privata aktiebolag och vissa länder har t.o.m. valt att slopa kapitalkravet helt. Danmark var ett av de länder där möjligheten fanns att bilda en viss bolagsform med begränsat personligt ansvar utan kapitalkrav, något som senare visade sig ge oönskade effekter och således avskaffades bolagsformen år 2019. Finland däremot gick åt motsatt håll och valde istället att slopa sitt kapitalkrav för privata bolag år 2019. Året därpå, år 2020, reformerades det svenska kravet och sänktes ytterligare. Kapitalkravet har och är fokus för förändring och dess framtida utveckling ser ut att gå mot allt fler reducerade kapitalkrav internationellt.Med tanke på de tre nordiska ländernas senaste förändringar av kapitalkravet angrips kravet och dess syfte att skydda borgenärerna genom en komparativ metod. Utöver den komparativa metoden analyseras det svenska aktiekapitalkravet genom en rättsdogmatisk metod. Härigenom ligger danska, finska och svenska rättskällor som grund för uppsatsens slutsatser.Uppsatsens slutsats är bl.a. att aktiekapitalkravet inte längre ses som ett borgenärsskydd utan incitamentet att göra associationsformen mer tillgänglig torde ersätta syftet att skydda borgenärerna. Kravets borgenärsskyddssyfte har blivit kraftlöst i takt med de successiva sänkningarna som gjorts under åren. Härigenom påverkas inte borgenärerna längre av reducerade kapitalkrav likt den sänkning som gjordes år 2020. Ytterligare slutsatser som görs i uppsatsen är att de nordiska länderna delar liknande teorigrunder vad gäller kapitalkravet som borgenärsskydd. Utredningen påvisar även hur de nordiska länderna haft liknande motiv för deras inbördes förändringar kring kapitalkravet under det senaste året.

Indiana University-Purdue University Indianapolis (IUPUI) / Thermal barrier coatings (TBCs) have been extensively employed as thermal protection in hot sections of gas turbines in aerospace and power generation applications. However, the fabrication of TBCs still needs to improve for better coating quality, such as achieving coating thickness' uniformity. However, several previous studies on the coating thickness prediction and a systematic understanding of the thickness evolution during the deposition process are still missing. This study aims to develop high-fidelity computational models to predict the coating thickness on complex-shaped components. In this work, two types of models, i.e., ray-tracing based and heat transfer based, are developed. For the ray-tracing model, assuming a line-of-sight coating process and considering the shadow effect, validation studies of coating thickness predictions on different shapes, including plate, disc, cylinder, and three-pin components. For the heat transfer model, a heat source following the Gaussian distribution is applied. It has the analogy of the governing equations of the ray-tracing method, thus generating a temperature distribution similar to the ray intensity distribution in the ray-tracing method, with the advantages of high computational efficiency. Then, using a calibrated conversion process, the ray intensity or the temperature profile are converted to the corresponding coating thickness. After validation studies, both models are applied to simulate the coating thickness in a rotary turbine blade. The results show that the simulated validation cases are in good agreement with either the experimental, analytical, or modeling results in the literature. The turbine blade case shows the coating thickness distributions based on rotating speed and deposition time. In summary, the models can simulate the coating thickness in rotary complex-shaped parts, which can be used to design and optimize the coating deposition process.

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Submitted by Edineia Teixeira (edineia.teixeira@unioeste.br) on 2019-03-11T18:41:13Z No. of bitstreams: 2 Heloyse_ Rossi_2018.pdf: 11853805 bytes, checksum: c9714d90ddb5b2c8134a833f815ea8e6 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2019-03-11T18:41:13Z (GMT). No. of bitstreams: 2 Heloyse_ Rossi_2018.pdf: 11853805 bytes, checksum: c9714d90ddb5b2c8134a833f815ea8e6 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2019-02-06 / The smartphones have become a vital part of human life, their great expansion and modernization make people connect in cyberspace from the moment they wake up until the time they go to sleep. Taking this into account, the educational processes can create strategies so that this everyday use of smartphones can be converted, at least in parts, into Learning activities. This dissertation, called English for Everybody and Everywhere: Connections and Convergences, linked to the research line Language: Linguistic, Cultural and Teaching Practices in the Master of Art from the State University of the West of Paraná (UNIOESTE), proposes the use of four smartphone applications, Let's Learn English, Duolingo, LyTrans English, and WhatsApp, in the process of English Language Learning, aiming to approach learning to the reality of 21st century students, in order to provide a more creative, interactive and dynamic environment in the classroom, in a process of convergence that establishes connections between students, teachers, cyberspace and their knowledge. This study is an action research with a qualitative approach, in which the researcher assumed the role of teacher, developing practical activities in the applications for smartphone, mentioned above, with a group of high school students from a public school in the city of Cascavel - PR. At the end of the activities with the applications in the school, the research used as data generation, besides the reflections on the practice, an interview with the regent teacher of the selected class, who participated as a listener of all the classes, a diagnostic questionnaire with the students involved and a journal, containing all the observations and impressions of the practice developed with the students. With the research, we sought to verify the possibility of smartphones being used as another way to access information that through integration and interactivity should become an additional knowledge in the students' lives. In the activities developed in the classroom with the selected group, we based ourselves on all the theoretical contribution described in the initial part of the text, and we based on concepts and theories of renowned authors in the area, such as: the Learning of Assmann (1999) and Dal Molin (2003); the importance of planning activities based on the advances of cyberspace and cyberculture, as Lévy points out (1999) and the influences of the culture of convergence in this scenario, according to Jenkins (2009); the characteristics of a rhizomatic teaching that creates maps and escape from from the tree models and decals, based on the theory of Deleuze and Guattari (1995); the new relations with knowledge that emerge from the age of cyberspace, with a collective intelligence and a teacher who passes from the only holder of the knowledge to animator and supervisor of this intelligence, in a process of flipped learning, based on the studies of Lévy (1998b), Moran (2015), Prensky (2001) and others; the advantages that mobile learning can bring both within the classroom and beyond the school environment, following UNESCO (2014), Motter (2013), Souza (2012) among other authors who collaborated for the present study. / Os smartphones tem se tornado parte vital da vida dos seres humanos, sua grande expansão e sua modernização fazem com que as pessoas estejam conectadas no ciberespaço desde o momento que acordam até a hora em que vão dormir. Levando isso em conta, os processos educacionais podem criar estratégias para que esse uso cotidiano dos smartphones possa ser convertido, ao menos em partes, para atividades de Aprendência. Essa dissertação, intitulada English for Everybody and Everywhere: conexões e convergências, vinculada à linha de pesquisa Linguagem: Práticas Linguísticas, Culturais e de Ensino, do Mestrado em Letras da Universidade Estadual do Oeste do Paraná (UNIOESTE) propõe o uso de quatro aplicativos para smartphone, Let’s Learn English, Duolingo, LyTrans English, e WhatsApp, no processo de Aprendência de Língua Inglesa, buscando aproximar a aprendizagem da realidade dos estudantes do século XXI, de modo a facultar um ambiente mais criativo, interativo e dinâmico em sala de aula, em um processo de convergência que estabelece conexões entre estudantes, professores, o ciberespaço e seus saberes. Esse estudo se configura como uma pesquisa-ação de abordagem qualitativa, na qual a pesquisadora assumiu o papel de professora, desenvolvendo atividades práticas nos aplicativos para smartphone, citados acima, com um grupo de estudantes do segundo ano do ensino médio de uma escola pública da cidade de Cascavel – PR. Ao final das atividades com os aplicativos na escola, a pesquisa utilizou como geração de dados, além das reflexões sobre a prática, uma entrevista com a professora regente da turma selecionada, que participou como ouvinte de todas as aulas, um questionário diagnóstico com os estudantes envolvidos e um diário de bordo, contento todas as observações e impressões da prática desenvolvida com os estudantes. Com a pesquisa, buscamos verificar a possibilidade dos smartphones serem utilizados como mais uma via de acesso às informações que pela integração e interatividade deve tornar-se um conhecimento a mais na vida dos estudantes. Nas atividades desenvolvidas em sala de aula com o grupo selecionado, baseamo-nos no aporte teórico descrito na parte inicial do texto, e nos embasamos em conceitos e teorias de autores renomados na área, tais como: a Aprendência de Assmann (1999) e Dal Molin (2003); a importância de planejar atividades fundamentadas nos avanços do ciberespaço e da cibercultura, como aponta Lévy (1999) e as influências da cultura de convergência nesse cenário, conforme Jenkins (2009); as características de um ensino rizomático que cria mapas e foge dos modelos de árvore e decalques, baseando-nos na teoria de Deleuze e Guattari (1995); as novas relações com o saber que surgem a partir da era do ciberespaço, com uma inteligência coletiva e um professor que passa de único detentor dos saberes para animador e orientador dessa inteligência, em um processo de flipped learning, tendo como base os estudos de Lévy (1998b), Moran (2015), Prensky (2001) e outros; as vantagens que a aprendizagem móvel pode trazer tanto para dentro de sala de aula quanto para além do ambiente escolar, seguindo UNESCO (2014), Motter (2013), Souza (2012) entre outros autores que colaboraram para o presente estudo.

Orientador: Gustavo Souza Pavani. / Dissertação (mestrado) - Universidade Federal do ABC. Programa de Pós-Graduação em Engenharia da Informação.

L'objectif de ce travail était d'étudier l'influence d'une pratique physique régulière sur la qualité de vie de personnes incarcérées. Au regard des difficultés sanitaires présentes en détention, les activités physiques et sportives (APS) ont été envisagées, dans le cadre du modèle intégratif et multifactoriel en psychologie de la santé, comme une stratégie d'ajustement particulière permettant aux sujets de pouvoir faire face efficacement à la situation. Quinze détenus ont suivi un programme physique spécifique durant 22 semaines et onze détenus ont constitué un groupe « contrôle ». Les données ont été obtenues par des questionnaires psychologiques, des tests physiques et une collecte d'impressions subjectives. Les analyses, réalisées par le modèle linéaire à effets-mixtes, mettent en évidence des bénéfices sanitaires issus de la pratique physique et témoignent d'un apport des APS quant à la qualité de vie des participants (bien-être psychologique, santé subjective).

<p>Organ-specific autoimmunity constitutes a large health problem, where both the clinical management and our understanding of the pathogenetic mechanisms need to improve. Women with Addison's disease have abnormally low levels of dehydroepiandrosterone (DHEA), its sulphate ester (DHEA-S) and androgens relative to age, and many patients complain of physical and mental fatigue and low stress tolerance. To define a suitable dose, the effect of oral DHEA replacement was evaluated in women with Addison's disease. </p><p> DHEA was administered for three months to nine women with Addison's disease in either of two doses, 50 mg (n=5) or 200 mg (n=4). A dose of 50 mg restored the DHEA(S) and androgen levels to normal without altering the insulin sensitivity, body composition or serum lipid profile.</p><p> Autoimmune polyendocrine syndrome type I (APS I) is a rare but useful model disorder of autoimmunity, characterised by multiple organ-specific autoimmune manifestations and high-titre autoantibodies and with adrenocortical insufficiency, Addison's disease, as one of its cardinal manifestations. Approximately 10-20% of APS I patients suffer from autoimmune hepatitis, which carries a high mortality, if untreated. The presence of putative antigenic targets in the liver was investigated.</p><p> Cytochrome P4501A2 (CYP1A2) and aromatic L-amino acid decarboxylase (AADC) were identified as hepatic autoantigens with the use of APS I sera for immunofluorescent staining of normal human liver, Western blot of microsomal and cytosol fractions of human liver homogenate, and immunoprecipitation of <i>in vitro</i> transcribed and translated radioactively labelled proteins. The presence of CYP1A2- and AADC-antibodies was significantly correlated to AIH, and CYP1A2 antibodies inhibited enzyme activity <i>in vitro</i>.</p><p><i> In conclusion</i>, a daily replacement dose of 50 mg of DHEA sufficiently restores levels of DHEA, DHEA(S) and androgens in women with Addison's disease, without severe side-effects. We have further identified CYP1A2 and AADC as hepatic autoantigens associated with autoimmune hepatitis in APS I.</p>

Organ-specific autoimmunity constitutes a large health problem, where both the clinical management and our understanding of the pathogenetic mechanisms need to improve. Women with Addison's disease have abnormally low levels of dehydroepiandrosterone (DHEA), its sulphate ester (DHEA-S) and androgens relative to age, and many patients complain of physical and mental fatigue and low stress tolerance. To define a suitable dose, the effect of oral DHEA replacement was evaluated in women with Addison's disease. DHEA was administered for three months to nine women with Addison's disease in either of two doses, 50 mg (n=5) or 200 mg (n=4). A dose of 50 mg restored the DHEA(S) and androgen levels to normal without altering the insulin sensitivity, body composition or serum lipid profile. Autoimmune polyendocrine syndrome type I (APS I) is a rare but useful model disorder of autoimmunity, characterised by multiple organ-specific autoimmune manifestations and high-titre autoantibodies and with adrenocortical insufficiency, Addison's disease, as one of its cardinal manifestations. Approximately 10-20% of APS I patients suffer from autoimmune hepatitis, which carries a high mortality, if untreated. The presence of putative antigenic targets in the liver was investigated. Cytochrome P4501A2 (CYP1A2) and aromatic L-amino acid decarboxylase (AADC) were identified as hepatic autoantigens with the use of APS I sera for immunofluorescent staining of normal human liver, Western blot of microsomal and cytosol fractions of human liver homogenate, and immunoprecipitation of in vitro transcribed and translated radioactively labelled proteins. The presence of CYP1A2- and AADC-antibodies was significantly correlated to AIH, and CYP1A2 antibodies inhibited enzyme activity in vitro. In conclusion, a daily replacement dose of 50 mg of DHEA sufficiently restores levels of DHEA, DHEA(S) and androgens in women with Addison's disease, without severe side-effects. We have further identified CYP1A2 and AADC as hepatic autoantigens associated with autoimmune hepatitis in APS I.