Esta dissertação discute os protagonistas do romance Laranja Mecânica, de Anthony Burgess, e dos filmes Laranja Mecânica e Vinyl, de Stanley Kubrick e Andy Warhol, respectivamente, comparando como tais personagens representam o indivíduo em sociedade. Para tanto, se apóia nas teorias de Joseph Campbell, Antonio Candido e Paulo Emílio Sales Gomes, sobre as personagens, e de Ítalo Calvino sobre a Leveza. São analisadas as três obras, para o entendimento das peculiaridades presentes em cada uma das narrativas, bem como a trajetória do protagonista nas três narrativas, até que estas atinjam o desfecho. Os conceitos de bem e de mal, mantidos sob concepções estabelecidas na nossa sociedade, são ameaçados quando o protagonista é submetido à Técnica Ludovico, tratamento que tem o objetivo de diminuir a quantidade de presos nas prisões e que, para isso, retira o poder de escolha do indivíduo, que passa a ser capaz de praticar somente atos de bondade, já que toda a exposição ao mal o leva à dor e ao incômodo insuportável. / This M.A. thesis discusses the protagonists in Burgess’ A Clockwork Orange and the films A Clockwork Orange and Vinyl, directed by Stanley Kubrick and Andy Warhol, respectively, comparing how such characters represent the individual in society. The thesis draws on the theories by Joseph Campbell, Antonio Candido, and Paulo Emílio Sales Gomes, concerning the characters, and by Italo Calvino, concerning Lightness. The three works are analyzed aiming at the understanding of the peculiarities present in each one of the narratives, as well as the trajectory of the protagonist in the three narratives, until they reach the end. The concepts of good and evil, maintained under conceptions established in our society, are threatened when the protagonist is subjected to the Ludovico Technique, treatment that has the objective of reducing the quantity of prisoners in jails. For that, it eliminates the power of choice of the individual, who happens to be able to practice acts of kindness only, since all exposure to evil brings him to pain and to unbearable discomfort.

Esta dissertação discute os protagonistas do romance Laranja Mecânica, de Anthony Burgess, e dos filmes Laranja Mecânica e Vinyl, de Stanley Kubrick e Andy Warhol, respectivamente, comparando como tais personagens representam o indivíduo em sociedade. Para tanto, se apóia nas teorias de Joseph Campbell, Antonio Candido e Paulo Emílio Sales Gomes, sobre as personagens, e de Ítalo Calvino sobre a Leveza. São analisadas as três obras, para o entendimento das peculiaridades presentes em cada uma das narrativas, bem como a trajetória do protagonista nas três narrativas, até que estas atinjam o desfecho. Os conceitos de bem e de mal, mantidos sob concepções estabelecidas na nossa sociedade, são ameaçados quando o protagonista é submetido à Técnica Ludovico, tratamento que tem o objetivo de diminuir a quantidade de presos nas prisões e que, para isso, retira o poder de escolha do indivíduo, que passa a ser capaz de praticar somente atos de bondade, já que toda a exposição ao mal o leva à dor e ao incômodo insuportável. / This M.A. thesis discusses the protagonists in Burgess’ A Clockwork Orange and the films A Clockwork Orange and Vinyl, directed by Stanley Kubrick and Andy Warhol, respectively, comparing how such characters represent the individual in society. The thesis draws on the theories by Joseph Campbell, Antonio Candido, and Paulo Emílio Sales Gomes, concerning the characters, and by Italo Calvino, concerning Lightness. The three works are analyzed aiming at the understanding of the peculiarities present in each one of the narratives, as well as the trajectory of the protagonist in the three narratives, until they reach the end. The concepts of good and evil, maintained under conceptions established in our society, are threatened when the protagonist is subjected to the Ludovico Technique, treatment that has the objective of reducing the quantity of prisoners in jails. For that, it eliminates the power of choice of the individual, who happens to be able to practice acts of kindness only, since all exposure to evil brings him to pain and to unbearable discomfort.

The concept of genocide is probably the most debated subject in Holocaust and genocide studies. The political implications to its usage, or resistance to do so, have also been lengthily discussed. Yet, when it came to the legal sphere of the concept it has been mostly descriptive, without much theorizing on the politicization of the convictions of genocide. This study investigates the relation between the International Criminal Tribunals for the former Yugoslavia and Rwanda application of the crime of genocide and how these judgements were informed. Through the court’s transcripts of a number of selected cases, the research will analyze the application qualitatively, identifying the key factors that determined its usage. The analyses rest on the legal and political aspects that influenced the chambers, evaluating which one explains best. The results indicate that there is no single explanation and that both legal and political reasonings merge in the international legal arena. The courts’ decisions have many inconsistencies that cannot be accounted by a solo description. Thus, matters of law interpretation, conflict’s ending, postcolonialism, and legitimacy all take a tool when convicting or acquitting someone for the crime of genocide.

Uma das principais complicações inerentes ao transplante de células-tronco hematopoiéticas é a doença do enxerto contra hospedeiro (DECH), que se trata da resposta imunológica contra os tecidos do receptor pelas células T do doador contidas no transplante. Este quadro é responsável por 15-30% das mortes que ocorrem após o transplante de células-tronco hematopoiéticas alogênicas. Apesar dos recentes avanços para reduzir a incidência de DECH através de alternância de regimes profiláticos reduzindo a intensidade do condicionamento, são poucos os tratamentos efetivos. Recentemente, o potencial imunomodulador das células-tronco mesenquimais tornou-se o foco de vários estudos. Alguns autores descreveram a atuação destas células na redução da resposta imunológica através da inibição da proliferação de células T, representando um novo potencial terapêutico para DECH. Mediante esse conhecimento, investigamos o papel das células-tronco mesenquimais na proliferação, apoptose e na produção de citocinas por linfócitos T. Nossos resultados mostraram que a presença de células-tronco mesenquimais nas culturas regulam negativamente a proliferação de linfócitos T estimulados de forma independente de contato e a apoptose de forma parcialmente dependente de contato. Observamos também que linfócitos T virgens em diferenciação para Th17 na presença de células-tronco mesenquimais apresentam redução na capacidade de produzir duas importantes citocinas efetoras implicadas na DECH, o interferon gama (IFN-y) e a interleucina 17A (IL-17A). Investigamos se a prostaglandina E2 (PGE2), por depletar triptofano, estava envolvida com a diminuição de proliferação de linfócitos T quando em cultivo com células-tronco mesenquimais. Utilizamos nas culturas a indometacina (IDT), um anti-inflamatório bloqueador de cicloxigenase (COX 1 e 2) e portanto da via da PGE2. Entretanto, observamos que o bloqueio da via da PGE2 inibia ainda mais a proliferação de linfócitos T e isto ocorria de acordo com a dose de IDT. Com o resultado deste experimento concluímos que, se a proliferação de linfócitos é inibida pela depleção de triptofano do meio, ela não ocorre via PGE2. Entretanto ainda não conseguimos esclarecer se esta via é ativada por outras moléculas, ou se é esta a via realmente responsável pela inibição da proliferação de linfócitos. No que concerne a via de inibição de apoptose, mostramos que a cadeia alpha do receptor de IL-7 (CD127) está aumentada na superfície de linfócitos T quando em presença de células-tronco mesenquimais. Verificamos que o bloqueio de IL-7 nas culturas aumenta a apoptose em linfócitos, bem como sua adição causa diminuição de apoptose. Identificamos a produção intracelular de IL-7 nas células-tronco mesenquimais, relacionando estas células e IL-7 com a inibição de apoptose em linfócitos T nestas condições. Este trabalho gerou dados que permitiram a compreensão de alguns possíveis mecanismos pelos quais as MSCs podem atuar sobre linfócitos T ativados e/ou alorreativos; mecanismos estes que podem ser utilizados como base para futuras investigações na elucidação e prevenção da DECH / A major complication after hematopoietic stem cell transplantation is the graft versus host disease (GVHD), which is an immunological response of transplanted donor T cells against the recipient tissues; this outline is responsible for 15-30% of deaths that can occur after allogeneic hematopoietic stem cells transplant. Despite recent advances in reducing GVHD incidence by alternating prophylactic regimens, thus reducing the intensity of conditioning, there are few effective treatments. Recently, the immune modulatory potential of mesenchymal stem cells has become the focus of several studies. Some authors described the role of these cells in reducing immune response by inhibiting T cell proliferation, representing a potential new therapy for GVHD. Through this knowledge, we investigated the mesenchymal stem cells role into T lymphocytes proliferation, apoptosis and cytokine production. Our results showed that the presence of mesenchymal stem cells into the cultures downregulates the proliferation of stimulated lymphocytes independent of contact and apoptosis of stimulated lymphocytes in partially contact-dependent manner. We also observed during naive T lymphocytes differentiation into Th17 cells, that the mesenchymal stem cell presence reduces the lymphocyte ability in producing the GVHD major effectors cytokines, interferon gamma (IFN-y) and interleukin-17A (IL-17A). We investigated whether prostaglandin E2 (PGE2) was involved in the reduction of T lymphocytes proliferation, when cultured with mesenchymal stem cells, by tryptophan depletion. Indomethacin (IDT), an anti-inflammatory drug blocker of cyclooxygenase (COX 1 and 2) and therefore PGE2 pathway, was used. However, we observed that, according to IDT dose, blocking this pathway further inhibited lymphocyte proliferation. With this result we conclude that if lymphocyte proliferation is inhibited by tryptophan depletion, it does not occur via PGE2. However, we still cannot say whether this pathway is activated by other molecules, or if this pathway is actually responsible for T lymphocytes proliferation inhibition. Regarding the apoptosis inhibition in T lymphocytes, we show that the IL-7 receptor alpha chain (CD127) is increased on the surface of T lymphocytes when in the presence of mesenchymal stem cells. We found that IL-7 blockage in the cultures increases apoptosis in T lymphocytes, as well as their addition causes apoptosis decrease. We also identified the intracellular production of IL-7 on mesenchymal stem cells, linking these cells and IL-7 directly with apoptosis inhibition in T lymphocytes under these conditions This work has generated data that allowed the understanding of some possible mechanisms by which MSCs can act on activated and/or alloreactive T lymphocytes; mechanisms that can be used as a basis for future research in the elucidation and prevention of GVHD

A doença do enxerto versus hospedeiro (DEVH) é uma grave complicação do transplante de órgãos sólidos, com alta mortalidade. Seu estudo tem sido limitado pela carência de modelos experimentais apropriados. Descreve-se um modelo de DEVH baseado no aumento do quimerismo, sua evolução clínica, histopatológica, do número das células quiméricas, do perfil das citocinas e da tolerância imunológica. Ratos Lewis (LEW) foram submetidos a transplante simultâneo de intestino delgado e medula óssea provenientes de ratos ACI (grupo de estudo - E) ou LEW (grupo controle - C), tratados com FK-506 (1 mg/Kg/dia) entre o 0 e 13o PO, e uma dose semanal daí por diante. Os ratos foram divididos nos seguintes grupos: E1- 6 ratos sacrificados no 120o PO. E2- 8 ratos após apresentarem sinais clínicos graves de DEVH entre o 189o e o 271o PO. Como controle, ratos LEW foram receptores dos mesmos tipos de enxertos provenientes de ratos LEW, submetidos à mesma imunossupressão e foram assim divididos: C1- 6 ratos sacrificados no 120o PO, C2- 5 ratos sacrificados entre o 223o e o 270o PO. A citometria de fluxo foi realizada para quantificar a porcentagem das células linfóides de ACI doadores no sangue periférico nos E1, E2 em 6 períodos: 30o PO, 65o PO, 95o PO, 120o PO, 160o PO, 200o PO. Os animais foram examinados 2 vezes por semana à procura de sinais de DEVH (rash cutâneo, perda de peso, de pelo e hiperqueratose). No sacrifício dos animais do grupo E1 e C1, foram colhidas amostras de língua (LI), de linfonodos cervicais (LC), intestino delgado do receptor e do enxerto para análise das citocinas IL-2, IL-4, IL-6, IL-10, IFN-gama e TNF-alfa por meio da reação em cadeia da polimerase. Em todos os grupos foram também colhidas amostras destes órgãos para histopatologia e nos animais do grupo E2 linfonodos cervicais foram processados para análise da reatividade celular por meio da reação mista dos linfócitos (MLR). A evolução clínica e histopatológica foi graduada de 0 a 3 de acordo com a severidade dos sintomas e do infiltrado mononuclear das amostras. Os ratos dos grupos E1 e E2 iniciaram sinais da DEVH entre o 84o e 115o PO. Os ratos dos grupos C1 e C2 não apresentaram evidência de DEVH. Amostras de LI e LC dos ratos do grupo E1 apresentaram alterações histopatológicas grau 2 e do grupo E2 apresentaram alterações histopatológicas grau 3, respectivamente. Nenhuma alteração histopatológica foi encontrada nos ratos do grupo controle e em amostras do ID. Nenhuma alteração histopatológica foi encontrada no intestino delgado do receptor e do enxerto. O aumento da porcentagem de células do doador no sangue periférico do receptor foi progressivo chegando a 5,4±2.3% no 10o período, 21±4,6% no 3o período e 39,3±4% no 6o período. IL-2, IL-6, IL-10, IFN-gma e TNF-alfa estiveram aumentados em língua e IL-4, IL-6, IL-10, IFN-gama e TNF-alfa em linfonodos cervicais. Os linfócitos de ratos do grupo E2 mostraram hiporreatividade aos de ratos ACI e hiperreatividade aos de ratos PVG (terceira parte) denotando tolerância imunológica. Neste modelo experimental há uma inexorável evolução imunológica para DEVH; existe correlação direta entre o aumento do quimerismo em sangue periférico e da expressão de citocinas em língua e linfonodos cervicais e a severidade da DEVH, além da indução de tolerância imunológica do rato do grupo E2 quimérico ao rato ACI normal. / Graft-versus-host disease (GVHD) has been a major concern after small bowel transplantation (SBTX) and the lack of suitable experimental models has limited the study of GVHD after solid organ transplantation. Here we describe a re1evant experimental model of GVHD after fully allogeneic SBTX based on chimerism augmentation, its clinical and histophatological evolution, cytokine involvement, responsible donor cell and immunologic tolerance analysis. LEW rat recipients received orthotopic SBTX and simultaneous donor bone marrow cell infusion (250x106), from ACI rats (experimental group - E) or LEW (control group C). FK-506 was administered dayly at a dose of 1 mg/kg on day 0 to 13, then continued as a weekly injection of same dose until the experimental end point. The recipients were divided in the following groups: E1 - 6 rats sacrificed at 120° POD. E2 - 8 rats sacrificed with critical GVHD between DPO 189 to 271. LEW recipient of LEW grafts, under the same immunossupression were used as control and divided as: C1 - 6 rats sacrificed at POD 120; C2- 5 rats sacrificed between 223 and 270 POD the number of donor cell in the recipient circulation was determined by flowcytometry in 6 pos-operative time: 30, 65, 95, 120, 160, 200. The rats were analyzed twice a week for body weigh and searching for signs of GVHD (cutaneous rush, hiperkeratosis and loss of hair and body weigh). At the sacrificed, samples from tongue (TG), cervical lymph node (CLN), donor (SBD) and recipient (SBR) small bowel were taken from all animals for histophatology and from E1 and C1l animals for IL-2, IL-4, IL-6, IL-10, IFN-gama e TNF-alfa cytokines analysis using reverse transcription polymerase chain reaction. Samples from cervical lynph nodes of 5 animals from group E2 were used for mixed lymphocyte reaction for tolerance analysis. The clinical and histophatological evolution of the disease were evaluated from degree 0 to 3 according to the severity. GVHD in E1 and E2 animals started between 84 and 115 POD. Histophatological analysis of TG and CLN showed that E1 animals present GVHD grade 2 and E2 animals grade 3. The increase of donors cells in the recipient circulation was progressive and account for 5.4± 2.3% at POD 30, 21.4±4.6% at POD 95 and 39.3±4% at POD 200. IL-4, IL-6, IL-10, IFN-gama e TNF-alfa were upregulated in CLN and IL-2, IL-6, IL-10, IFN-gama e TNF-alfa were upregulated in TG when compared with the respective controls. The lymphocytes from E2 group showed hyporeactivety to lymphocytes of normal ACI and hypereactivety to those of PVG, meaning tolerance. No cytokines alteration was noted in SBD neither SBR. Animals from group C1 and C2 did not present any sign of disease. This result show that GVHD is a inexoravel evolution under the experimental conditions of this study and the evolution of the disease is near correlated with the augmentation of the donor cells in the recipient circulation and upregulation of cytokines gene expression in target organs. Tolerance to the same donor strain lynphocytes was also noted.

Orientadores: Cármino Antonio de Souza, Jeane Eliete Laguila Visentainer / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T17:20:39Z (GMT). No. of bitstreams: 1 Cardozo_DanielaMaira_D.pdf: 3033896 bytes, checksum: b4696b2dc5fc0ec422091c74289aed9f (MD5) Previous issue date: 2013 / Resumo: No organismo humano, as moléculas HLA (Human Leukocyte Antigens) são proteínas expressas na superfície da maioria das células nucleadas e são codificadas por genes localizados no braço curto do cromossomo 6 na região do Complexo Principal de Histocompatibilidade (CPH). Essas proteínas são caracterizadas pelo alto grau de polimorfismo, e também faz a ligação com receptores KIR (Immunoglobulin-like Receptors), expressos nas células Natural Killer. Os receptores KIR, que reconhecem moléculas do complexo HLA de classe I, estão entre os principais receptores inibidores dos linfócitos NK. Células infectadas por vírus e células tumorais perdem ou têm diminuída a expressão de moléculas HLA de classe I e, por isso, são eliminadas pela ausência de ligação entre moléculas HLA e receptores KIR inibitórios. Atualmente, muitos estudos têm destacado a importância dos genes KIR e HLA no Transplante de Células Progenitoras Hematopoiéticas (TCPH). O TCPH é o tratamento de escolha para muitas doenças hematológicas e dependem de vários fatores incluindo o estágio da doença, o regime de condicionamento, a fonte de células, o grau de identidade HLA entre doador e receptor e o desenvolvimento da doença do enxerto contra o hospedeiro (DECH). Estudos recentes indicam que a presença de células NK alorreativas no enxerto representa um fator favorável à recuperação de pacientes, uma vez que essas células têm a capacidade de eliminar células tumorais residuais pela ausência ou diminuição da expressão de moléculas HLA e sem a indução da DECH. Também outros fatores podem estar envolvidos na resposta pós-transplante, como a presença e ausência de determinados alelos HLA e genes KIR, os quais podem estar ligados à melhor ou pior resposta pós-transplante. O primeiro ensaio investigou a associação entre HLA e a ocorrência da DECH aguda e crônica em pacientes que receberam transplante de células progenitoras hematopoiéticas HLA-idêntico, aparentados. No total, foram 176 pacientes que receberam o primeiro transplante entre 1997 e 2009. DECH aguda foi positivamente associada ao HLA-A10 (P = 0.0007), HLA-A26 (P = 0.002), B55 (P = 0.001), DRB1*15 (P = 0.0211) e DQB1*05 (P = 0.038), enquanto que HLA-B16 (P = 0.0333) foi mais frequente em pacientes sem DECH aguda. DECH crônica foi positivamente associada com HLA-A9 (P = 0.01) e A23 (P = 0.0292) e negativamente associada com HLA-A2 (P = 0.0031) e B53 (P = 0.0116). HLA-B35 (P = 0.0373), B49 (P = 0.0155) e B55 (P = 0.0024) foi alta em pacientes com DECH aguda grau 3 ou mais, do que os outros pacientes. Nos pacientes com DECH crônica extensa, HLA-A9 (P = 0.0004), A24 (P = 0.0059) e A26 (P = 0.0411) foi maior do que nos outros pacientes, enquanto HLA-A2 foi baixo (P = 0.0097). O objetivo do segundo ensaio foi avaliar as possíveis interações dos genes KIR e HLA com o curso clínico do transplante HLA compatível, aparentado e não depletado de linfócitos T, particularmente na doença do enxerto contra o hospedeiro (DECH) aguda e crônica, recaída, sobrevida global e sobrevida livre de evento. A maioria dos doadores (78%) apresentaram o haplótipo B do KIR enquanto que 22% apresentaram o haplótipo A. Dos pacientes que receberam o haplótipo A do doador, 90% tiveram DECH, aguda ou crônica, comparados com os que receberam o haplótipo B (58%) (dados não estatisticamente significantes). Não houve diferença significativa para recaída entre pacientes que receberam os haplótipo A ou B (27% vs 23%). Não houve diferença no desenvolvimento da DECH e recaída para os pacientes homozigotos (C1C1 ou C2C2) e heterozigotos (C1C2) e nem para aqueles com HLA-Bw4 presente e ausente. Também, a sobrevida global não foi diferente para os grupos de pacientes analisados. No entanto, houve forte correlação entre o grupo de pacientes heterozigotos para HLA-C (C1C2) e a incidência de DECH aguda e recaída. A SLE foi maior nos pacientes heterozigotos que não desenvolveram DECHa (p<0,0001). Resultados mostraram que as variantes de HLA podem influenciar na ocorrência de DECH em transplante alogênico, com doadores relacionados, HLA-idênticos, tanto como fatores de proteção, quanto como fatores de susceptibilidade. Ainda, a interação KIR/HLA tem impacto significante no resultado dos transplantes relacionados, HLA compatível, sem depleção de linfócitos T, influenciando na incidência de recaída e na ocorrência da DECH. Resultados mostraram que para o grupo heterozigoto (C1C2) a maioria dos pacientes não desenvolveu DECH aguda e apresentou maior SLE, sugerindo um possível efeito protetor para esse grupo / Abstract: In the human organism, the HLA (human leukocyte antigens) are proteins expressed on the surface of most nucleated cells and are encoded by genes located on the short arm of chromosome 6 in the region of the Major Histocompatibility Complex (MHC). These proteins are characterized by a high degree of polymorphism, and also make the connection with KIR (Immunoglobulin-like Receptors), expressed in Natural Killer cells. KIR receptors that recognize HLA molecules of class I are among the major inhibitory receptors of NK-cells. Virus infected cells and tumor cells have lost or diminished expression of HLA class I molecules and therefore are eliminated by the absence of binding between HLA molecules and inhibitory KIR receptors. Currently, many studies have highlighted the importance of KIR and HLA genes in Hematopoietic Stem Cell Transplantation (HSCT). HPCT is the treatment of choice for many hematological malignancies and depends on various factors including stage of disease, the conditioning regimen, the source of cells, the degree of identity between donor and recipient HLA and development of chronic graft-versus-host (GVHD). Recent studies indicate that the presence of alloreactive NK cells in the graft is a factor aiding the recovery of patients, since these cells have the ability to eliminate residual tumor cells by the absence or diminution of expression of HLA molecules and without inducing GVHD. Also other factors may be involved in response post-transplant, as the presence or absence of certain HLA genes and KIR, which can be connected to a better or worse response after transplantation. The first trial investigated the association between HLA and the occurrence of acute and chronic GVHD in patients receiving hematopoietic stem cell transplant HLA-identical related. In total, 176 patients who received a first transplant between 1997 and 2009. GVHD was positively associated with HLA-A10 (P = 0.0007), HLA-A26 (P = 0.002), B55 (P = 0.001), DRB1 * 15 (P = 0.0211) and DQB1 * 05 (P = 0.038), while that HLA-B16 (P = 0.0333) was more frequent in patients without acute GVHD. Chronic GVHD was positively associated with HLA-A9 (P = 0.01) and A23 (P = 0.0292) and negatively associated with HLA-A2 (P = 0.0031) and B53 (P = 0.0116). HLA-B35 (P = 0.0373), B49 (P = 0.0155) and B55 (P = 0.0024) was high in patients with acute GVHD grade 3 or more, than the other patients. In patients with extensive chronic GvHD, HLA-A9 (P = 0.0004), A24 (P = 0.0059) and A26 (P = 0.0411) was greater than in the other patients, whereas HLA-A2 was low (P = 0.0097). The objective of the second test was to evaluate the possible interactions of KIR and HLA genes with the clinical course of the transplant HLA compatible related and not depleted of T lymphocytes, particularly in chronic graft versus host disease (GVHD) acute and chronic relapse, survival overall and event-free survival. Most donors (78%) presented the KIR B haplotype while 22% were haplotype A. Of the patients who received the donor haplotype A, 90% had GvHD, acute or chronic, compared with those who received the haplotype B (58%) (data not statistically significant). There was no significant difference in relapse between patients who received the haplotype A or B (27% vs 23%). There was no difference in the development of GVHD and relapse for patients homozygous (C1C1 or C2C2) and heterozygous (C1C2) and not for those with HLA-Bw4 present and absent. Also, the overall survival was not different for the groups of patients studied. However, there was strong correlation between the group of patients heterozygous for HLA-C (C1C2) and the incidence of acute GVHD and relapse. The SLE was higher in patients who did not develop GVHD heterozygotes (p <0.0001). Results showed that the HLA variants may influence the occurrence of GVHD in allogeneic transplantation with related donors, HLA-identical, both as protective factors, such as susceptibility factors. Furthermore, the interaction KIR / HLA has a significant impact on the outcome of transplantation related HLA-compatible, without depletion of T cells, influencing the incidence of relapse and the occurrence of GVHD. Results showed that for the heterozygous group (C1C2) most patients did not develop acute GVHD and showed higher SLE, suggesting a possible protective effect for this group / Doutorado / Clinica Medica / Doutora em Clínica Médica

This Master Thesis aims to answer the question why the EU foreign policy-makers decided toimplement the Eastern Partnership (EaP). As the EU foreign policy decision-making processis based upon consensus between all EU Member States, an argumentation analysis isconducted to find the arguments that the policy-makers use to convince the others. By usingHabermas’ Theory of Communicative Action, the arguments are categorized into pragmatic(security and economic interests), moral (humanitarian values) or ethical-political (culturalvalues) logics. The research material consists of official documents and statements of the EUinstitutions. Then, the arguments are evaluated as whether they can be said to be legitimate,‘mobilizing’ arguments: intelligible, appropriate and true. The main result is that even if allargumentation categories are used by policy-makers, none of the categories can be said to becompletely legitimate. Therefore, an ideological perspective is a possible complement to thecategories within the Theory of Communicative Action. This perspective would possibly addto the understanding why the EaP was implemented.

The thesis entitled “Regioselective Functionalization of Indoles using Directing Group Strategy: An Efficient Transition Metal Catalysis” is divided into two sections. Section A, which is presented in three chapters, describes the regioselective alkenylation of indoles using directing group strategy. Whereas, Section B, which is divided in to two chapters, narrates the synthesis of 4-amino indoles using directing group strategy and site selective addition of maleimide to indole at C2-position. Section A Chapter 1. C2-Alkenylation of indoles The indole ring system is one of the most abundant heterocycles present in nature. The synthesis and functionalization of indoles is one of the major areas of focus for synthetic organic chemists.1 Alkenylation of indole at C2-position is a challenging task due to the electrophilic nature of the reaction. For this reason, the functionalization of indole at C2-position is less addressed. In this chapter, a highly regioselective alkenylation of indole at the C2-position has been described by using the Ru(II) catalyst and employing a directing group (DG) strategy.2 This directing group strategy offers rare selectivity for the alkenylation of N-benzoylindole at the C2-position in the presence of the more reactive C3-position. A variety of N-benzoylindole derivatives are shown to undergo alkenylation at C2-positon. Deprotection of the benzoyl group has also been demonstrated, and the resulting products serve as a useful synthon for synthesizing a variety of natural products. A few representative examples are highlighted in Scheme 1.3 1 (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b) Karamyan, K. A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489. 2 (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (b) Engle, K. M.; Mei, T.-S.; Wasa, M.; J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788. (c) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936. (d) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. 3 Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 2818. Scheme 1: C2- Alkenylation of indoles Chapter 2 describes a highly regioselective alkenylation of indoles at the C4-position by employing aldehyde functional group as a directing group, and Ru as a catalyst, under a mild reaction conditions. This approach leads to a short synthetic route for C4-alkenylated indoles, which serve as precursors for ergot alkaloids and related heterocyclic compounds.4 Further The potential of the present strategy has been demonstrated by performing (i) scale up reaction, (ii) selective reduction of olefin double bond and (iii) synthesizing substituted 1,3,4,5-tetrahydrobenzo[cd] in two steps with an overall yield of 68%. 1,3,4,5-Tetrahydrobenzo[cd] is one of the key intermediates for synthesizing ergot alkaloids. A few examples are highlighted in Scheme 2.5 4 (a) Horwell, D. C. Tetrahedron 1980, 36, 3123. (b) Kozikowski, A. P.; Ishida, H. J. Am. Chem. Soc. 1980, 102, 4265. (c) Oppolzer, W.; Grayson, J. I.; Wegmann, H.; Urrea, M. Tetrahedron 1983, 39, 3695. (d) Hatanaka, N.; Ozaki, O.; Matsumoto, M. Tetrahedron Lett. 1986, 27, 3169. (e) Horwell, D. C.; Verge, J. P. Phytochemistry 1979, 18, 519. 5 anke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 6262. Scheme 2: C4- Alkenylation of indoles Chapter 3 of Section A, presents a novel mode of selective alkenylation of indoles using Ru and Rh catalyst. In these alkenylation reactions, selectivity between C2- and C4-positions of indole framework has been achieved by altering the property of directing group. Methyl ketone, as directing group, furnishes exclusively C2-alkenylated product, whereas trifluoromethyl ketone as a directing group changes the selectivity to C4, indicating that electronic nature of the directing group controls the choice between a 5-membered and 6-membered metallacycle. Developing such divergent and selective C-H functionalizations, between C2- and C4-positions, on the indole framework can lead to easy and short synthetic routes for natural, unnatural and biologically-active compounds.6 Further screening of other carbonyl derived directing groups revealed that strong and weak directing groups exhibit opposite selectivity. Experimental 6 (a) Bronner, S. M.; Goetz, A. E.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 3832. (b) Nathel, N. F. F.; Shah, T. K.; Bronner, S. M.; Garg, N. K. Chem. Sci., 2014, 5, 2184. (c) A Beilstein/Crossfire search shows that more than 600 C4- substituted indole-containing natural products exist and nearly 10,000 bioactive C4-substituted indoles have been reported. controls, deuteration experiments and preliminary DFT calculations lend support to the proposed mechanism. A few representative examples are highlighted in Scheme 3.7 Scheme 3: C4- vs C2-Alkenylation of ndoles Deuterium Labeling studies were carried out to shed light on the site of metallacycle formation and hence the origin of selectivity. Both COCF3 and COCH3 substrates were independently subjected to both standard conditions A and B, along with either D2O or AcOD as deuterium sources (Scheme 4). 7 Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Manuscript submitted. Scheme 4: Deuterium labeling studies The Section B is divided into 2 chapters. Chapter 1 presents a method for synthesizing of 3-(indol-2-yl) succinimide derivatives by using a directing group strategy. Selective functionalization at C2-position of indole in the presence of highly reactive C3-position has been achieved. A conjugate addition, instead of Heck-type reaction, has been achieved by careful selection of the alkene partner (maleimides and maleate esters). This selectivity has been achieved by avoiding β-hydride elimination. Succinimide derivatives are structural motifs that are found in many natural products and drug molecules. Moreover, succinimides can be easily reduced into 5-membered pyrrolidine rings, γ-lactams and lactims, which are part of structural scaffolds of useful natural products.8 Further the application of the protocol has been showcased by performing reduction to obtain pyrrolidine and 1,4 diols. A few representative examples are highlighted in Scheme5.9 8 (a)Crider, A. M.; Kolczynski, T. M.; Yates, K. M. J. Med. Chem. 1980, 23, 324. (b) Isaka, M.; Rugseree, N.; Maithip, P.; Kongsaeree, P.; Prabpai, S.; Thebtaranonth, Y. Tetrahedron 2005, 61, 5577. (c) Uddin, J.; Ueda, K.; Siwu, E. R. O.; Kita, M.; Uemura, D. Bioorg. Med. Chem. 2006, 14, 6954. (d) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N. Tetrahedron 1975, 31, 1437. (e) Wijnberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W. N. Tetrahedron 1978, 34, 179. 9 Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Org. Lett. 2015, 17, 4662. Scheme 5: Addition of Maleimide to Indole at C2-position Chapter 2 describes a highly regioselective amidation of unprotected indoles at the C4-position by employing aldehyde functional group as a directing group. This reaction has been performed using Ir(III) catalyst, under mild reaction conditions. Thus, an efficient, simple, short synthetic route for C4-amido indoles has been achieved. C4-Amido indoles are privileged molecules, which serve as precursors for indolactum V,10 teleocidin and related heterocyclic compounds.11 To the best our knowledge, this is the first report of using aldehyde as a directing group for amidation reactions. The potential of the present strategy has been demonstrated by performing scaling up reaction, and deprotection of tosyl group to obtain corresponding amines. A few representative examples are highlighted in Scheme 6.12 10 Garg, N. K. et al., J. Am. Chem. Soc. 2011, 133, 3832 11 Kehler, J. J. Med. Chem. 2014, 57, 5823 12 Lanke, V.; Prabhu, K. R. (Manuscript submitted). Scheme 6: C4- amidation of indoles 7

Gemeinsamer Workshop von Universitaetsrechenzentrum und Professur Rechnernetze (Fakultaet Informatik) der TU Chemnitz. Globales Thema: Produktive und sichere Netzanwendungen

Ce projet de recherche est situé à l’interface des soins infirmiers et des pratiques sécuritaires en milieu psycho-légal. Il vise non seulement à situer la pratique infirmière dans un contexte de travail extrême, mais aussi à explorer une pratique professionnelle influencée par une forte présence masculine. Malgré les tensions que génèrent la cohabitation des aspects sécuritaires (voire disciplinaires) et des soins infirmiers, il reste que la dangerosité de la population à soigner intensifie les manifestations « hyper-masculines » des soins infirmiers. Bien que certains chercheurs aient abordé le sujet de façon superficielle, les rapports sociaux de genre en sciences infirmières, jusqu’ici sous-explorés, donc sous-théorisés, constituent une variable importante qui motive, la plupart du temps, la division « genrée » des rôles infirmiers au sein du dispositif de psychiatrie légale. Le milieu psycho-légal est le site souvent dramatique d’interventions musclées pour maintenir la sécurité des lieux. Un regard critique sur les rapports sociaux de genre nous fait comprendre comment ils peuvent (re)définir l’expression des soins infirmiers dans ce type de contexte. Le processus précis de cette division genrée en milieux psycho-légaux reste peu documenté dans les écrits scientifiques et nécessite une attention particulière. Parce que très peu de recherches en regard d’une telle problématique ont été effectuées, notre recherche essentiellement descriptive et compréhensive nécessitait une méthode qualitative permettant de décrire et comprendre les rapports sociaux de genre sur la pratique des soins infirmiers dans un contexte de psychiatrie légale. Afin de répondre à cette exigence, la théorisation ancrée comme méthodologie de recherche a été privilégiée ; puisque cette dernière se prête particulièrement bien à la description des pratiques infirmières en milieu de psycho-légal ainsi qu’à l’étude concomitante de la socialisation professionnelle du personnel infirmier dans un tel milieu. Pour assurer la collecte des données, des entrevues semi-structurées ont été réalisées. Plus de 128 heures de présence dans le milieu et 20 entrevues ont été essentielles pour achever ce projet doctoral. Notre analyse a permis d'identifier trois grandes catégories descriptives : 1) Risques de violence et contraintes sécuritaires ; 2) Socialisation professionnelle et 3) Souffrances et mécanisme d’adaptation. Nos résultats montrent que le personnel infirmier se trouve « coincé » entre une philosophie caritative associée aux idéaux infirmiers (éléments fondateurs) et une philosophie coercitive (sécuritaire) associée au milieu psycho-légal. Parallèlement, nous notons que les dynamiques de groupe sont des facteurs non négligeables au regard du sentiment de sécurité et de gestion des comportements violents. D’une part, on fait mention de l’expérience des hommes qui implique une vulnérabilité (souffrance) liée au maintien de sécurité et au besoin de protéger leurs collègues. D’autre part, les femmes se font reprocher leur souplesse – invoquant le manque de rigueur dans le renforcement de règles – empêchant ainsi, de part et d’autre, le déploiement d’une pratique professionnelle complète. Le but premier de cette thèse doctorale consistait à explorer les rapports sociaux de genre en milieu psycho-légal – un milieu typiquement masculin. Notre recherche a d’ailleurs souligné en quoi le maintien de la sécurité est un élément indispensable à la pratique infirmière. En effet, l’aspect sécuritaire du milieu nous a permis d’explorer comment les risques de violence polarisent les interventions selon le sexe biologique du personnel soignant, dans la mesure où ce dernier est lié à des caractéristiques/attributs stéréotypées. Le milieu psycho- légal encourage une virilisation des soins et ce discours sexué participe aux divisions genrées. Il est important d’apprécier l’impact des stéréotypes sexués sur la pratique infirmière et le fait que celle-ci soit partagée entre deux perspectives divergentes. Les rôles sexués entraînent selon nous une violence entre les sexes ce qui facilite l’instrumentalisation des deux sexes. L’effet du discours hétéronormatif sur les rapports sociaux de genre, a permis de comprendre comment les comportements sont modulés par la conception de l’homme fort et de la femme à risque dans un milieu potentiellement violent. Le cadre hétéronormatif jumelé au milieu psycho-légal facilite l’amplification des normes hétérosexuelles. Les résultats de recherche ont permis de mieux comprendre comment le personnel soignant est confronté à un ensemble d’injonctions et de mandats contradictoires. En dépit des stratégies déployées par le personnel soignant pour s'adapter au milieu, l’exercice des soins infirmiers demeure difficile vu les contraintes organisationnelles ; ces dernières représentent d'ailleurs un obstacle à la pratique et soulèvent des enjeux éthiques importants.