Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A trans-desidrocrotonina (t-DCTN) Ã o principal composto diterpenÃide presente no extrato da casca do caule de Croton cajucara (Euphorbiaceae). Este diterpeno possui um amplo espectro de atividades farmacolÃgicas que inclui antiinflamatÃria, antinociceptiva, e efeitos hipoglicemiante e hipolipidÃmico. SubstÃncias com esse perfil farmacolÃgico sÃo comumente associadas a efeitos deletÃrios sobre o fÃgado. Tendo em vista que estudos in vitro e in vivo mostraram uma hepatotoxicidade da t-DCTN, o presente estudo objetivou analisar em maior profundidade o seu potencial em causar dano hepÃtico e, entÃo, buscar estratÃgias farmacolÃgicas para mitigar tal toxicidade. Desta forma, os experimentos iniciais foram direcionados para observaÃÃo do dano hepÃtico em camundongos que receberam, por gavagem, uma Ãnica (aguda) ou repetidas administraÃÃes de t-DCTN, em doses que variam de 10 a 300 mg/kg. A segunda sÃrie de experiÃncias foi projetada para avaliar os efeitos do (i) prÃ-condicionamento com a menor dose de t-DCTN (10 mg/kg) ou etanol (1 g/kg), e do (ii) prÃ-tratamento com Vitamina E ou N-acetilcisteÃna (NAC) no dano hepÃtico associado a altas doses de t-DCTN em camundongos. Um possÃvel envolvimento de NO tambÃm foi verificado no efeito prÃ-condicionante de t-DCTN e/ou Etanol. t-DCTN em doses mais altas (100 e 300 mg/kg, v.o.) causou dano hepÃtico severo, comprovado por aumentos significativos (p <0,001) nos nÃveis sÃricos de ALT e AST e por alteraÃÃes histopatolÃgicas, quando administrada isolada ou repetidamente. Em contraste, as doses de 10 e 30 mg/kg nÃo promoveram alteraÃÃes significantes, sugerindo que a toxicidade da t-DCTN Ã dose dependente. O prÃ-condicionamento farmacolÃgico com t-DCTN (10 mg/kg, v.o.) e Etanol (1 g/kg, v.o.) atenuaram significativamente (p <0,001) a hepatotoxicidade associada a alta dose (100 mg/kg) de t-DCTN, como comprovado pela reduÃÃo na atividade das transaminases sÃricas, como tambÃm nas lesÃes hepÃticas. A suplementaÃÃo em camundongos com L-arginina, um substrato para geraÃÃo de NO, preveniu parcialmente o efeito hepatotÃxico da t-DCTN, possivelmente devido a um aumento na microcirculaÃÃo hepÃtica. Adicionalmente, o prÃ-tratamento com Vitamina E, mas nÃo com NAC, reduziu efetivamente os efeitos hepatotÃxicos de t-DCTN, comprovado pela diminuiÃÃo dos nÃveis sÃricos de ALT e AST, de TBARS hepÃtico e das alteraÃÃes histolÃgicas. Isto sugere que Vitamina E protege contra o aumento da peroxidaÃÃo lipÃdica hepÃtica promovido por alta dose de t-DCTN. Paradoxalmente, comparada a outros hepatotoxicantes relatados na literatura, a t-DCTN aumenta os nÃveis de glutationa hepÃtica que pode ser uma conseqÃÃncia do estresse oxidativo prolongado. Em conjunto, estes resultados confirmam as observaÃÃes anteriores sobre o potencial hepatotÃxico da t-DCTN e sugerem que um aumento no estresse oxidativo e na peroxidaÃÃo lipÃdica das membranas dos hepatÃcitos contribui para o dano hepÃtico desse diterpeno. A suplementaÃÃo com Vitamina E, um antioxidante lipossolÃvel, ou o prÃ-condicionamento com doses menores de t-DCTN ou etanol poderiam ser profilaticamente Ãtil para superar os efeitos hepatotÃxicos de t-DCTN / The trans-dehydrocrotonin (t-DCTN) is a major diterpenoid compound present in bark extracts of Croton cajucara (Euphorbiaceae) stem. This diterpene possesses a wide spectrum of pharmacological activity that include anti-inflammatory, antinociceptive, hypoglycemic and antihyperlipidemic effects. Deleterious effects on liver are not uncommon with substances having this pharmacological profile. Keeping in view the reported hepatotoxicity of t-DCTN in vitro and in vivo, the present study was carried out to analyse in greater depth its potential to cause hepatic damage and then to seek pharmacological strategies to mitigate such a toxicity. Accordingly, our initial experiments were aimed to observe the hepatic damage in mice that received the single (acute) or repeated administrations of t-DCTN by oral gavage, at doses ranging from 10 to 300 mg/kg. The second series of experiments were designed to evaluate the effects of (i) pre-conditioning with a smaller dose t-DCTN or ethanol, and (ii) pre-treatments with Vitamin E or NAC on high-dose -associated hepatic injury in mice. A possible involvement of NO was also verified on the pre-conditioning effects of t-DCTN and or Ethanol. t-DCTN at higher doses (100 e 300 mg/kg, v.o.) caused severe hepatic damage as evidenced by significant (p<0,001) increases in the serum levels of ALT and AST and histopathological alterations, whether administered singly or repeatedly. In contrast, at the doses of 10 e 30 mg/kg, there were no significant alterations suggesting that the toxicity is a dose-related one. Pharmacological pre-conditioning with t-DCTN (10 mg/kg, p.o.) e Ethanol (1 g/kg, p.o.) significantly (p<0,001) attenuated the high-dose t-DCTN (100 mg/kg) -associated hepatotoxicity, as evidenced by reductions in serum enzyme activities as well as the hepatic lesions. In mice supplemented with L-arginine, the substrate for NO generation only partially prevented the hepatotoxic effect of t-DCTN most possibly due to an improved hepatic microcirculation. Additionally, pre-treatment with Vitamin E but not the NAC effectively reduced hepatotoxic effect of t-DCTN, evidenced by diminished serum levels of ALT, AST and hepatic TBARS and histological alterations. This suggests that Vitamine E protects against the increased hepatic lipid peroxidation promoted by high-dose t-DCTN. Paradoxically, compared to other hepatotoxicants reported in literature, t-DCTN enhanced the hepatic glutathione levels, which may be a consequence of prolonged oxidative stress. Taken together, these results confirm the earlier observations on the hepatotoxic potential of t-DCTN and suggest that an increased oxidative stress and lipid peroxidation of hepatocyte membranes contributes to hepatic damage. Supplementation with liposoluble antioxidant Vitamina E, or prÃ-conditioning with smaller doses of t-DCTN or ethanol might be useful prophylactically to overcome hepatotoxic effects of t-DCTN

trans-Sialidase de Trypanosoma cruzi (TcTS) pertence à família de glicoproteínas de superfície do parasita e constitui um dos poucos exemplos naturais de glicosiltransferases superficiais encontradas em eucariotes. T. cruzi é incapaz de sintetizar ácido siálico e utiliza esta enzima para retirar este monossacarídeo de glicoconjugados do hospedeiro para sialilar moléculas aceptoras, como mucina-GPI (glicosilfosfatidilinositol), presentes na sua membrana plasmática. Esta enzima é específica em catalisar, preferencialmente, a transferência de ácido siálico para moléculas de mucina, originando ligações -2,3 com moléculas de galactose aceptoras na superfície do parasita. Considerando a heterogeneidade das moléculas de mucina de T. cruzi, é necessário que novas moléculas sejam sintetizadas a fim de que estas atuem como substratos glicopeptídicos, os quais podem levar ao melhor entendimento das interações entre enzima e substratos e permitir o planejamento racional de inibidores seletivos. Por isso, o trabalho foi divido em três rotas sintéticas: (i) preparação do doador de galactose, (ii) preparação dos aceptores-doadores e (iii) acoplamento dos dissacarídeos com aminoácidos aceptores para obtenção dos blocos de construção. Apesar dos objetivos propostos inicialmente não terem sido totalmente alcançados, o trabalho desenvolvido durante esse período permitiu a síntese do doador de galactose (3) em três etapas, aceptor de galactose (6) em cinco etapas, dissacarídeo (11) na glicosilação de 6 com 3, aminoácidos aceptores (13 e 14) e também dos blocos de construção (17 e 18) decorrente do acoplamento de 11 com os aminoácidos aceptores. Não obstante, é importante ressaltar que apesar da extensa rota planejada, porém necessária, a síntese dos blocos de construção é inédita. Portanto, pode-se concluir que o trabalho trouxe relevante contribuição no que diz respeito à química de carboidratos e à disponibilização de dados espectrométricos de compostos orgânicos para a literatura. / Trypanosoma cruzi trans-sialidase (TcTS) belongs to the family of glycoproteins expressed on the surface of the parasite and constitutes one of the few examples of natural surface glycosyltransferases found in eucariotes. T. cruzi can not synthesize sialic acid itself and uses this enzyme to scavenge this monosaccharide from host glycoconjugates to sialylate acceptors molecules, such as GPI (glycosylphosphatidylinositol) mucins, that are present in parasite plasma membrane. This enzyme is specific to catalyze, preferentially, the transference of sialic acid to mucin glycoproteins, generating -2,3-linkages with acceptor galactose molecules in the parasite surface. Considering the heterogeneity of T. cruzi mucin molecules, its necessary to synthesize new compounds that can act as glycopeptide substrates, leading to a better understanding concerning the enzyme and substrates and allow the rational design of some selective inhibitors. Thus, this work was developed in three synthetic routes: (i) the synthesis of galactose donor, (ii) synthesis of donor-acceptors and (iii) coupling between disaccharides and acceptors amino acids in order to obtain building blocks. Despite of some objectives initially proposed had not been accomplished, the developed work during this period allow the synthesis of the galactose donor (3) in three steps, donor-acceptor (6) in five steps, disaccharide (11), acceptors amino acids (13 and 14) and also the building blocks (17 and 18). However, its important highlight that the synthesis of the building blocks by this necessary, but extensive, synthetic route is unpublished. Therefore, it can be concluded that the present work brought rich contribution concerning the carbohydrate chemistry and the availability of spectrometric data of organic compounds to the literature.

Esta tese é sobre a mobilidade que construiu o Brasil desde o período anterior à colonização: é o que chamamos de trans-formação. O trabalho percorre a cronologia da construção do país tal qual o conhecemos hoje. Inicia-se com uma abordagem teórica, tratando das culturas em movimento, destacando a mobilidade como básica para a própria existência humana em sua relação com o ambiente. O caminho da trans-formação do Brasil começa com as várias culturas ameríndias, de forma especial, os tupis, devido à marcha nacional que empreenderam mesmo antes da chegada por portugueses. Os europeus encontraram um país já descoberto. Percebem-se que elementos ecológicos/ambientais e as guerras foram preponderantes para a mobilidade tupi. Então, chega a invasão portuguesa. Aborda-se a interculturalidade lusitana a partir dos fatores que levaram à sua formação. Os portugueses trazem os escravos africanos. Analisam-se as diversas áfricas que desembarcaram no Brasil pelo tráfico de escravos. Dessa forma se evidenciará um dos mais importantes produtos das três matrizes multiculturais (as ameríndias, a portuguesa e as africanas) que trans-formaram o Brasil: o bandeirante. As bandeiras dependiam essencialmente das três vertentes culturais, mestiçadas e/ou separadamente. Percorreram quase toda a extensão do território nacional. Seguiram-nos os monçoneiros, especialmente no ressuprimento de vilas estabelecidas pela exploração do ouro. Também os missionários católicos, de forma especial, os jesuítas, colaboraram com a trans-formação do Brasil. Por fim, toma-se o lócus Sorocaba como exemplo de uma interculturalidade brasileira já trans-formada, destacando o tropeirismo, a feira de muares, e a experiência intercultural de dois ilustres personagens: o primeiro pastor protestante brasileiro, Rev. José Manoel da Conceição, e o primeiro dos monges do Contestado, João Maria de Agostini. / This thesis is about the mobility that built Brazil from the period before colonization: this is what we call transformation. The work goes through the construction chronology of the country as we know it today. It begins with a theoretical approach, dealing with the cultures in movement, highlighting the mobility as basic for the human existence itself in its relationship with the environment. The path of Brazil\'s transformation begins with the various Amerindian cultures, especially the Tupi, because of the \"national\" march they undertook even before the arrival of the Portuguese. Europeans have found an already \"discovered\" country, with all geographical landscape already named. It is perceived that ecological / environmental elements and wars were preponderant for Tupi mobility. Then, the Portuguese invasion arrives. The Lusitanian interculturality is approached from the factors that led to its formation. The Portuguese bring the African slaves. It\'s possible to analyze the various \"Áfricas\" that have landed in Brazil for the slave traffic. In this way, one of the most important products of the three multicultural matrices (Amerindian, Portuguese and African) that transforms Brazil will become evident: the bandeirante. The bandeiras depended essentially on the three cultural strands, mestizo and / or separately. They traveled almost the entire length of the national territory. Monsoons followed us, especially in the resupply of villages established by the exploitation of gold. Also, the Catholic missionaries, especially the Jesuits, collaborated in the transformation of Brazil. Finally, the Sorocaba locus is taken as an example of an already trans- formed Brazilian interculturality, highlighting the tropeirismo, the muares fair, and the intercultural experience of two illustrious characters: the first Protestant Brazilian pastor, Rev. José Manoel da Conceição, and the first of the \"monks\" of the Contestado, João Maria de Agostini.

Os ácidos graxos trans competem com os ácidos graxos essenciais inibindo as enzimas envolvidas na síntese dos ácidos graxos polinsaturados de cadeia longa. Quantidades adequadas de ácidos graxos essenciais na dieta minimizam este efeito. No entanto, pouco se conhece da ação dos isômeros trans, sob condições de restrição ou deficiência dietética dos ácidos graxos essenciais, sobre o percentual de deposição tanto dos próprios isômeros trans, como dos ácidos graxos polinsaturados nos lipídios dos tecidos. Foram avaliadas dietas ricas em ácidos graxos trans e com diferentes concentrações de ácidos graxos essenciais em ratos. A incorporação de ambos foi proporcional à concentração na dieta, mas variou entre os tecidos estudados. Verificou-se que as quantidades de ácidos graxos trans incorporadas pelo tecido adiposo foi a maior, enquanto que o cérebro incorporou a menor quantidade. A despeito da incorporação dos ácidos graxos trans, o perfil de ácidos graxos do cérebro manteve-se estável em relação às variações dietéticas. Não se observou acúmulo dos ácidos graxos trans em função do prolongamento do consumo da dieta. Os ácidos graxos essenciais incorporados aos tecidos também foram modulados pela dieta, e em concentrações adequadas influenciaram na menor deposição dos isômeros trans no tecido adiposo, plasma e tecido cardíaco. Avaliando-se a composição dos ácidos graxos nos fosfolipídios do tecido cardíaco, observou-se que a fosfatidiletanolamina incorporou a maior porcentagem dos isômeros trans seguida da fosfatidilcolina e da cardiolipina, respectivamente. Embora tenha incorporado quantidades intermediárias dos ácidos graxos trans a fosfatidilcolina teve uma maior alteração no perfil de ácidos graxos em comparação aos demais. A reduzida concentração de ácidos graxos trans incorporados na cardiolipina das mitocôndrias e no cérebro sugere a existência de um mecanismo protetor para a manutenção da composição lipídica necessária às atividades funcionais. / Trans fatty acids compete with essential fatty acids inhibiting the enzymes of the long chain polyunsaturated fatty acids synthesis. Appropriate amounts of dietary essential fatty acids minimize this effect. However, little is known about the action of trans isomers on the deposition percentage of these own trans isomers itself or as polyunsaturated fatty acids in tissue lipids, when under dietary restriction or deficiency conditions of essential fatty acids. Diets high in trans fatty acids and with different concentrations of essential fatty acids were assessed. The incorporation of trans isomers and of essential fatty acids was proportional to their dietary concentration, but varied among the tissues studied. It was verified that the adipose tissue incorporated the largest amount of trans fatty acids while the brain incorporated the smallest. In spite of the trans fatty acids incorporation, the profile of brain fatty acids was maintained stable in relation to dietary variations. No accumulative deposition of trans fatty acids was observed in relation to extended length of time of dietary consumption Essential fatty acids incorporated in tissues were also modulated by diet and in moderate concentrations influenced the lower deposition of trans isomers in adipose tissue, blood plasma and heart. By assessing fatty acids composition in phospholipids of heart, it was verified that phosphatidylethanolamine incorporated the largest percentage of trans isomers followed by phosphatidylcholine and cardiolipin, respectively. Phosphatidylcholine presented the greatest change in fatty acids profile when compared to the others phospholipids, although incorporating intermediate amounts of trans isomers. The reduced concentration of trans fatty acids incorporated in cardiolipin and brain suggests that there is a protector mechanism for maintenance of the lipids composition required for functional activities.

O trabalho teve por objetivo o desenvolvimento de bases gordurosas para margarinas utilizando o método de modificação por interesterificação, como alternativa ao processo de hidrogenação parcial, que forma isômeros trans. / The aim of the study was to develop soft margarines by using intertesterification, as an alternative of hydrogenation, which forms trans isomers.

Syftet med denna uppsats är att genom att använda ett specifikt teoretiskt ramverk kunna undersöka och problematisera den stora förekomsten av transpersoner med erfarenhet av ätstörningar. Ramverket är baserat på Sara Ahmeds teorier om orientering och bygger på synen på samhället som uppbyggt av heteronormativa linjer vilka transpersoner förhåller sig till. Genom att välja ut illustrerande exempel från två antologier kretsade kring kropp och identitet har jag kunnat peka på att den press som transpersoner utsätts för i samhället leder till minskat handlingsutrymme, maktlöshet, kroppslig dysfori och assimilation. Med behovet av att reglera de känslor som uppstår samt den fysiska kroppen kan ätstörningen ses som ett verktyg med dubbel funktion. Dels för att hantera maktlösheten inför världen och återta kontroll över den kropp som någon annan definierat och begränsat. Och dels utifrån behovet av att skapa sig själv som begriplig inför sig själv och världen - för att kunna existera.

As long as the states of East Asia can keep the growing rate of their economies, they can become the centre of the world economy in oncoming years. China and India have potetial to become regional superpowers and to dominate the world economy and replace the USA in this position. The USA must not lose their influance in Asia to remain the world superpower and creator of the world order. They need to find allies in Asia, that can help them to become a part of asian regional integrations and have influence on their development. The US goal is to carry through their own trans-pacific integration, that could be basis for Asia-Pacific Free Trade Area. The success of this integration indipends on U.S.-China`s relations and on the way how they will be able to solve their mutual disputes (chinese currency policy, commitments to WTO, chinese indigenous innovation policy etc.).

The purpose of this transcendental phenomenological study was to explore Black transgender men's experiences navigating systems of racism and transphobia. To this end, I utilized a critical race theory and intersectionality theory framework to answer the following question: What are Black transgender men's experiences with power, privilege, and oppression? The ten Black transgender men and transmasculine people who participated in this study provided detailed and moving accounts of their experiences with systems of oppression. Six major themes were prominent throughout participant narratives: (1) developing an empowered view of self, (2) navigating double consciousness, (3) having a target on your back, (4) strategies of resilience, (5) culture of silence, and (6) finding quality care. Overall, participants offered insight and keen awareness of their intersecting racial and gender identities, as well as speaking intimately about how the shift from societal perceptions and identification as a Black woman to a Black man impacted their sense of self and views of the world. Additionally, implications and conclusions drawn from the stories of participants offer recommendations for counselors, mental health professionals, practitioners, and programs to consider implementing to provide culturally responsive and competent care to Black transgender men.

An essay and short story collection about rebirth and being trans and neurodivergent. The essays and stories cover the entire length of my MA, but are mostly written before I came out as trans and edited after. The arc follows this discovery as well as the discovery of my writing following more experimental means including the twisting and playing with the braided essay, the introduction of essaying moves to fiction forms, and moving from what I thought was about death to what I realized I was writing all along about rebirth.

La maladie de Huntington (MH) est une maladie autosomale dominante causée par une expansion de la répétition CAG codant pour une expansion de la polyglutamine dans le premier exon du gène Huntingtine (HTT). Ce gène code pour une protéine ubiquitaire dont la mutation entraine de graves symptômes moteurs, psychiatriques et cognitifs, dus à la dégénérescence spécifique des neurones GABAergique épineux moyens du striatum. Nous proposons d'utiliser le trans-épissage pour développer un vecteur de thérapie génique qui réduira significativement voir éliminera l'expression de la protéine mutée tout en restaurant un niveau physiologique de HTT normale dans les cellules affectées par la mutation du gène Huntingtine. Cette technologie est basée sur le remplacement de l'exon muté par un exon sans mutation pendant l'étape de maturation de l'ARNm. Du fait du caractère dominant de la mutation,l'efficacité thérapeutique nécessitera une réaction de trans-épissage très efficace capable de convertir une portion significative de pre-ARNm HTT mutés en en ARNm HTT normaux. Nous avons donc développé un système rapporteur fluorescent permettant la détection des évènements de trans-épissage afin d’identifier les séquences les plus performantes parmi une centaine de molécules candidates. Nous avons validé notre stratégie de criblage basée sur la fluorescence et réalisé le criblage sur plusieurs introns HTT (3, 9 et 20) qui ont démontré des zones favorables au trans-épissage. Une méthode de quantification directe et absolue du taux de trans-épissage a également été validée pour déterminer très précisément le taux de correction. L’ensemble de ce travail a permis de contribuer à la mise en évidence de la faisabilité du trans-épissage dans le contexte de la MH. / Huntington’s disease (HD) is an autosomal dominant genetic disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract in the first exon of the Huntingtin gene (HTT). This gene encode a ubiquitous protein in which mutation lead to severe motor, psychiatric and cognitive deficits and causes degeneration of specific neuronal populations, in particular the GABAergic medium spiny neurons of the striatum. We propose to use trans-splicing to develop a gene therapy vector that will significantly reduce or eliminate the expression of the mutant protein while restoring a physiological level of normal HTT in cells affected by the HD mutation. This technology is based on replacement of the mutated exon by a normal version during the mRNA maturation process. HTT mutation being dominant, therapeutic benefits necessitates a highly efficient trans-splicing reaction that would convert a significant proportion of mutant-HTT pre-mRNA into normal HTT mRNA. For this purpose, we developed a fluorescent reporter system enabling the detection of trans-splicing events in high content screening in order to identify the most potent trans-splicing sequences among hundreds of molecules. We validated our fluorescent screening strategy and implement trans-splicing screening on 3 HTT introns (3, 9 and 20), in which we demonstrated the presence of hotspot promoting trans-splicing reactions. A direct and absolute quantification method was also validated to accurately assess the correction rate. Overall, this work generated additional evidences of trans-splicing feasibility in HD.