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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
81

Estado, mídia e criminalização do MST: um estudo a partir do Caso de Pocinhos (PB). / State, media and criminalization of the MST: a study from the Case of Pocinhos (PB).

ADISSI, Paula Oliveira. 17 September 2018 (has links)
Submitted by Johnny Rodrigues (johnnyrodrigues@ufcg.edu.br) on 2018-09-17T18:46:01Z No. of bitstreams: 1 PAULA OLIVEIRA ADISSI - DISSERTAÇÃO PPGCS 2011..pdf: 2293044 bytes, checksum: 2c000507afc4982726afcd9874ebbf06 (MD5) / Made available in DSpace on 2018-09-17T18:46:01Z (GMT). No. of bitstreams: 1 PAULA OLIVEIRA ADISSI - DISSERTAÇÃO PPGCS 2011..pdf: 2293044 bytes, checksum: 2c000507afc4982726afcd9874ebbf06 (MD5) Previous issue date: 2011-08-23 / A proposta dessa dissertação é estudar o processo de criminalização dos movimentos sociais, em especial do Movimento dos Trabalhadores Rurais Sem Terra (MST). Fazemos este estudo a partir de um caso emblemático de criminalização do MST, ocorrido em primeiro de maio de 2009 no município de Pocinhos no estado da Paraíba, no nordeste do Brasil. Analisamos que, neste, os sujeitos ativos dessa criminalização foram o Estado, com suas instituições coercitivas e punitivas; e a Mídia, através de uma criminalização ideológica. Investigamos este caso buscando conceituar a criminalização dos movimentos sociais, e estudar como se dão os elos que ligam proprietários de terra, promovedores de violência contra os integrantes do MST; o Estado; e a Mídia. Afirmamos que o processo de criminalização do MST e seus integrantes, no caso estudado, é “articulado” entre os latifundiários; as polícias; o Poder Judiciário; o Ministério Público; e a mídia local. Essas ações foram se complementando através da ideologia. Deste modo, defendemos a hipótese de que é pela ideologia que os discursos e as violências criminalizantes se homogenizam contra o MST. Realizamos este estudo utilizando, especialmente, de entrevistas, análise documental e pesquisa bibliográfica. / The aim of this dissertation is to study the process of criminalization of the social movements, especially the Landless Rural Workers' Movement (MST, from the Brazilian acronym). We stem from an emblematic case of criminalization of the MST, which occurred on May 1st 2009 in the municipality of Pocinhos, State of Paraíba, Northeast of Brazil. We have analyzed that the active subjects of this criminalization were the State, with its coercive and punitive institutions, and the mass media, by means of an ideological criminalization. We investigated this case seeking to conceptualize the criminalization of the social movements, and trying to study the bonds that link the land owners, who promote violence against the members of the MST; the State; and the Media. We claim that the process of criminalization of the MST and its members, in this particular case, involves land owners, the police, the Judicial Branch, the Public Ministry, and the local media. These actions were gradually complemented by the ideology. Thus, we defend the hypothesis that it is through ideological mechanisms that the speeches and the criminalizing violences homogenize themselves against the MST. We carried out this study mainly by means of interviews, documental analysis and bibliographical research.
82

Ruralismo pedagógico versus concepção de educação do MST: abordagens divergentes de projetos de educação do campo no Brasil / Pedagogical ruralism versus education conception of the mst: divergent approaches of education projects of the field in Brazil

Ramal, Camila Timpani [UNESP] 17 October 2016 (has links)
Submitted by CAMILA TIMPANI RAMAL null (camilatimpani@hotmail.com) on 2016-12-12T18:28:22Z No. of bitstreams: 2 TEXTO FINAL - Camila T Ramal (1).pdf: 3063046 bytes, checksum: a572cf35118cd999e53d12a44ba0b5c9 (MD5) TEXTO FINAL - Camila T Ramal (1).pdf: 3063046 bytes, checksum: a572cf35118cd999e53d12a44ba0b5c9 (MD5) / Approved for entry into archive by Felipe Augusto Arakaki (arakaki@reitoria.unesp.br) on 2016-12-13T13:15:13Z (GMT) No. of bitstreams: 1 ramal_ct_dr_ararcl.pdf: 3063046 bytes, checksum: a572cf35118cd999e53d12a44ba0b5c9 (MD5) / Made available in DSpace on 2016-12-13T13:15:13Z (GMT). No. of bitstreams: 1 ramal_ct_dr_ararcl.pdf: 3063046 bytes, checksum: a572cf35118cd999e53d12a44ba0b5c9 (MD5) Previous issue date: 2016-10-17 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Este trabalho tem como objetivo discutir a ideologia educacional do movimento do ruralismo pedagógico que atribuiu à escola rural a responsabilidade de cessar o êxodo rural, iniciado com o processo de industrialização do Brasil, no início do século XX. Embasados num contexto político, econômico e social demarcado pelo grande latifúndio, os ruralistas acreditavam que a conservação da população rural no campo evitaria a migração, o inchaço nas cidades e manteria assim, essa subjugada às práticas de mandonismo empregadas pelo sistema coronelista. Toda a ideologia de formação do homem rural perpassa por representações de alguns autores da época com a visão pejorativa do homem caipira. É através do pensamento do autor Sud Mennucci que ora fazemos este recorte histórico. Neste sentido, também é possível demonstrar como se apresenta a desvalorização do homem do rural no contexto nacional, principalmente no que se refere ao seu processo educacional e à manutenção do status quo muito presente no Brasil, no período assinalado. A outra abordagem temática recai sobre o século XXI, e assim, busca observar como o MST conduz, no contexto atual, a sua proposta de educação para o homem do campo, imbuídos por uma conjuntura de transformação social e histórica do sujeito do campo. Para esta segunda temática, os referenciais teóricos são embasados em autores como Paulo Freire, Dulce Whitaker, Miguel Arroyo, Roseli Caldart e Bernardo Mançano Fernandes que perpassam por discursos que colocam o homem do campo num ambiente educacional que propõe uma luta efetiva contra o latifúndio e a exploração do trabalho e demanda valorização das práticas e da cultura desse homem. Coloca-se assim, a diferença entre as duas propostas pedagógicas, que na busca por desenvolver uma concepção de educação do campo, condicionada por marcos históricos, políticos e sociais distintos, rumam por caminhos essencialmente divergentes. / This paper aims to discuss the educational ideology of the pedagogical rural movement, witch assigned to rural schools the responsibility to cease rural exodus, started with the process of industrialization in Brazil in the early twentieth century. Grounded in a political, economic and social context marked by the large estates (latifundium), the ruralists believed that maintaining the rural population in the countryside it would avoid migration, swelling of the cities, and it would keep that population subjugated to despotic practices employed by the landowner system – “coronelista” system. All the concepts of the rural man´s structure is permeated with representations of some contemporaneous authors, with pejorative view of a “yokel” man. It is through the thoughts of the author Sud Mennucci that now we frame this historical period. In this picture, it is also possible to demonstrate the devaluation of the rural man in the national context, especially regard to their educational process, and the maintenance of the “status quo”, very present in Brazil in the early twentieth century. The other thematic approach falls on the twenty-first century, and seeks to observe how the MST leads, in the current context, its education proposal for the countryman, imbued in a situation of social and historical transformation of that subject. For this second theme, the theoretical frameworks are grounded in authors such as Paulo Freire, Dulce Whitaker, Miguel Arroyo, Roseli Caldart and Bernardo Mançano Fernandes, that puts the countryman in an educational environment that proposes an effective fight against landlordism and labor exploitation and demands appreciation for this man´s practices and culture. So, it´s shown the differences between the two educational proposals, that seek to develop a concept of rural education, conditioned by distinct historical, social and political frameworks, flocks by essentially divergent paths
83

Educação Ambiental nos Assentamentos Rurais do MST

Galvão, Maria Neuma Clemente 06 September 2006 (has links)
Made available in DSpace on 2015-05-07T15:10:11Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2185696 bytes, checksum: 5f08f2866080a542ce8c1f223fbfc741 (MD5) Previous issue date: 2006-09-06 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Ce travail démontre l EA chez les « assentamentos » du MST, ayant comme objectif général l analyse des principes et des pratique des « assentados » sur le milieu naturel et l EA dans ces « assentamentos » rurales de la réforme agraire suivis pas le MST. Des observations ont été faites en sept aires du MST à Paraíba, pour reconnaitre la conception de milieu naturel, nature et EA chez les « assentados » et « assentadas », prenant comme échantillon le questionnaire répondu par les représentants de 19 états , dans un total de 53 membres du MST qui étaient présents au cours d Histoire pour les éducateurs de Campagne à l UFPB. Des visites d observation on été faites, en parlant, en photographiant et en analysant les aspects social, culturel et de relation avec le milieu dans ses aires, en ayant considération pour l intervention de la recherche-action aux « assentamentos » de Massangana III et Patativa do Assaré PB. La méthodologie utilisée c est celle de la recherche participative commenté ci-dessus, avec l aide de la phénoménologie et de l ethnographie, ayant en considération la réalité rurale et l EA. Dans la recherche participative, l informant est conduit à produire la connaissance et dévient le sujet de la production. Les instruments utilisés pour complémenter les données de l intervention participative étaient les suivants : le questionnaire déjà cité, avec des questions discussives et à multiple choix, l interview démi-structurée et l analyse de la pratique, en voyant la conception de nature, milieux naturel, et EA des participants (dans les catégories de Sauvé (1997), Reigota (2002) et Tamaio (2002) entre autres). En plus les documents du MST on été consultés. J ai pu constater que l EA existe dans la plus part des «assentamentos ». Dans le mouvement, ils sont en train d implanter cette réalité de manière massive, avec la base, et pas seulement avec quelques familles ni restrictif à quelques régions mais dans les écoles, dans les familles, dans les associations et en utilisant l agro-écologie en sachant que ça reste un défi construire un monde meilleur, laissant bien claire qu il faudra des années, des décennies et que peut être ses enfants et ses petits enfants cueillerons ses fruits. Un des objectifs du MST c est développer des technologies adéquates à la réalité, en préservant et récupérant les ressources naturelles, avec un modèle agricole auto sustenté. Chez l organisation de la production, le modèle technologique actuel adopté à l agriculture vise seulement les rapports d argent et compromets les ressources naturelles des futures générations, en cherchant l augmentation de la production du travail, des terres. Dans ses principes il est clair l inquiétude avec la terre, les êtres vivants de la nature, en améliorant les connaissances à propos de la nature et de l agriculture, évitant la monoculture, l utilisation de produits toxiques, en se battant contre les pratiques de contaminations et agression en produisant des aliments pour éliminer la famine dans le monde. Le mouvement, dans le processus éducationnel, à ouvert les yeux pour les préoccupations du milieu naturel. Dans les documents aussi bien que dans la pratique le MST démontre une attention spéciale envers la nature. L EA est présente de forme plus cohérente, quand la terre a été légalisée et les familles sont bien installées avec l aide du MST, des techniciens, avec des ressources et une assistance dans tous les domaines. / O presente trabalho apresenta a EA nos assentamentos do MST, tendo como objetivo geral analisar os princípios e a prática dos/as assentados/as sobre meio ambiente e EA nos assentamentos rurais da reforma agrária acompanhados pelo MST. Fiz observação em sete áreas do MST, na Paraíba, conhecendo a concepção de meio ambiente, natureza e de EA das assentadas e assentados, tomando como amostra do questionário respondido pelos/as representantes dos dezenoves Estados brasileiros, num total de 53 pessoas do MST, presentes no curso de História para educadores do Campus na UFPB em João Pessoa. Realizamos as visitas de observação, conversando, fotografando e analisando os aspectos social, cultural e ambiental nessas áreas, considerando a intervenção da pesquisa-ação nos assentamentos Massangana III e Patativa do Assaré -PB. A abordagem metodológica foi a pesquisa participante citada acima, considerando a realidade rural e a EA. Na pesquisa participante, o informante é conduzido à produção do conhecimento e se torna o sujeito dessa produção. Os instrumentos utilizados para complementar dados da intervenção participante foram os seguintes: o já citado questionário, com questões abertas e fechadas, a entrevista-semi estruturada e a análise da prática, vendo a concepção de natureza, meio ambiente e EA dos participantes (recorrendo as categorias de Sauvé(1997), Reigota(2002.a )e Tamaio (2002), entre outros. Além disso, consultei os documentos do MST. Constatei que a EA existe na maioria dos assentamentos. No movimento, estão implementando essa realidade de forma massiva, com a base, e não, com algumas famílias, e restrito a determinados locais, atuando nas escolas, nas famílias, nas associações e usando a agroecologia, sabendo que ainda é um desafio para se construir um mundo melhor, tendo claro que ainda levará anos, décadas, e talvez os filhos e netos colherão os frutos semeados. Um dos objetivos do MST é desenvolver tecnologias adequadas à realidade, conservando e recuperando os recursos naturais, com um modelo agrícola auto-sustentável. Na organização da produção, o atual modelo tecnológico adotado na agricultura visa apenas ao lucro, o que compromete os recursos naturais para as futuras gerações, buscando o aumento da produtividade do trabalho, das terras. Nos seus princípios, o MST deixa claro o cuidado com a terra, os seres vivos da natureza, melhorando os conhecimentos sobre a natureza e a agricultura, evitando a monocultura, o uso de agrotóxicos, combatendo todas as práticas de contaminação e agressão, produzindo alimentos para eliminar a fome da humanidade. O movimento, no processo educacional, tem despertado para as preocupações ambientais, promovendo uma modificação nos valores e atitudes, propiciando a construção de habilidades e mecanismos necessários á sustentabilidade ambiental. Nos documentos e na prática, o MST demonstra o cuidado com a natureza. A EA acontece de forma mais coerente, quando a terra já foi legalizada, e as famílias estão bem mais estruturadas com acompanhamento do MST, dos técnicos, com recursos e assistência em todos os sentidos .
84

O espaço agrário, a educação do campo e a formação técnica e política em agroecologia no MST / The agricultural area, the field of education and training policy and agroecology in the MST

Fabio Wellington Blanc 06 February 2009 (has links)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Este trabalho está inserido no cenário do projeto popular de Educação do Campo. A questão central da investigação são as principais formas e maneiras da formação de técnico em agroecologia propiciar ao trabalhador rural e sua família a construírem alternativas que favoreçam a sua permanência na terra. Trata-se de um estudo realizado sobre as propostas de educação técnico-profissional em agroecologia no contexto do Movimento dos Trabalhadores Rurais Sem Terra (MST). Pretendemos analisar as propostas e as ações educacionais na perspectiva dessa formação e discorrer sobre a concepção de trabalho, sempre em construção, no Projeto Político da Escola Agrícola 25 de Maio, localizada no assentamento Vitória da Conquista, situado no município de Fraiburgo - SC.
85

Egressos do curso pedagogia da terra e suas práticas educativas: um estudo de caso no Assentamento 25 de maio, Madalena, Ceará

Simplício, Antonia Vanderlucia de Oliveira 02 May 2011 (has links)
Dissertação (mestrado)—Universidade de Brasília, Faculdade de Educação, 2011. / Submitted by Jaqueline Ferreira de Souza (jaquefs.braz@gmail.com) on 2011-09-23T11:50:58Z No. of bitstreams: 1 2011_AntoniaVanderluciadeOliveiraSimplicio.pdf: 1915598 bytes, checksum: 27df6a4015e36d275a089e46629ac953 (MD5) / Approved for entry into archive by Jaqueline Ferreira de Souza(jaquefs.braz@gmail.com) on 2011-09-23T11:51:28Z (GMT) No. of bitstreams: 1 2011_AntoniaVanderluciadeOliveiraSimplicio.pdf: 1915598 bytes, checksum: 27df6a4015e36d275a089e46629ac953 (MD5) / Made available in DSpace on 2011-09-23T11:51:29Z (GMT). No. of bitstreams: 1 2011_AntoniaVanderluciadeOliveiraSimplicio.pdf: 1915598 bytes, checksum: 27df6a4015e36d275a089e46629ac953 (MD5) / Esta pesquisa é o resultado de um estudo de caso sobre as práticas educativas de nove educadores do Assentamento 25 de Maio, localizado no Município de Madalena, Ceará, egressos do curso de Licenciatura em Pedagogia da Terra da Universidade Federal do Rio Grande do Norte – UFRN, 2002 a 2006. O curso foi realizado em parceria com o Movimento dos Trabalhadores Rurais Sem Terra (MST) e o Programa Nacional de Educação na Reforma Agrária (Pronera). O objetivo desta pesquisa foi analisar em que medida o processo formativo vivenciado por estes educadores no curso de Pedagogia da Terra influencia as práticas educativas por eles desenvolvidas nas escolas e no assentamento em que atuam. A partir da opção metodológica de se realizar um estudo de caso, a presente pesquisa analisou o processo de formação vivenciado pelos educandos/educadores, através da análise de documentos tais como PPP do referido curso; Relatório de Execução de suas etapas; Monografias produzidas pelos educandos/as; acompanhamento das práticas desenvolvidas por eles nas escolas e no assentamento; realização de grupos focais e entrevistas semi-estruturadas com estes educadores, membros do assentamento onde atuam. Foram identificados diferentes tipos de mudanças positivas desencadeadas na escola e na comunidade, desde o início da atuação destes nove educadores no 25 de Maio. Entre elas destaca-se a melhora nos índices de avaliação das escolas do assentamento no IDEB; conquista de escolas e ampliação do nível de escolaridade; PPP aberto em movimento, organicidade do coletivo de educação do assentamento; escolas com primeiro lugar no município no Programa de Alfabetização na Idade Certa; Escola com 93% de aprovação no ENEM; escola abrindo fronteiras; articulação da Educação do Campo com outros municípios a partir da escola; fortalecimento da identidade Sem Terra e coletiva. O processo da pesquisa e os resultados encontrados demonstram ter havido uma influência positiva do processo formativo vivenciado pelos educadores do campo, especialmente no que diz respeito aos aprendizados construídos a partir da existência dos diferentes tempos educativos no curso de Pedagogia da Terra, destacando-se, entre eles, os vínculos e os trabalhos formativos propiciados na execução do tempo comunidade. __________________________________________________________________________________________ ABSTRACT / This research is a result of a case study on educational practices of nine educators from Settlement 25 de Maio, located at Madalena City of Ceará. They are former students from the Pedagogy of Land Gradutation of the Universidade Federal do Rio Grande do Norte - UFRN, from 2002 to 2006. This course was accomplished in partnership with Landless People’s Movement (MST) and National Program of Education in Land Reform - PRONERA. This research aims to analyze at what extent the formational process lived by these educators during the course influences the educational practices developed by them in their actions in the schools and community they are involved in. Starting from the methodological option of doing this case study, the current research did an assessment on the formation process lived by educator/students through the analyses of documents such as PPP (Pedagogical Political Project); reports from the developed phases; monographs produced by students; accompaniment of the developed practices done by them in the school or local communities; focal groups gatherings and semi-structured interviews with these educators; locals from the settlement where they act. It has been identified different types of positive changes triggered in the school and local community, since the beginning of the activism of these educators in the settlement 25 de Maio. Among them we underline the improvement of the rates of evaluation no IDEB; more schools and enlarging of level of education; PPP opens and in movement; educational collective more organized in the settlement; schools in the first place on the score of the city, in the Literacy Program in the Right Age; School with 93% of approval in the ENEM; school crossing borders; networking of Rural Education with other cities out of the school; strengthening of the Landless identity and collective identity. The research process and the results out of it has demonstrated to have had a positive influence coming from the formative process lived by the rural educators, especially in terms of the learning contend built from the existence of the distinct educational “times” in the Pedagogy of Land Course. The most important were the bounds and the formative works done during the local community time.
86

Neuronal representation and attentional modulation of space and feature information in primate vision

Xue, Cheng 19 October 2016 (has links)
No description available.
87

Improving thermal fracture resistance in ceramic microcomponents for spacecraft propulsion / Ökad motståndskraft mot termiskt orsakade sprickor i keramiska mikroraketer

Åkerfeldt, Erika January 2018 (has links)
Because of thermal transients and gradients occurring upon rapid heating or cooling, microcomponents made from High-Temperature Co-fired Ceramics (HTCC) often fail at temperatures far below what the materials can withstand per se. This work investigates how resistance to thermal fracture in HTCC microcomponents can be increased by improving the component design, aiming at increasing the thermal performance of a microthruster with integrated heaters. The effect of four design parameters:  component and cavity geometries (circular or square), heater placement (central or peripheral), and addition of embedded platinum layers, on thermal fracture resistance was investigated experimentally through a study employing design of experiments. Components of different designs were manufactured, and their thermal fracture resistance tested by rapid heating until the occurrence of failure. Peripheral heater placement and presence of embedded platinum layers were seen to improve resistance to thermal fracture, whereas the shape of the component and the cavity did not significantly affect thermal performance. The most favourable design was then applied for a microthruster that was fabricated and evaluated with respect to thermal fracture resistance. The microthruster survived rapid heating up to 1461°C, and was operated as a cold gas microthruster at temperatures up to 772°C. None of these temperatures were limited by component failure, but by the component interface.
88

Pluralist identities and empowering 'the people' : Brazil's Landless Workers' Movement (MST) at the crossroads

Flynn, Alex James January 2010 (has links)
This thesis centres its analysis upon the fascination for the collective at the potential cost of a delimitation of individual expression, within the confines of the Movimento dos Trabalhadores Rurais Sem Terra (MST). From the perspective of an applied anthropology, and to the end of contributing a constructive critique of the MST, the thesis seeks to ascertain how the movement has structured itself through the micro-actions of its membership around the domain of collective tropes of identity and where this complex set of understandings is leading the movement, both in the immediate, and more long-term, futures. To these ends, the principal focus of analysis is how actors within the movement construct and understand experiences of movement logic and emotion, as they perceive it, in and around their ambit. The thesis is thus orientated from an ethnographic perspective; throughout, actors’ accounts and experiences are privileged to attempt to throw light upon the manifold processes that being a member of the MST renders part of daily life. The thesis argues that in this extraordinarily dynamic time in Brazil, with socio-economic conditions so different to when the movement was founded, flexibility is going to be key as to whether the MST can endure, remaining relevant to its members and in a position where it can attempt to address its strategic aims. The thesis suggests that the movement faces a signal dilemma regarding the very device on which it has built its success, the unified collective front into which MST members’ identities can be subsumed. This fascination for the collective and its correlates, a hostile attitude to the media and the polarisation that can separate MST members from wider society, is explored through a series of differing contexts and the thesis closes with conclusions embedded within the framework of an applied anthropology; in pragmatic terms, how can the MST best achieve its stated goals at this historically significant point of its trajectory.
89

Příprava a charakterizace neutrální trehalasy pro strukturní studie / Preparation and characterization of neutral trehalase for structural studies

Šmídová, Aneta January 2016 (has links)
This study is part of a project which aim is solving the structure of the catalytic domain of neutral trehalase Nth1 from Saccharomyces cerevisiae. The main goal of this thesis is the preparation of new constructs of yeast Nth1 and optimization of their purification protocols, the selection of the ideal buffer for crystallization trials using the method of differential scanning fluorimetry (DSF) and at last the protein crystallization. Another part of the thesis is the measurement of the enzymatic activity of pNth1 WT in the presence of Bmh1 protein, verification of trehalose binding to the selected constructs of Nth1 using differential scanning fluorimetry (DSF), thermoforesis (MST) and further crystallization with trehalose. Neutral trehalase is highly conserved trehalase that has been found in a wide variety of organisms. These enzymes belong to the class of hydrolases, subgroup of glycosidases and hydrolytically cleave trehalose into two glucose molecules. Trehalose is a naturally occurring non-reducing disaccharide serving in yeast cells a source of carbon and energy as well as protection against stress conditions such as a thermal shock. Trehalose hydrolysis is essential for flying insects, because it is present as the main sugar component of insect haemolymph, therefore trehalase inhibitors...
90

Functional Dynamics of ASH1L Histone Methyltransferase and its Activation mechanism(s)

Al-Harthi, Samah 03 1900 (has links)
The human Absent, small, or homeotic disc1 (ASH1L) is a member of the Trithorax group (TrxG) proteins that play a role in epigenetic gene activation of developmental HOX genes via H3K36me2 methylation mark. ASH1L contains the evolutionarily conserved SET domain responsible for catalyzing monomethylated and dimethylated lysine formation. The crystal structure of the SET domain of ASH1L revealed a substrate-binding pocket blockage caused by an autoinhibitory loop (AI-loop) that undergoes dynamic changes during catalysis and could be exploited for inhibitor development. Studies have shown that the AI-loop regulates the SET domain, thus the KMTase activity of ASH1L. The SET domain adopts an autoinhibited state where the AI-loop blocks the entry of substrate to the active site, have made it a difficult target for the development of inhibitors. The emerging ASH1L's role in multiple oncogenic processes leading to cancer makes it a viable therapeutic target. Effective targeted inhibition of ASH1L enzymatic activity would be a potential therapeutic approach in cancers driven by high HOX gene expression. We employed the state-of-the-art 1H and 13C-detected solution NMR to better understand the ASH1L regulatory mechanism. We investigated the AI-loop's dynamic structure and conformational mobility of backbone and side chains in the absence and presence of the first- in-class small molecule inhibitors. Numerous backbone amide signals across the AI loop and the catalytic cleft of the SET domain are being broadened, indicating the complex interplay of fast local to slow segmental dynamics across the ASH1L SET domain. The binding of the first-in-class inhibitors perturbs the signals around the AI-loop and SAM binding cleft, validating the inhibitor binding site in the solution. The recently published crystal structures of the MRG domain bound to the ASH1L SET domain revealed disordered conformations of the AI-loop and rearrangement in the SAM binding site compared to the apo ASH1L SET domain. It has been proposed that MRG15 allosterically activates ASH1L by releasing the AI loop. Therefore, we performed extensive studies in an aqueous solution to understand the role of MRG15 in stimulating the catalytic activity of ASH1L. We found that the full-length MRG15 is necessary to induce histone methyltransferase activity of the catalytic SET domain of ASH1L. In contrast, the MRG domain alone cannot enhance the catalytic activity. Furthermore, we found that only the complex of ASH1L SET domain with MRG15 but not with isolated MRG domain can interact with nucleosomes. In summary, I have established the direct link between the structural dynamics of the ASH1L SET domain and its enzymatic activity. Moreover, I have defined the adaptor role of the complete MRG15 protein as the substrate recognition factor for the ASH1L protein without perturbing the AI loop or SAM binding site. The atomic level studies mentioned above, supported by the detailed structure and dynamics studies of the first-in-class inhibitor complex with ASH1L, establish the solid foundations for further drug candidate development, selectively targeting the ASH1L and potentially other H3K36me2 methyltransferases.

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