966 resultados para Legalization of regulation
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Based on the proposal entitled anti-prohibitionist, contrary to prohibition and illegality of cannabis and its use, the anti-prohibitionist Collectives proposes to discuss the topic of drugs, especially marijuana, aiming decriminalization and legalization of this psychoactive. With this idea was articulated anti-prohibitionist movement in Natal, by organizing collectives that discuss issues related to drug use and conduct activities directed to this issue, such as Marijuana Marches and Cycles of Debates anti-prohibitionist. In this study we sought to understand the positioning in social and cultural terms, the marijuana users participating of the collectives, on the situation of illegality of their actions, in front of social, legal and moral question involved in the illicit psychoactive, through initiatives conferences, events and demonstrations for this purpose
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The career of civil engineer Henrique de Novaes, a remarkable figure in the academic, technical and political fields, demonstrates its extensive and relevant work across Brazil in the first half of the twentieth century. It covered from the design of water supply and sewage works, road and rail transport networks, works against drought in the Northeast, hydroelectric and harbor facilities to the urbanization planning and architectural projects, which displays a systematic and multiple production. City and territory conformed to his fields of verification, practical and above all, transformation. The search for understanding of the inclusion of a social actor in this process thus contributes to the specific analysis of the doings of Henrique de Novaes, who graduated at Polytechnic School of Rio de Janeiro in 1906. From a polymorphic activity in different scales, one tries to figure how, through academic education or professional practice, urban history in Brazil can be told or built. The introduction of technological innovations matched the purposes of planning and urban sprawl, as well as met the specifications of regulation and institutionalization of public infrastructure services at the time. The overall plans proposed by the engineer thought of the city as a whole, interconnected to the structural networks. At the same time, the knowledge of a larger physical scale the territory bounces back in the urban in a relationship of reciprocity and completeness. The objective research, therefore, tries to understand the roles played by Henrique de Novaes s works and academic education in the accomplishment of systematic modernization of Brazilian urban space and territory, recovering a little known historical figure by current historiography. It is proposed, as methodological axis, that the study of this professional career configures itself as an essential element for understanding the idea of progress embodied in the technical studies and proposals for improvements and sanitation nationwide in the first half of the twentieth century . The primary sources for the construction of this analysis were technical articles in journals of the period ( Clube de Engenharia , Viação e Revista Brasileira de Engenharia ), and technical reports, government messages, newspaper articles published at the time, autobiographical reports and the engineer s verbal communications with relatives. The work is structured in three chapters: "Biographical traces, academic education and 'technical and political' activities" illustrates the initiation into the technical, public and political environment; Chapter 2, "Technique and territory" outlines his network understanding through sanitation and transport services; Chapter 3 "Technique and City" describes the influence of polytechnics knowledge on the propositions of modernization of cities; Finally, "Final Thoughts: An Evaluation," presents an overview of the affiliations and practice of an engineer in the different scales, and its contribution to the modernization of Brazilian urban and territorial space
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The Sectoral Plan was inserted as an urban instrument in Master Plan of Natal (LC82/07), since then it has been deepened. It is guided to the equitable distribution of the benefits of urbanization, aimed the efetivation of the Right to the City and the Environmental function of property in the context of urban planning. Thereby, the Sectoral Plan was inserted into the perspective of promoting a favorable field for applying articulated of instruments defined in the Master Plan, and them with urban interventions, through the deepening of macrozoning - coming out of dimension of the city and going to a small fraction of the urban by reducing scaling - facilitating democratic management in accordance with the City Statute. However, the absence of regulation and the conceptual and operational fragility of the instrument, approached it of other existent experiences and instruments, limiting its application and evaluation. Considering the innovative nature of the instrument and the intense social participation, we inquire about conceptual and operational elements which could give greater effectiveness to Sector Plan in construction? Guided by that question, this dissertation aim to understand the nature and operational procedures of Sectoral Plan, seeking to do indications about the conceptual and operational aspects of implementing a Sector Plan. The neighborhood of Ponta Negra was selected as empirical universe because it was the first sector defined in the Master Plan. This research adopts reference authors who´s make reflection and insights about the matrix of Urban Reform, whose principles constitute the basis of the trajectory of revision of urban planning in Brazil since the 1980s, highlighting Raquel Rolnik, Nelson Saule Júnior and Orlando Alves dos Santos Júnior. For the local monitoring, we use the authors Alexsandro Ferreira Cardoso Silva, Rosa Maria Pinheiro Oliveira e Marise Costa da Souza Duarte, in order to understand the growth dynamics of Natal, lawfully and urbanistically
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Interações sociais são frequentemente descritas como trocas sociais. Na literatura, trocas sociais em Sistemas Multiagentes são objeto de estudo em diversos contextos, nos quais as relações sociais são interpretadas como trocas sociais. Dentre os problemas estudados, um problema fundamental discutido na literatura e a regulação¸ ao de trocas sociais, por exemplo, a emergência de trocas equilibradas ao longo do tempo levando ao equilíbrio social e/ou comportamento de equilíbrio/justiça. Em particular, o problema da regulação de trocas sociais e difícil quando os agentes tem informação incompleta sobre as estratégias de troca dos outros agentes, especificamente se os agentes tem diferentes estratégias de troca. Esta dissertação de mestrado propõe uma abordagem para a autorregulacao de trocas sociais em sistemas multiagentes, baseada na Teoria dos Jogos. Propõe o modelo de Jogo de Autorregulacão ao de Processos de Trocas Sociais (JAPTS), em uma versão evolutiva e espacial, onde os agentes organizados em uma rede complexa, podem evoluir suas diferentes estratégias de troca social. As estratégias de troca são definidas através dos parâmetros de uma função de fitness. Analisa-se a possibilidade do surgimento do comportamento de equilíbrio quando os agentes, tentando maximizar sua adaptação através da função de fitness, procuram aumentar o numero de interações bem sucedidas. Considera-se um jogo de informação incompleta, uma vez que os agentes não tem informações sobre as estratégias de outros agentes. Para o processo de aprendizado de estratégias, utiliza-se um algoritmo evolutivo, no qual os agentes visando maximizar a sua função de fitness, atuam como autorregulares dos processos de trocas possibilitadas pelo jogo, contribuindo para o aumento do numero de interações bem sucedidas. São analisados 5 diferentes casos de composição da sociedade. Para alguns casos, analisa-se também um segundo tipo de cenário, onde a topologia de rede é modificada, representando algum tipo de mobilidade, a fim de analisar se os resultados são dependentes da vizinhança. Alem disso, um terceiro cenário é estudado, no qual é se determinada uma política de influencia, quando as medias dos parâmetros que definem as estratégias adotadas pelos agentes tornam-se publicas em alguns momentos da simulação, e os agentes que adotam a mesma estratégia de troca, influenciados por isso, imitam esses valores. O modelo foi implementado em NetLogo.
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Research has pointed to the importance of artists in the early stages of gentrification; however, few studies have examined specifically the meaning of gentrification and place-change from the perspective of artists themselves, and few studies have investigated the role of ‘creative city’ policies as unintended drivers of gentrification processes. This study generates insights into artists’ own views of gentrification processes within the gentrifying bohemia of the Ouseburn Valley in Newcastle upon Tyne in the North East of England. We stress that gentrification in this area cannot solely be understood as a process of displacement, but is also clearly linked to the growth of modes of regulation and commercialisation within social space. Increasing regulation, brought about by greater local state focus on ‘creative districts’, has impacted the Valley. Alongside this, projects of property development as well as a general growth in the popularity of the Valley as a nightlife consumption district and area of production for commercially-orientated creative class workers have challenged artists’ values of the area as a ‘secret garden’ where romantically inflected values of self-expression, autonomy, spontaneity and non-instrumental artist cooperation can be found.
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This thesis examines the regulatory and legislative approach taken in the United Kingdom to deal with deaths arising from work related activities and, in particular, deaths that can be directly attributed to the behaviour of corporations and other organisations. Workplace health and safety has traditionally been seen in the United Kingdom as a regulatory function which can be traced to the very earliest days of the Industrial Revolution. With an emphasis on preventing workplace accidents and ill-health through guidance, advice and support, the health and safety legislation and enforcement regime which had evolved over the best part of two centuries was considered inadequate to effectively punish corporations considered responsible for deaths caused by their activities following a series of disasters in the late twentieth and early twenty-first centuries. To address this apparent inadequacy, the Corporate Manslaughter and Corporate Homicide Act 2007 was introduced creating the offence of corporate manslaughter and corporate homicide. Based on a gross breach of a relevant duty of care resulting in the death of a person, the Act effectively changed what had previously considered a matter of regulation, an approach that had obvious weaknesses and shortcomings, to one of crime and criminal law. Whether this is the best approach to dealing with deaths caused by an organisation is challenged in this thesis and the apparent distinction between ‘criminal’ and ‘regulatory’ offences is also examined. It was found that an amended Health and Safety at Work etc. Act 1974 to include a specific offence of corporate killing, in conjunction with the Health and Safety (Offences) Act 2008 would almost certainly have resulted in a more effective approach to dealing with organisations responsible for causing deaths as consequence of their activities. It was also found that there was no substantive difference between ‘regulatory’ and ‘criminal’ law other than the stigma associated with the latter, and that distinction would almost certainly disappear, at least in the context of worker safety, as a consequence of the penalties available following the introduction of the Health and Safety (Offences) Act 2008.
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Résumé : Le nucléole est considéré comme étant une « usine » à produire des ribosomes. Cette production est la fonction la plus énergivore de la cellule. Elle met en jeu les trois ARN polymérases et représente 80% de l’activité de transcription au sein d’une cellule. Les trois quarts de cette activité de transcription correspondent à la synthèse des ARNr par l’ARN polymérase I (ARNPI). Ainsi mieux comprendre les mécanismes cellulaires se déroulant à l’intérieur de ce compartiment permettra le développement de nouveaux traitements contre le cancer. La synthèse d’ARNr par l’ARNPI est régulée à trois niveaux : l’initiation de la transcription, l’élongation et le nombre de gènes de l’ARNr en transcription. La plupart des travaux qui se sont intéressés à ces niveaux de régulation ont été réalisés avec des cellules en phase exponentielle de croissance. Au cours de mes travaux, je me suis attardé sur la régulation de la transcription par l’ARNPI au cours de la phase G1 du cycle cellulaire et au début de la phase S. Ainsi mes résultats ont montré que si la chromatine des gènes de l’ARNr est essentiellement dépourvue de nucléosomes, la régulation de l’ARNPI diffère dans des cellules en G1 et au début de la phase S. J’ai pu de ce fait observer qu’en G1, la transcription de l’ARNPI se concentre sur un nombre réduit de gènes en transcription. Dans des cellules arrêtées au début de la phase S avec de l’hydroxyurée, la transcription de l’ARNPI est perturbée par un défaut de maturation de l’ARNR. Fort de ces résultats sur la nature des gènes ribosomaux en phase G1, je me suis attardé à la réparation de ces gènes lors de cette phase. Alors que dans des cellules en phase exponentielle de croissance irradiées avec des UVC, la chromatine des gènes de l’ARNr se ferme ; je n’ai pas observé la formation de nucléosomes suite à l’irradiation de cellules synchronisée en G1. Mes résultats montrent également que la réparation est plus efficace. Parallèlement, j’ai exploré l’assemblage du complexe de réparation par excision de nucléotides. Toutefois, les résultats obtenus sont peu concluants.
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Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a member of the ATP binding cassette (ABC) transporter superfamily that functions as a cAMP-activated chloride ion channel in fluid-transporting epithelia. There is abundant evidence that CFTR activity (i.e., channel opening and closing) is regulated by protein kinases and phosphatases via phosphorylation and dephosphorylation. Here, we review recent evidence for the role of protein kinases in regulation of CFTR delivery to and retention in the plasma membrane. We review this information in a broader context of regulation of other transporters by protein kinases because the overall functional output of transporters involves the integrated control of both their number at the plasma membrane and their specific activity. While many details of the regulation of intracellular distribution of CFTR and other transporters remain to be elucidated, we hope that this review will motivate research providing new insights into how protein kinases control membrane transport to impact health and disease.
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Em Portugal o “Sistema Nacional de Sangue” subsiste com base numa cadeia de abastecimento de sangue assente em dádivas provenientes 100% de Dadores Voluntários não Remunerados, com um serviço nacional de sangue de base exclusivamente pública. O seu modelo organizacional assenta numa estrutura de âmbito nacional com funções de regulação, fiscalização, produção e distribuição de sangue e componentes sanguíneos às organizações de saúde públicas e privadas. Em complemento a esta rede de abastecimento existem ainda outras fontes de abastecimento, como os hospitais licenciados e outras instituições, que também procedem a todas as actividades de colheita, processamento e validação para uso final de componentes sanguíneos. Nestas situações a produção de componentes sanguíneos é realizada numa perspectiva de auto-suficiência, local ou regional, um dos princípios fundamentais de todos os serviços nacionais de sangue. Esta dissertação pretende contribuir para o conhecimento do sistema de abastecimento e consumo de sangue, aproveitando para colocar algumas questões em relação ao pode significar a gestão eficiente e eficaz da cadeia de abastecimento de sangue. A gestão eficaz da cadeia de abastecimento passa pelo conhecimento profundo da sua população de dadores, saber quem são, o que os move, quais os seus comportamentos perante a dádiva. Só assim é possível intervir eficazmente e adequar as estratégias mais eficazes à sua motivação e fidelização dádiva regular. Assim, foi efectuado um caso de estudo relativo à população de dadores do Serviço de ImunoHemoterapia do Centro Hospitalar de Vila Nova de Gaia- Espinho (CHVNG- Espinho), por forma a procurar oportunidades de melhoria nas estratégias de angariação de dadores e promoção da dádiva de sangue, acrescentando valor ao serviço e ao CHVNG-Espinho.
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Acute myeloid leukemia (AML) involves the proliferation, abnormal survival and arrest of cells at a very early stage of myeloid cell differentiation. The biological and clinical heterogeneity of this disease complicates treatment and highlights the significance of understanding the underlying causes of AML, which may constitute potential therapeutic targets, as well as offer prognostic information. Tribbles homolog 2 (Trib2) is a potent murine oncogene capable of inducing transplantable AML with complete penetrance. The pathogenicity of Trib2 is attributed to its ability to induce proteasomal degradation of the full length isoform of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα p42). The role of TRIB2 in human AML cells, however, has not been systematically investigated or targeted. Across human cancers, TRIB2 oncogenic activity was found to be associated with its elevated expression. In the context of AML, TRIB2 overexpression was suggested to be associated with the large and heterogeneous subset of cytogenetically normal AML patients. Based upon the observation that overexpression of TRIB2 has a role in cellular transformation, the effect of modulating its expression in human AML was examined in a human AML cell line that expresses high levels of TRIB2, U937 cells. Specific suppression of TRIB2 led to impaired cell growth, as a consequence of both an increase in apoptosis and a decrease in cell proliferation. Consistent with these in vitro results, TRIB2 silencing strongly reduced progression of the U937 in vivo xenografts, accompanied by detection of a lower spleen weight when compared with mice transplanted with TRIB2- expressing control cells. Gene expression analysis suggested that TRIB2 modulates apoptosis and cell-cycle sensitivity by influencing the expression of a subset of genes known to have implications on these phenotypes. Furthermore, TRIB2 was found to be expressed in a significant subset of AML patient samples analysed. To investigate whether increased expression of this gene could be afforded prognostic significance, primary AML cells with dichotomized levels of TRIB2 transcripts were evaluated in terms of their xenoengraftment potential, an assay reported to correlate with disease aggressiveness observed in humans. A small cohort of analysed samples with higher TRIB2 expression did not associate with preferential leukaemic cell engraftment in highly immune-deficient mice, hence, not predicting for an adverse prognosis. However, further experiments including a larger cohort of well characterized AML patients would be needed to clarify TRIB2 significance in the diagnostic setting. Collectively, these data support a functional role for TRIB2 in the maintenance of the oncogenic properties of human AML cells and suggest TRIB2 can be considered a rational therapeutic target. Proteasome inhibition has emerged as an attractive target for the development of novel anti-cancer therapies and results from translational research and clinical trials support the idea that proteasome inhibitors should be considered in the treatment of AML. The present study argued that proteasome inhibition would effectively inhibit the function of TRIB2 by abrogating C/EBPα p42 protein degradation and that it would be an effective pharmacological targeting strategy in TRIB2-positive AMLs. Here, a number of cell models expressing high levels of TRIB2 were successfully targeted by treatment with proteasome inhibitors, as demonstrated by multiple measurements that included increased cytotoxicity, inhibition of clonogenic growth and anti-AML activity in vivo. Mechanistically, it was shown that block of the TRIB2 degradative function led to an increase of C/EBPα p42 and that response was specific to the TRIB2-C/EBPα axis. Specificity was addressed by a panel of experiments showing that U937 cells (express detectable levels of endogenous TRIB2 and C/EBPα) treated with the proteasome inhibitor bortezomib (Brtz) displayed a higher cytotoxic response upon TRIB2 overexpression and that ectopic expression of C/EBPα rescued cell death. Additionally, in C/EBPα-negative leukaemia cells, K562 and Kasumi 1, Brtz-induced toxicity was not increased following TRIB2 overexpression supporting the specificity of the compound on the TRIB2-C/EBPα axis. Together these findings provide pre-clinical evidence that TRIB2- expressing AML cells can be pharmacologically targeted with proteasome inhibition due, in part, to blockage of the TRIB2 proteolytic function on C/EBPα p42. A large body of evidence indicates that AML arises through the stepwise acquisition of genetic and epigenetic changes. Mass spectrometry data has identified an interaction between TRIB2 and the epigenetic regulator Protein Arginine Methyltransferase 5 (PRMT5). Following assessment of TRIB2‟s role in AML cell survival and effective targeting of the TRIB2-C/EBPα degradation pathway, a putative TRIB2/PRMT5 cooperation was investigated in order to gain a deeper understanding of the molecular network in which TRIB2 acts as a potent myeloid oncogene. First, a microarray data set was interrogated for PRMT5 expression levels and the primary enzyme responsible for symmetric dimethylation was found to be transcribed at significantly higher levels in AML patients when compared to healthy controls. Next, depletion of PRMT5 in the U937 cell line was shown to reduce the transformative phenotype in the high expressing TRIB2 AML cells, which suggests that PRMT5 and TRIB2 may cooperate to maintain the leukaemogenic potential. Importantly, PRMT5 was identified as a TRIB2-interacting protein by means of a protein tagging approach to purify TRIB2 complexes from 293T cells. These findings trigger further research aimed at understanding the underlying mechanism and the functional significance of this interplay. In summary, the present study provides experimental evidence that TRIB2 has an important oncogenic role in human AML maintenance and, importantly in such a molecularly heterogeneous disease, provides the rational basis to consider proteasome inhibition as an effective targeting strategy for AML patients with high TRIB2 expression. Finally, the identification of PRMT5 as a TRIB2-interacting protein opens a new level of regulation to consider in AML. This work may contribute to our further understanding and therapeutic strategies in acute leukaemias.
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Centrée essentiellement autour de la parole épiscopale congolaise, la présente recherche porte sur les articulations de la religion et du politique dans une perspective limitée au catholicisme en RDC. En prenant pour base empirique la ville de Kinshasa, elle thématise les effets des dynamiques religieuses sur les fermentations sociales et les changements politiques dans un contexte d’autoritarisme. Celui-ci est, dans ce travail, problématisé comme le fait conjoint de l’institution étatique et de l’organisation religieuse catholique. Le choix de cette approche relationnelle basée sur les interactions entre religion et politique, permet d’inscrire ce travail dans le champ d’études des sciences des religions. L’approche retenue s’appuie également sur les avancées de la sociologie politique et éclaire la régulation religieuse du politique, rarement étudiée par les sciences humaines. Cette recherche s’inscrit donc à l’intersection entre l’histoire, la sociologie, les sciences politiques, l’anthropologie, l’analyse du discours, la philosophie et la théologie. Sa thèse centrale est organisée autour d’une question principale : comment la religion participe-t-elle à la régulation du politique dans le contexte d’autoritarisme caractéristique de la RDC ? La réponse à cette question croise l’approche fonctionnelle de la religion et l’analyse des déclarations institutionnelles de l’épiscopat congolais. Elle esquisse les relations entre, d’une part, contextes et événements sociopolitiques et d’autre part, discours et pratiques religieuses. Elle construit la scène religieuse à partir de la trajectoire sociopolitique, économique et culturelle de la RDC entre 1990 et 2015, sous les Présidents J.-D. Mobutu, L.-D. Kabila et J. Kabila. Elle étudie l'offre normative de sens de leurs éminences J.-A. Malula, F. Etsou et L. Monsengwo. L’analyse de la rhétorique de l’épiscopat sur les élections vérifie la plausibilité sociale et l’efficience politique de la parole épiscopale congolaise. Elle se ressource dans la pragmatique de la communication telle que mise en œuvre dans l’analyse argumentative du discours de R. Amossy et dans celle du discours politique de P. Charaudeau. En mettant la focale sur l’objet linguistique « vérité des urnes », la recherche pose au niveau normatif, juridique et éthique, le problème de l’institutionnalisation d’un État de droit en RDC. Les élaborations sur ce dernier niveau s’articulent autour de l’inscription de l’éthique dans l’agir politique. L’examen des modes conventionnels d’action des chrétiens (élections de 2006 et 2011) et non conventionnels (marche des chrétiens de 1992 et 2012) conduit à éclairer les modes de reproduction ou de contestation de l’autoritarisme étatique par l’organisation religieuse. Il permet de promouvoir une démocratie des valeurs et d’action adossée à la parrhêsia. L’introduction de l’aléthique dans la vie publique donne à voir la parole épiscopale congolaise comme un discours ethopoïétique. C’est sur ce point précis que les élaborations de M. Foucault sur la parrhêsia aident à thématiser la capacité de la religion à informer et à influencer la démocratisation de la RDC. De là, la requête formulée pour un nouveau système d’action institutionnelle de l’organisation religieuse, susceptible de promouvoir le courage de la vérité en situation autoritaire. Cette innovation permet de tenir ensemble les valeurs démocratiques et les valeurs de l’Évangile, en les corrélant à la cohérence axiologique, à la probité morale et à l’intégrité existentielle des protagonistes de la démocratisation de la RDC.
Resumo:
This work is a study in the Local Productive Arrangement of confections from Agreste of Pernambuco, as a relevant sector in economic and social aspect. This research has as central aim to understand how the inter-organizational relations influence the collective efficiency of arrangement. The theoretical framework employed highlights the approaches that deal with the benefits of business agglomeration for the development of firms and regions. It has discussed the approach of small and medium enter prises and industrial districts (SCHMITZ, 1997), which introduce the concept of col lective efficiency, explaining that only those externalities explained by Marshall (1996) are not sufficient to explain the competitive advantage of enterprises, expanding the idea that organizations achieve competitive advantage not acting alone. To examine the influences of relations in the collective efficiency, it has been taken as analytical perspective theory of social networks (GRANOVETTER, 1973, 1985; BURT, 1992; UZZI, 1997) because it has believe that this approach provides subsi dies for a structural analysis of social relationships in face the behavior of human action. By examining the organizations in a social network, you should understand the reason of this establishment of the relationship, their benefits, and as the information flow takes place and density of links between the actors (Powell; SMITH-DOERR, 1994). As for the methods, this study is characterized as a case study, in according to the purposed objectives, in addition to qualitative method. Also, due to recovering of the historical milestones of the arrangement, it is used a sectional approach with longitudinal perspective (VIEIRA, 2004). The primary and secondary data were used in order to understand the evolutionary process of the sector and their inter-actors re lationships in the arrangement for the promotion of development, for both, was used the contend and documentary analysis technique, respectively (DELLAGNELO ; SILVA, 2005). The approach of social networks has permitted understand that social relationships may extend the collective efficiency of the arrangement, and therefore need to develop policies that encourage the legalization of informal companies in arrangement, by showing up themselves representative. Thus, the relations estab lished in LPA of confections from Agreste of Pernambuco need for more effective mechanisms to broaden the collective efficiency. Therefore, this way as take place has directly benefited only a group of companies that are linked in some way the supportive institutions. So we can conclude that the inter-actor relations have limited the collective efficiency of LPA, being stimulated by the institutions in support only to groups of entrepreneurs, even those that produce external relations for all clustered companies
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L’ubiquitination, une modification post-traductionnelle importante pour le contrôle de nombreux processus cellulaires, est une réaction réversible. La réaction inverse, nommée déubiquitination est catalysée par les déubiquitinases (DUB). Nous nous sommes intéressés dans nos travaux à étudier l’ubiquitination de l’histone H2A (H2Aub), au niveau des résidus lysines 118 et 119 (K118/K119), une marque épigénétique impliquée dans la régulation de la prolifération cellulaire et la réparation de l’ADN. Le régulateur transcriptionnel BAP1, une déubiquitinase nucléaire, a été initialement identifié pour sa capacité à promouvoir la fonction suppressive de tumeurs de BRCA1. BAP1 forme un complexe multi-protéique avec plusieurs facteurs transcriptionnels et sa fonction principale est la déubiquitination de H2Aub. Plusieurs études ont démontré que BAP1 est un gène suppresseur de tumeurs majeur et qu’il est largement muté et inactivé dans une multitude de cancers. En effet, BAP1 émerge comme étant la DUB la plus mutée au niveau des cancers. Cependant, le ou les mécanismes d’action et de régulation du complexe BAP1 restent très peu connus. Dans cette étude nous nous sommes intéressés à la caractérisation moléculaire et fonctionnelle des partenaires protéiques de BAP1. De manière significative nous avons caractérisé un mécanisme unique de régulation entre deux composants majeurs du complexe BAP1 à savoir, HCF-1 et OGT. En effet, nous avons démontré que HCF-1 est requis pour maintenir le niveau protéique de OGT et que cette dernière est indispensable pour la maturation protéolytique de HCF-1 en promouvant son clivage par O-GlcNAcylation, une signalisation cellulaire nécessaire au bon fonctionnement de HCF-1. Également, nous avons découvert un nouveau mécanisme de régulation de BAP1 par l’ubiquitine ligase atypique UBE2O. En effet, UBE2O agit comme un régulateur négatif de BAP1 puisque l’ubiquitination de ce dernier induit sa séquestration dans le cytoplasme et l’inhibition de sa fonction suppressive de tumeurs. D’autre part nous nous sommes penchés sur la caractérisation de l’association de BAP1 avec deux facteurs de la famille des protéines Polycombes nommés ASXL1 et ASXL2 (ASXL1/2). Nous avons investigué le rôle de BAP1/ASXL1/2, particulièrement dans les mécanismes de déubiquitination et suppression de tumeurs. Nous avons démontré que BAP1 interagit directement iii via son domaine C-terminale avec le même domaine ASXM de ASXL1/2 formant ainsi deux complexes mutuellement exclusifs indispensables pour induire l’activité déubiquitinase de BAP1. De manière significative, ASXM s’associe avec BAP1 pour créer un nouveau domaine composite de liaison à l’ubiquitine. Ces interactions BAP1/ASXL1/2 régulent la progression harmonieuse du cycle cellulaire. De plus, la surexpression de BAP1 et de ASXL2 au niveau des fibroblastes induit la sénescence de manière dépendante de leurs interactions. D’autre part, nous avons identifié des mutations de cancers au niveau de BAP1 le rendant incapable de lier ASXL1/2, d’exercer sa fonction d’autodéubiquitination et de ce fait d’agir comme suppresseur de tumeurs. Ainsi nous avons révélé un lien étroit entre le gène suppresseur de tumeurs BAP1, son activité déubiquitinase et le contrôle de la prolifération cellulaire.
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Based on the proposal entitled anti-prohibitionist, contrary to prohibition and illegality of cannabis and its use, the anti-prohibitionist Collectives proposes to discuss the topic of drugs, especially marijuana, aiming decriminalization and legalization of this psychoactive. With this idea was articulated anti-prohibitionist movement in Natal, by organizing collectives that discuss issues related to drug use and conduct activities directed to this issue, such as Marijuana Marches and Cycles of Debates anti-prohibitionist. In this study we sought to understand the positioning in social and cultural terms, the marijuana users participating of the collectives, on the situation of illegality of their actions, in front of social, legal and moral question involved in the illicit psychoactive, through initiatives conferences, events and demonstrations for this purpose
Resumo:
A presente dissertação tem como objeto de estudo a pesca do bacalhau feita por portugueses sob a bandeira de Portugal durante o período do Estado Novo (1933-1974). Investigou-se as razões para um investimento e um protecionismo tão forte à indústria da pesca do bacalhau. É indissociável do estudo da demanda portuguesa por este peixe, à época muito abundante no noroeste atlântico, as políticas autárcicas e de subsistência pilares da economia do Estado Novo, assim como a implantação e robustecimento da Instituição Corporativa. Subjacente a estas linhas de matriz económica mas paradigmáticas do novo regime, estava também a reconstrução da identidade portuguesa, a sacralização do trabalho e a heroicidade do pescador português do bacalhau. A existência da tentativa de revivificação da glória dos descobrimentos na pesca do bacalhau. A criação de um ambiente social, político e religioso que levaram à persecução destas políticas e consequentemente do engrandecimento da estrutura do Estado Novo, resultando até na sedimentação de apoio popular. O desenvolvimento da frota de pesca longínqua foi quase uma única janela de oportunidades para o conhecimento de novos mundos. A montante e a jusante da atividade piscatória também se desenvolveram indústrias e comércio internacional. A participação em organizações internacionais de regulação das pescas proporcionou contatos Institucionais com outras nações, não raro utilizados para quebrar isolamentos e propagandear o Estado Novo e as suas manifestações culturais e identitárias que suscitaram relacionamentos interculturais. Para além destes contatos mais formais, também se desenvolveram contatos informais, que se repercutiram na criação e manifestação de conhecimento mútuo e claro de condições para a gestação da interculturidade. Estes desenvolvimentos de relações informais, de contatos profissionais também geraram relações culturais que se manifestaram em projetos individuais de vida associados às migrações.