É possível medir a eficiência do Estado? A proposta desta dissertação de mestrado é apresentar a avaliação de impacto regulatório AIR como uma das ferramentas possíveis e existentes para atender a esse desafio exigido pela Constituição Federal a partir da Emenda Constitucional 19/98, tendo como referencial analítico as decisões regulatórias. A AIR é instrumento de controle da atividade regulatória do Estado por meio de procedimento administrativo voltado à análise das decisões regulatórias a serem adotadas ou já adotadas pelos agentes reguladores com base em evidências empíricas, resultando na introdução de mecanismos de legitimação democrática e de responsabilização do regulador. Ela se baseia no uso sistemático de análises dos possíveis custos e benefícios das várias alternativas existentes para atender à(s) finalidade(s) desejada(s) e sinalizada(s) nas políticas públicas setoriais. Fala-se em mecanismos de legitimação democrática e de responsabilização do regulador diante do seu potencial de reduzir o déficit democrático presente no modelo do Estado regulador, em que o agente administrativo não eleito, no exercício de seus poderes, toma decisões que podem gerar impacto significativo aos particulares. Sustenta-se que isso é possível por meio da transparência e da publicidade do processo de tomada de decisão a partir da utilização da AIR pelos agentes reguladores. Esse aspecto leva a outro: a AIR como instrumento de controle. Essa ferramenta também possibilita a redução do risco da agência presente na delegação de poder do principal (Poder Legislativo e o Chefe do Poder Executivo) para o agente (agentes reguladores). A AIR ganha especial importância com o Programa de Fortalecimento da Capacidade Institucional para Gestão em Regulação (instituído pelo Decreto 6.062 de 16 de março de 2007) que tem como objetivo idealizar e implementar essa ferramenta na administração pública federal. / Is it possible to measure State efficiency? This dissertation aims to introduce regulatory impact assessment RIA as an existing possible tool to tackle this challenge assigned by the Federal Constitution in the constitutional amendment 19/98. RIA is an instrument to control the State via an administrative procedure based on the analysis of empirical evidences of regulatory decisions either to be taken or already taken by regulators. As a result, it introduces democratic legitimacy mechanisms and accountability of regulators. Its methodology is based on the systematic use of cost-benefit analysis of proposed alternatives in order to apply a public policy in a regulated sector. The mechanisms for democratic legitimation and accountability of regulators are justified by its potential to reduce the democratic deficit within the regulatory State, in which the non-elected administrative agent, in the exercise of his/hers own powers, makes decisions that can impact individuals. This is due to the transparency and publicity of the decision-making process that derives from the adoption of RIA. Another aspect then arises: RIA as an instrument of control. This tool will enable the reduction of the agency risk characteristic of the power delegation from the principal (Legislative Power and chief of Executive Power) to the agent (regulators). RIA gets more attention with the creation of the governmental program for strengthening the institutional capacity for regulation (Presidential Decree 6.062, March, 16th of 2007), whose scope is to conceptualize and implement such a tool in the federal public administration.

Submitted by Mariana Tsuha Moreno (mariana.moreno@raizen.com) on 2016-10-21T13:48:46Z No. of bitstreams: 1 Dissertação (v 2016 - v final).pdf: 1034853 bytes, checksum: 5c83d9a498dbbf7d7c57a487e570299d (MD5) / Approved for entry into archive by Joana Martorini (joana.martorini@fgv.br) on 2016-10-21T13:52:47Z (GMT) No. of bitstreams: 1 Dissertação (v 2016 - v final).pdf: 1034853 bytes, checksum: 5c83d9a498dbbf7d7c57a487e570299d (MD5) / Made available in DSpace on 2016-10-21T14:45:46Z (GMT). No. of bitstreams: 1 Dissertação (v 2016 - v final).pdf: 1034853 bytes, checksum: 5c83d9a498dbbf7d7c57a487e570299d (MD5) Previous issue date: 2016-09-02 / Essential condition for the proper functioning of the new State model sought by the Federal Constitution of 88, the Brazilian regulatory system is significantly behind the American congeneric in what concern to the employment of advanced regulatory practices. Taking the national petroleum agency-ANP as a reference, not much besides public consultations and hearings are required for the issuing of new regulation. Tools such as (1) mechanisms for coordination, planning and control of the regulatory action, (2) the fixing of a minimum content for the regulatory reasons, including the obligatory usage of regulatory impact analysis, and (3) the compulsory periodic review of existing regulation, among several other tools incorporated by the American system throughout the evolution experimented in the 20th century, are whether not used or not mandatory. Such fact, combined with an unreasoned tendency to deference by the Judiciary when asked to review such agent’s action, explains how a crucial agency like ANP remains indifferent to such practices after two decades since its foundation. Given that the conclusions of this work are based on a single case of a single agency, such conclusions cannot (and should not) be taken as a representative sample of the modus operandi of all agencies or, in general, as a representative sample of the quality of the entire Brazilian regulatory system. And this is not, in fact, the objective; our claim is that due to the absence of a regulatory framework requiring the adoption of uniform and mandatory regulatory practices, combined with the undemanding attitude demonstrated by the Judiciary in the control of the actions of these agents, the Brazilian regulatory system admits such a low level of performance that should be cause for concern and immediate attention. / Condição fundamental para o bom funcionamento do novo modelo de Estado pretendido pela Constituição Federal de 88, o sistema regulatório brasileiro está significativamente atrasado em relação ao seu congênere norte-americano no que se refere ao emprego de boas práticas de regulação. Tomando-se como referência a Agência Nacional do Petróleo – ANP, veremos neste trabalho que não se encontram nas normas de criação das agências brasileiras muito mais do que menções genéricas a necessidade de realização de consultas e audiências públicas para a discussão de propostas de regulação que, de alguma maneira, possam afetar direitos dos entes regulados. Ferramentas como (1) mecanismos de coordenação, planejamento e controle da ação regulatória, (2) fixação de conteúdo mínimo para a fundamentação da ação regulatória pretendida, incluindo a exigência da apresentação de análise de impacto regulatório e detalhamento sobre seu decision-making process, e (3) a obrigatoriedade de revisão periódica da regulação existente, dentre várias outras ferramentas incorporadas ao sistema americano ao longo da evolução pela qual este sistema passou ao longo da segunda metade do século XX, ou não são utilizadas ou não são obrigatórias. Tal fato, aliado à tendência verificada à deferência não fundamentada que o Judiciário demonstra quando chamado a realizar o controle judicial das normas editadas por estes agentes, é o que permite que uma agência tão importante quanto ANP, quase duas décadas após a sua criação, permaneça indiferente à tais práticas. Evidentemente, por estarem as conclusões deste trabalho baseadas na análise da experiência concreta de um único caso, de uma única agência, tais conclusões não podem (e não devem) ser tomadas como amostra representativa do modus operandi de todas as agências ou, de maneira geral, da qualidade de todo o sistema regulatório brasileiro. E não é esta, de fato, a pretensão; o argumento que se pretende marcar é que, em razão da ausência de um marco regulatório que obrigue a adoção uniforme e obrigatória de boas práticas de regulação, combinada com a postura pouco exigente demonstrada pelo Judiciário no controle dos atos destes agentes, o sistema regulatório brasileiro, em seu estágio atual de evolução, admite atuação como a que veremos no caso concreto da ANP, o que deve ser motivo de preocupação e atenção imediata.

Submitted by Paulo Junior (paulo.jr@fgv.br) on 2011-04-27T19:06:46Z No. of bitstreams: 1 Carina C. Coelho.pdf: 619431 bytes, checksum: 399cdc20dd245e1b67336c5680daaa97 (MD5) / Approved for entry into archive by Paulo Junior(paulo.jr@fgv.br) on 2011-04-27T19:07:15Z (GMT) No. of bitstreams: 1 Carina C. Coelho.pdf: 619431 bytes, checksum: 399cdc20dd245e1b67336c5680daaa97 (MD5) / Made available in DSpace on 2011-05-03T12:52:12Z (GMT). No. of bitstreams: 1 Carina C. Coelho.pdf: 619431 bytes, checksum: 399cdc20dd245e1b67336c5680daaa97 (MD5) Previous issue date: 2011-02-11 / This study aimed to analyse the potencial and obstacles of the adoption of the Regulatory Impact Analysis and the oversight body in the Brazilian context. For this, we carried out a field research with representatives of institutions involved with AIR, such as regulatory agencies and Civil House, as well as experts with publications on the top. Twelve semi-structured interviews were conducted around questions compiled from the previously explored in the theoretical knowledge of the work. It was concluded that from an environment of concern for regulatory quality in Brazil, both the central administration and regulatory bodies investigated have undertaken efforts to achieve a more effective regulatory system. However, there is a long way to go and many hurdles to overcome. Concerning the RIA and the oversight body, the strength, technical expertise, institutional design are some of the obstacles that must be overcome to reach the Brazil actually an improvement of regulatory quality. / Esta pesquisa teve por objetivo analisar a potencialidade e obstáculos da adoção da Análise de Impacto Regulatório e do órgão supervisor no contexto brasileiro. Para isso, realizou-se uma pesquisa de campo com representantes de instituições envolvidas com a AIR, com as agências reguladoras e a Casa Civil da Presidência da República, além de especialistas com publicações relativas ao tema. Foram realizadas assim, doze entrevistas semi-estruturadas em torno de perguntas previamente elaboradas a partir dos conhecimentos explorados no referencial teórico do trabalho. Concluiu-se que a partir de um ambiente de preocupação com a qualidade regulatória no Brasil, tanto a esfera mais central da administração – a Casa Civil como os entes reguladores investigados, têm empreendido esforços em prol de um sistema regulatório mais eficaz. Entretanto, há um longo caminho a ser percorrido e diversos obstáculos a serem ultrapassados. Com relação à AIR e ao órgão de supervisão, a resistência, a especialização técnica, o desenho institucional são alguns desses percalços que deverão ser transpostos a fim de que o Brasil alcance de fato uma melhoria da qualidade regulatória

Changes in cis- and trans-regulatory elements are among the prime sources of genetic and phenotypical variation at species level. The introduction of cis- and trans- regulatory variation has played important roles in driving diversity, phenotypical differentiation, and evolution of humans. Therefore, variation that occurs on cis- and trans- regulatory elements becomes imperative to better understanding of human genetic diversity and its evolution. In this research, around 3360 gene regulatory factors (GRF) from the human genome were catalogued. This catalog includes genes that code for proteins that perform gene regulatory activities such DNA-depending transcription, RNA polymerase II transcription cofactor and co-repressor activity, chromatin binding and remodeling, among other 218 regulatory functions. This GRF catalog allowed us to initially explore how some GRF genes have evolved in humans, archaic humans (Neandertal and Denisovan) and non-human primate species. We discussed the likely phenotypical and medical effects that evolutionary changes in GRF genes may have introduced into the human genome; for instance, traits associated to speech and language capabilities, genomic recombination hotspots, diseases, among others. By using genome-wide datasets, we additionally looked for GRFs likely to be candidates for positive selection in three human populations: Utah Residents with Northern and Western Ancestry (CEU), Han Chinese in Beijing (CHB), and Yoruba in Ibadan (YRI). As result, we produced a set of candidates that gathers genes that may have contributed in shaping the phenotypical diversity currently observed in these populations; for instance, by introducing regulatory diversity at population-specific level. We additionally identified six GRF classes enriched for genes located in regions that are likely candidates for positive selection at population specific level. We found that out of the 41 DNA-binding GRF classes classified so far, six groups exhibited enrichment for genes located on regions that may have been under positive selection: C2H2 zinc finger, KRAB-ZNF zinc finger, Homeo domain, Tryptophan cluster, Fork head/winged helix and, and High-mobility HMG domain. We additionally identified three KRAB-ZNF gene clusters, in the chromosomes one, three, and 16, for the Asian population that exhibit regions with extended haplotype homozygosity EHH (larger than 100 kb). This EHH suggests that these regions have undergone positive selection in CHB population. Finally, considering that a representative fraction of the phenotypic diversity observed between humans and its closely related species are likely explained by changes in cis-regulatory elements (CREs), we investigated putative binding sites for the transcription factor GABPa. Using ChIP-Seq data generated from a human cell line (HEK293T), 11,619 putative GABPa CREs were found, Out of which 224 are putative human-specific. To experimentally validate the transcriptional activity of these human-specific CREs, reporter gene essays and knock-down experiments were performed. Our results supported the functionality of these human-specific GABPa CREs and suggest that at least 1,215 genes are primary targets of GABPa. Finally, further analyses depict scenarios that put together transcriptional regulation by GABPa and the evolution of particular human traits; for instance, cognitive abilities, breast morphology, lipids and glucose metabolic pathways, among others.

Transcriptional regulatory complexes control gene expression patterns and permit cellular responses to stimuli. Deregulation of complex components upsets target gene expression and can lead to disease. This dissertation examines proteins involved in two distinct regulatory complexes: C-terminal binding protein (CtBP) 1 and 2, and Interferon Regulatory Factors (IRF) 3 and 5. Although critical in developmental processes and injury response, CtBP transcriptional repression of cell adhesion proteins, pro-apoptotic factors, and tumor suppressors has been linked to the pathogenesis of multiple forms of cancer. IRFs function in the immune system and have been implicated in autoimmune disorders. Understanding IRF activation is critical to treating pathogens that target IRF function or for future autoimmune disease therapies. We attempted to determine crystal structures that would provide the details of IRF activation, allowing insight into mechanisms of pathogen immune evasion and autoimmune disorders. Although no new structures were solved, we have optimized expression of C-terminal IRF-3 / co-activator complexes, as well as full-length IRF3 and IRF5 constructs. Modifying the constructs coupled with new crystal screening will soon result in structures which detail IRF activation, advancing understanding of the roles of IRF family members in disease. Through structural and biochemical characterization we sought to identify and develop inhibitors of CtBP transcriptional regulatory functions. High concentrations of CtBP substrate, 4-Methylthio 2-oxobutyric acid (MTOB), have been shown in different cancer models to interfere with CtBP transcriptional regulation. We began the process of structure based drug design by solving crystal structures of both CtBP family members bound to MTOB. The resulting models identified critical ligand contacts and unique active site features, which were utilized in inhibitor design. Potential CtBP inhibitors were identified and co-crystallized with CtBP1. One such compound binds to CtBP more than 1000 times more tightly than does MTOB, as a result of our structure-based inclusion of a phenyl ring and a novel pattern of hydrogen bonding. This molecule provides a starting point for the development of compounds that will both bind more tightly and interfere with transcriptional signaling as we progress towards pharmacologically targeting CtBP as a therapy for specific cancers.

Insider trading on the JSE can be linked, directly or indirectly, to the reputation of the South African financial market. The regulation thereof is essential and a non-negotiable requirement for the successful attraction and retention of investment flows. Inadequacies associated with the regulatory framework regulating insider trading, the onus of proof in a criminal trial and the lack of civil remedies associated with insider trading as a form of market abuse, motivates a critical analysis into the regulatory framework on insider trading in South Africa. The aim of this study is therefore to identify international best practice principles to fill the gap in South Africa’s regulatory framework. This gap relates to the practical application and execution of legislative and other instruments in order to combat insider trading as a form of market abuse. A further aim focuses on the simultaneous development of the legislation relating to financial markets in conjunction with developments in the economy. A final aim is to determine whether and how South Africa can improve its current legislative dispensation on insider trading. In order to arrive at the aim of the study the historical development on the regulation of insider trading is discussed. A critical analysis of the relevant insider trading sections in the Securities Services Act 36 of 2004 is compared with the corresponding sections of the Financial Markets Act 19 of 2012. A discussion on the roles, duties and authority of the Financial Services Board, the Directorate of Market Abuse and the Enforcement Committee will assist in analysing these organisations' contribution in regulating insider trading in South Africa. A look into the application of other regulatory instruments including the JSE’s Code of Conduct is required. In order to determine whether and how South Africa can improve its current legislative dispensation on insider trading, a comparative study is conducted with Hong Kong. It is submitted that the South African regulatory framework on insider trading has to be revised in order to align with international best practice principles and to promote transparency of the JSE, promote investor confidence and ensure justice for all. / LLM (Import and Export Law), North-West University, Potchefstroom Campus, 2015

Insider trading on the JSE can be linked, directly or indirectly, to the reputation of the South African financial market. The regulation thereof is essential and a non-negotiable requirement for the successful attraction and retention of investment flows. Inadequacies associated with the regulatory framework regulating insider trading, the onus of proof in a criminal trial and the lack of civil remedies associated with insider trading as a form of market abuse, motivates a critical analysis into the regulatory framework on insider trading in South Africa. The aim of this study is therefore to identify international best practice principles to fill the gap in South Africa’s regulatory framework. This gap relates to the practical application and execution of legislative and other instruments in order to combat insider trading as a form of market abuse. A further aim focuses on the simultaneous development of the legislation relating to financial markets in conjunction with developments in the economy. A final aim is to determine whether and how South Africa can improve its current legislative dispensation on insider trading. In order to arrive at the aim of the study the historical development on the regulation of insider trading is discussed. A critical analysis of the relevant insider trading sections in the Securities Services Act 36 of 2004 is compared with the corresponding sections of the Financial Markets Act 19 of 2012. A discussion on the roles, duties and authority of the Financial Services Board, the Directorate of Market Abuse and the Enforcement Committee will assist in analysing these organisations' contribution in regulating insider trading in South Africa. A look into the application of other regulatory instruments including the JSE’s Code of Conduct is required. In order to determine whether and how South Africa can improve its current legislative dispensation on insider trading, a comparative study is conducted with Hong Kong. It is submitted that the South African regulatory framework on insider trading has to be revised in order to align with international best practice principles and to promote transparency of the JSE, promote investor confidence and ensure justice for all. / LLM (Import and Export Law), North-West University, Potchefstroom Campus, 2015

<p>As a major component of the adaptive immune system, CD4+ T cells play a vital role in host defense and immune tolerance. The potency and accuracy of CD4+ T cell-mediated protection lie in their ability to differentiate into distinct subsets that could carry out unique duties. In this dissertation, we dissected the roles and interplays between two emerging mechanisms, miRNAs and epigenetic processes, in regulating CD4+ T cell-mediated responses. Using both gain- and loss-of-function genetic tools, we demonstrated that a miRNA cluster, miR-17-92, is critical to promote Th1 responses and suppress inducible Treg differentiation. Mechanistically, we found that through targeting Pten, miR-17-92 promotes PI3K activation. Strong TCR-PI3K activation leads to the accumulation of DNMT1, elevated CpG methylation in the foxp3 promoter, and suppression of foxp3 transcription. Furthermore, we demonstrated that an epigenetic regulator, methyl CpG binding protein 2 (MeCP2), is critical to sustain Foxp3 expression in Tregs, and to support Th1 and Th17 differentiation in conventional CD4+ T cells (Tcons). In Tregs, MeCP2 directly binds to the CNS2 region of foxp3 locus to promote its local histone H3 acetylation; while in Tcons, MeCP2 enhances the locus accessibility and transcription of miR-124, which negatively controls SOCS5 translation to support STAT1, STAT3 activation and Th1, Th17 differentiation. Overall, miRNAs and epigenetic processes may crosstalk to control CD4+ T cell differentiation and function.</p> / Dissertation

Background: Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation. Results: To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1-9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs). Conclusions: We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury.

This thesis examines the role of the media in the Kurdistan Region focusing on developments since the fall of Saddam Hussein's regime in 2003 in order to identify the challenges which have faced journalists there, and the construction of national identity and the potential opportunities which this sector presents for shaping public opinion and strengthening the nascent democracy in the region. After tracing the history of the Kurdish media against the broader backdrop of Iraq, using an interdisciplinary approach, this thesis analyses the strengths and weaknesses of the Kurdish media, with particular reference to regulation, examining the Press Law (2008). It concludes with a series of recommendations regarding the growth and development of new opportunities in the Kurdish media. In addition, it will present arguments to support the urgent need to develop a legal and regulatory framework which is fit-for-purpose for the media in this style democracy.