Oscillations lie at the core of many biological processes, from the cell cycle, to circadian oscillations and developmental processes. They are essential to enable organisms to adapt to varying conditions in environmental cycles, from day/night to seasonal. Transcriptional regulatory networks are one of the mechanisms behind these biological oscillations. One of the main problems of computational systems biology is elucidating the interaction between biological components. A common mathematical abstraction is to represent these interactions as networks whose nodes are the reactive species and the interactions are edges. There is abundant literature dealing with the reconstruction of the network structure from steady-state gene expression measurements; still, there are lots of advancements to be made because of the complex nature of biological systems. Experimental design is another obstacle to overcome; we wish to perform experiments that help us best define the network structure according to our current knowledge of the system. In the first chapters of this thesis we will focus on reconstructing the network structure of biological oscillators by explicitly leveraging the cyclical nature of the transcriptional signals. We present a method for reconstructing network interactions tailored to this special but important class of genetic circuits. The method is based on projecting the signal onto a set of oscillatory basis functions. We build a Bayesian hierarchical model within a frequency domain linear model in order to enforce sparsity and incorporate prior knowledge about the network structure. Experiments on real and simulated data show that the method can lead to substantial improvements over competing approaches if the oscillatory assumption is met, and remains competitive also in cases it is not. Having defined a model for gene expression in oscillatory systems, we also consider the problem of designing informative experiments for elucidating the dynamics and better identify the model. We demonstrate our approach on a benchmark scenario in plant biology, the circadian clock network of Arabidopsis thaliana, and discuss the different value of three types of commonly used experiments in terms of aiding the reconstruction of the network. Finally we provide the architecture and design of a software implementation to plug in statistical methods of gene expression inference and network reconstruction into a biological data integration platform.

Accounting information for decision making needs to be reliable, unless the information is audited, it cannot be regarded as reliable. Therefore, although extensive research in the area of accounting in general, and auditing in particular, has been conducted in the developed countries, similar investigations within developing countries have so far been relatively limited. Moreover, global financial crises, the most recent in 2007/8, have increased the pressures for better regulations with the aim of harmonising the auditing profession globally. This study therefore aims to help fill the gap in research and to provide recommendations to the governing body of the Libyan auditing profession, in order to address the difficulties faced by the profession, and advance and improve the quality of professional auditing practice. This study is predominantly positivist in essence, but, based on the nature of the problem and research questions, a mixed methods approach to gathering data from stakeholders in the auditing profession is adopted. A questionnaire (196 respondents), and a set of semi-structured interviews (nine participants), represent the quantitative and qualitative instruments of the study respectively. The research sample for both empirical exercises is comprised of individuals from five different groups representing the Libyan auditing profession stakeholders. This wide spread of participants is selected in order to generate valid, reliable, generalizable, and meaningful data, and conclusions. The overall conclusion drawn from the analysis is that the Libyan audit profession regulations are considered inadequate by the profession itself, since they fall short of meeting international standards, as supported by the fact that many foreign companies invest in Libya, and they insist on their auditing using ISAs as a guarantee of transparent and high quality auditing. The Libyan audit profession is unwilling to implement these international standards, and this weakness needs to be addressed. Furthermore, issues relating to licensing, accounting and auditing education, examination for entry to the profession, and Continuing Professional Development (CPD) must all be reviewed. In addition, a new regulatory framework, that involves government supervision, and the use of internationally-recognised standards in the performance of auditing duties, must be introduced. In terms of the most appropriate regulatory approach, the results indicated that the independent regulator model is preferred; and with respect to auditing standards, the study finds that the preferred approach is to harmonise all auditing standards used in Libya, and to adopt the ISAs with certain modifications that suit the Libyan context. Furthermore, the study sample identified six factors that impact positively on the adoption of the ISAs, and a further six factors that had negative influences. This research contributes to the body of literature by filling the gap regarding the Libyan auditing profession in general, and identifying factors that have an impact on the adoption of ISAs in particular. Recommendations are provided to the authority responsible for supervising the Libyan auditing profession that essentially require the upgrading of all professionals, and perseverance to ensure national and international development of the profession in particular, and to other countries with similar characteristics in general.

Esta dissertação tem como objetivo geral analisar se e de que modo o cooperativismo pode ser um meio eficiente para auxiliar a concretização do ideal democrático de uma economia de mercado com inclusão econômica e social, oportunizando o desenvolvimento de caráter endógeno, em um modelo desenvolvimentista com participação da sociedade civil e novas formas de organização econômica, favorecendo a emergência de uma nova classe empresarial. Como objetivos específicos, figuram analisar as origens do cooperativismo e as conformações específicas deste sistema, enquanto valores e ideais de sociedade; analisar os aspectos econômicos e institucionais do cooperativismo; analisar o cooperativismo na atual Constituição brasileira, de acordo com os valores que regem essa norma e sua relevância teleológica; bem como, formular sugestões de princípios de organização institucional do cooperativismo, para potencializar seu emprego como meio de concretizar os ideais democráticos e suprir carências brasileiras, como as existentes nas áreas de educação, infraestrutura e saúde. São empregadas conjuntamente diretrizes teóricas tanto da área econômica quanto de áreas correlatas ao tema, com o intuito de demonstrar a possibilidade de adoção do cooperativismo como ferramenta de desenvolvimento social. O trabalho é composto por quatro partes, sendo a primeira focada na análise das origens do cooperativismo. Na segunda parte, são analisados os aspectos econômicos e institucionais do cooperativismo. Esse item do trabalho foi complementado por três anexos de cunho jurídico: um sobre a evolução da legislação referente ao cooperativismo no Brasil, o segundo sobre a personalidade jurídica das cooperativas e o terceiro sobre as sociedades cooperativas no Código Civil. Na terceira parte, consta a análise do cooperativismo na Constituição Federal de 1988. Na quarta seção, são formuladas propostas de princípios de organização institucional do cooperativismo. Mais precisamente, dado que o ambiente e os arranjos institucionais têm acentuada influência sobre o comportamento dos agentes econômicos, são citadas propostas para mitigar eventuais dificuldades microeconômicas próprias das cooperativas, bem como para constituir incentivos na adoção do cooperativismo como ferramenta auxiliar na concretização dos ideais democráticos e na supressão das carências atuais existentes no Brasil. / This paper has as its main objective to analyze whether and how cooperativism can be an efficient means to assist the realization of the democratic ideal of a market economy with economic and social inclusions, providing opportunities for the development of endogenous character, in a developmental model with participation of civil society and new forms of economic organization, favoring the emergence of a new entrepreneurial class. Specific objectives include analyzing the origins of the cooperativism and the specific conformations of this system, while values and ideals of society; analyze the economic and institutional aspects of cooperativism; analyze cooperativism in the current Brazilian Constitution, in accordance with the values that govern this standard and its teleological significance; as well as make suggestions of principles of institutional organization of cooperativism to enhance their employment as a means of achieving democratic ideals and meet Brazilian needs, as those existing in the areas of education, infrastructure and health. They are employed together both theoretical guidelines of the economic area as well as of those related to correlated areas, in order to demonstrate the possibility of adoption of cooperativism as a tool for social development. The paper consists of four parts, the first focused on the analysis of the origins of cooperativism. In the second part, the economic and institutional aspects of cooperativism are analyzed. This item was complemented by three appendixes of legal nature: one on the evolution of the legislation on cooperativism in Brazil, the second about the legal status of cooperatives and the third on the cooperative societies in the Civil Code. The third part consists in the analysis of cooperativism in the Federal Constitution of 1988. In the fourth section, proposed principles of institutional organization of cooperativism are formulated. More precisely, since the environment and institutional arrangements have marked influence on the behavior of economic agents, proposals are cited to mitigate eventual microeconomic difficulties characteristic of cooperatives, as well as provide incentives for the adoption of cooperativism as an auxiliary tool in the realization of democratic ideals and suppression of current deficiencies in Brazil.

Universidade Federal do Cearà / A hansenÃase à uma doenÃa crÃnica causada pelo Mycobacterium leprae, que representa um importante problema de saÃde pÃblica mundial, especialmente no estado do CearÃ, Brasil. A incidÃncia nos menores de 15 anos de idade reflete a endemicidade da regiÃo e a dificuldade no seu controle. A doenÃa apresenta um espectro variado de manifestaÃÃes clÃnicas que està relacionado a resposta imune desenvolvida pelo indivÃduo, com as respostas Th1 e Th2 relacionadas com as formas paucibacilar e multibacilar, respectivamente. CÃlulas T regulatÃrias (Tregs) tÃm recebido atenÃÃo especial na literatura e tÃm sido relacionadas com o desenvolvimento de infecÃÃes crÃnicas, entretanto seu papel na hansenÃase nos menores de 15 anos ainda nÃo foi elucidado. Esse trabalho teve por objetivo avaliar a freqÃÃncia das Tregs CD4+CD25+FOXP3high, CD8+CD25+FOXP3high, CD4+CD25highFOXP3+ e CD8+CD25highFOXP3+ em pacientes com hansenÃase e contatos intradomiciliares, ambos menores de 15 anos. CÃlulas mononucelares de sangue perifÃrico foram cultivadas por 72 horas com ativadores (anti-CD3 e anti-CD28) e/ou com M.leprae total sonicado. ApÃs cultura, a frequÃncia das Tregs foi identificada por citometria de fluxo. Observamos maior freqÃÃncia de cÃlulas CD4+CD25+FOXP3high em pacientes do que em contatos,nÃo havendo diferenÃas entre eles com relaÃÃo Ãs outras populaÃÃes avaliadas. Os pacientes multibacilares apresentaram maior freqÃÃncia de cÃlulas CD4+CD25+FOXP3high e CD8+CD25+FOXP3high do que os contatos. Apenas nesses pacientes, as cÃlulas CD4+CD25+FOXP3high foram negativamente correlacionadas com linfÃcitos CD4+ e CD8+ nÃo-regulatÃrios e as cÃlulas CD8+CD25+FOXP3high com linfÃcitos CD4+ nÃo-regulatÃrios. A maior frequÃncia de Tregs com elevada expressÃo de FOXP3 nos menores de 15 anos com hansenÃase multibacilar, bem como sua correlaÃÃo inversa com a frequÃncia de linfÃcitos nÃo regulatÃrios nesses pacientes sugere a participaÃÃo dessas cÃlulas na perpetuaÃÃo da infecÃÃo pelo M. leprae. / Leprosy is a chronic disease caused by Mycobacterium leprae, which represents an important health problem worldwide, especially in CearÃ, Brazil. The incidence in under-15-year-olds reflects the endemicity of the region and the difficulty in its control. The disease presents a wide spectrum of clinical manifestations that reflects the immune response developed, with Th1 and Th2 responses related to the paucibacillary and multibacillary (MB) forms, respectively. Regulatory T cells(Tregs) cells have received special attention in the literature and have been associated with development of chronic infections, however its role in leprosy in children under-15-years-old has not yet been elucidated. This study aimed to evaluate the frequency of CD4+CD25+FOXP3high, CD8+CD25+FOXP3high, CD4+CD25highFOXP3+ and CD8+CD25highFOXP3+ Treg cells in patients with leprosy and household contacts(HHC), both under 15 years. Peripheral blood mononucelares cells were cultured for 72 hours with activators(anti-CD3 and anti-CD28) and/or with M.leprae total sonicated. After culture, Treg cells were identified by flow cytometry. We found a greater frequency of CD4+CD25+FOXP3high cells in patients than in HHC, where there were no differences in the other cell populations evaluated. The multibacillary patients had a higher frequency of CD4+CD25+FOXP3high and CD8+CD25+FOXP3high cells compared to HHC. Only these patients, CD4+CD25+FOXP3high cells were negatively correlated with CD4+ and CD8+ non-Treg lymphocytes , and CD8+CD25+FOXP3high cells with CD4+ non-Treg lymphocytes. The greater frequency of Tregs with high expression of FOXP3 in individuals with multibacillary leprosy under-15-years-old and its inverse correlation with the frequency of non-regulatory lymphocytes in these patients suggests the involvement of these cells in the perpetuation of M. leprae infection.

In nature, biofilm is a complex structure resulted of multicellular bacterial communities that provide important nutritional functions and the acquisition of protective traits such as antibiotics resistance and horizontal gene transfer. The development from the planktonic, lonely bacteria, to the mature multilayered biofilm structure consists of three main phases: motility, attachment and biofilm maturation. At cellular level, the process is controlled by several genes such as flhD, fliA, rpoS, csgD, adrA, cpxR all acting as master regulators. Additionally, the global regulators CRP, IHF, Fis, and others in less frequency, have been related to biofilm formation, although blurry information has been provided. In this thesis we used synthetic, molecular and cellular biology approaches to understand the effect of CRP, IHF and Fis in the transcriptional regulatory network in the bacterium Escherichia coli. In the first chapter, we employed network analysis to reconstruct and analyze part of the entire regulatory network described to modulate the flagella-biofilm program. With this analysis we identified some critical interactions responsible for the planktonic-biofilm transition. Next, we selected the top ten effectors nodes of the network and cloned the promoter region of those genes in a reporter system. As extensively explained in chapter II, this system allowed us to validate as well as suggest new interactions in the network. Additionally, the measurement of the promoter activity during bacterial development show that CRP, IHF and Fis differentially modulate most of the surveyed genes suggesting that those Global Regulators participate to modulate gene expression in different phases of the planktonic-biofilm development. At chapter three, to get a better overview of the entire process, we performed motility, adherence/early biofilm and mature biofilm assays. We describe the intrinsic ability of E. coli to perform motility, adherence and mature biofilm at 37?C. In contrast, the absence of ihf, fis as well as Carbon Catabolite Repression (CCR), lead to altered phenotypes at both motility and biofilm development. At the end, we discussed how the changes of promoter activity of target genes, together with our network analysis, could explain part of the altered phenotypes observed. For instance, we observed changes at the main stress responders rpoS and rpoE that, in combination with alterations at specific genes such as fliA, can explain the enhanced motility in the E. coli ?ihf strain. Altogether, in this thesis, we provided evidence that CRP, IHF and Fis control the activity of the promoter regions of genes involved in the planktonic-biofilm development. / Na natureza, o biofilme é uma estrutura complexa resultante de comunidades bacterianas multicelulares que fornece importantes funções nutricionais e a aquisição de traços de proteção como resistência a antibióticos e transferência horizontal de genes. O desenvolvimento das bactérias planctônicas solitárias para uma estrutura de biofilme maduro consiste em três fases principais: motilidade, fixação e maturação do biofilme. Ao nível celular, o processo é controlado por vários genes tais como flhD, fliA, rpoS, csgD, adrA, cpxR, todos agindo como reguladores mestre. Além disso, os reguladores globais CRP, IHF, Fis e outros em menor freqüência, têm sido relacionados à formação de biofilme, embora tenham sido fornecidas informações nao conclusivas sobre esse processo. Nesta tese foram utilizadas abordagens de bioinformática, assim como de biologia molecular e celular para entender o efeito de CRP, IHF e Fis na rede reguladora da transição de motilidade para biofilme na bactéria Escherichia coli. No primeiro capítulo, utilizamos a análise de rede para reconstruir e analisar parte da rede regulatória descrita para modular o programa flagelo-biofilme. Com esta análise identificamos algumas interações críticas responsáveis pela transição planctônica-biofilme. Em seguida, selecionamos os dez principais nós efetores da rede e clonamos a região promotora desses genes em um sistema repórter. Conforme explicado amplamente no capítulo II, este sistema nos permitiu validar e sugerir novas interações na rede. Adicionalmente, a medição da atividade do promotor durante o desenvolvimento bacteriano mostra que a CRP, a IHF e a Fis modulam diferencialmente a maioria dos genes analisados sugerindo que estes Reguladores Globais participam para modular a expressão génica em diferentes fases do desenvolvimento de estado planctónico para biofilme. No capítulo três, para obter uma melhor visão geral de todo o processo, realizamos ensaios de motilidade, aderência / biofilme precoce e biofilmes maduros. Descrevemos a capacidade intrínseca de E. coli para realizar motilidade, adesão e biofilme maduro a 37 °C. Em contraste, a ausência de ihf, fis, bem como o fenômeno de Repressão de Catabolite de Carbono (CCR), levam a fenótipos alterados, tanto na motilidade como no desenvolvimento do biofilme. No final, discutimos como as mudanças da atividade do promotor de genes alvo, juntamente com a nossa análise de rede, poderia !xi explicar parte dos fenótipos alterados observados. Por exemplo, observamos mudanças nos principais respondedores de estresse rpoS e rpoE que, em combinação com alterações em genes específicos como fliA, podem explicar a motilidade aumentada na estirpe de E. coli ?ihf. Em conjunto, nesta tese, apresentamos evidências de que CRP, IHF e Fis controlam a atividade das regiões promotoras de genes envolvidos no desenvolvimento planctônico-biofilme.

Esta dissertação tem como objetivo geral analisar se e de que modo o cooperativismo pode ser um meio eficiente para auxiliar a concretização do ideal democrático de uma economia de mercado com inclusão econômica e social, oportunizando o desenvolvimento de caráter endógeno, em um modelo desenvolvimentista com participação da sociedade civil e novas formas de organização econômica, favorecendo a emergência de uma nova classe empresarial. Como objetivos específicos, figuram analisar as origens do cooperativismo e as conformações específicas deste sistema, enquanto valores e ideais de sociedade; analisar os aspectos econômicos e institucionais do cooperativismo; analisar o cooperativismo na atual Constituição brasileira, de acordo com os valores que regem essa norma e sua relevância teleológica; bem como, formular sugestões de princípios de organização institucional do cooperativismo, para potencializar seu emprego como meio de concretizar os ideais democráticos e suprir carências brasileiras, como as existentes nas áreas de educação, infraestrutura e saúde. São empregadas conjuntamente diretrizes teóricas tanto da área econômica quanto de áreas correlatas ao tema, com o intuito de demonstrar a possibilidade de adoção do cooperativismo como ferramenta de desenvolvimento social. O trabalho é composto por quatro partes, sendo a primeira focada na análise das origens do cooperativismo. Na segunda parte, são analisados os aspectos econômicos e institucionais do cooperativismo. Esse item do trabalho foi complementado por três anexos de cunho jurídico: um sobre a evolução da legislação referente ao cooperativismo no Brasil, o segundo sobre a personalidade jurídica das cooperativas e o terceiro sobre as sociedades cooperativas no Código Civil. Na terceira parte, consta a análise do cooperativismo na Constituição Federal de 1988. Na quarta seção, são formuladas propostas de princípios de organização institucional do cooperativismo. Mais precisamente, dado que o ambiente e os arranjos institucionais têm acentuada influência sobre o comportamento dos agentes econômicos, são citadas propostas para mitigar eventuais dificuldades microeconômicas próprias das cooperativas, bem como para constituir incentivos na adoção do cooperativismo como ferramenta auxiliar na concretização dos ideais democráticos e na supressão das carências atuais existentes no Brasil. / This paper has as its main objective to analyze whether and how cooperativism can be an efficient means to assist the realization of the democratic ideal of a market economy with economic and social inclusions, providing opportunities for the development of endogenous character, in a developmental model with participation of civil society and new forms of economic organization, favoring the emergence of a new entrepreneurial class. Specific objectives include analyzing the origins of the cooperativism and the specific conformations of this system, while values and ideals of society; analyze the economic and institutional aspects of cooperativism; analyze cooperativism in the current Brazilian Constitution, in accordance with the values that govern this standard and its teleological significance; as well as make suggestions of principles of institutional organization of cooperativism to enhance their employment as a means of achieving democratic ideals and meet Brazilian needs, as those existing in the areas of education, infrastructure and health. They are employed together both theoretical guidelines of the economic area as well as of those related to correlated areas, in order to demonstrate the possibility of adoption of cooperativism as a tool for social development. The paper consists of four parts, the first focused on the analysis of the origins of cooperativism. In the second part, the economic and institutional aspects of cooperativism are analyzed. This item was complemented by three appendixes of legal nature: one on the evolution of the legislation on cooperativism in Brazil, the second about the legal status of cooperatives and the third on the cooperative societies in the Civil Code. The third part consists in the analysis of cooperativism in the Federal Constitution of 1988. In the fourth section, proposed principles of institutional organization of cooperativism are formulated. More precisely, since the environment and institutional arrangements have marked influence on the behavior of economic agents, proposals are cited to mitigate eventual microeconomic difficulties characteristic of cooperatives, as well as provide incentives for the adoption of cooperativism as an auxiliary tool in the realization of democratic ideals and suppression of current deficiencies in Brazil.

Esta dissertação compreende um estudo acerca da estrutura de governança regulatória do Brasil, a partir da análise dos setores de telecomunicação e eletricidade. Tal estudo é feito à luz do modelo teórico desenvolvido por Pablo Spiller e Mariano Tommasi que define os meios pelos quais as instituições de um país afetam a habilidade dos atores políticos de sustentar políticas ao longo do tempo e, conseqüentemente, de garantir a credibilidade regulatória do país. Guiada pelo modelo teórico em questão, a análise das características mais marcantes da dotação político-institucional do país, bem como dos processos políticos que deram origem às estruturas regulatórias dos dois setores permite identificar, entre outros aspectos, que o papel de destaque ocupado pelo Executivo no sistema politico brasileiro se confirma também nas arenas das políticas regulatórias dos setores regulados. A análise do desenho das estruturas de governança regulatória desses setores evidencia que, apesar da preocupação em instituir uma regulação de caráter técnico e imune a pressões políticas, nem sempre o desenho escolhido se adapta eficientemente às peculiaridades e características da dotação institucional do País, coibindo o comportamento oportunista dos atores políticos nos setores estudados. A inferência descritiva realizada permite a avaliação do modelo teórico em questão e evidencia a importância de que ao mesmo sejam incorporadas outras variáveis, como as preferências dos atores e os atores com poder de veto. Feito isso, o modelo poderá explicar e avaliar com mais precisão os diversos desenhos de estruturas de governança regulatória. / This thesis consists of a study of Brazils regulatory governance structure, through an analysis of the telecommunications and electricity sectors. The analytical efforts are guided by the theoretical model - developed by Pablo Spiller and Mariano Tommasi that defines the means through which a countrys institutions can affect the ability of politicians to engage in intra-temporal exchanges and, as a consequence, determines the countrys regulatory credibility. Guided by this theoretical model, the analysis of Brazils institutional endowment and of the processes that led to the creation of the regulatory institutions in each sector allows the conclusion that the broad role played by the Executive in the Brazilian political system was also reflected in the specific arenas where the regulatory bodies were shaped. The analysis of the design of the regulatory governance structures demonstrates that, despite initial concerns about the implementation of technical and nonpolitical regulation, these structures are yet to be completely and effectively adapted to the peculiarities and characteristics of Brazils institutional endowment. In addition, the descriptive inference highlights the importance of including the preferences of actors, and the influence of veto players, within the models variables, in order to refine its explanatory power.

Genetic regulatory networks are of great importance in terms of scientific interests and practical medical importance. Since a number of high-throughput measurement devices are available, such as microarrays and sequencing techniques, regulatory networks have been intensively studied over the last decade. Based on these high-throughput data sets, statistical interpretations of these billions of bits are crucial for biologist to extract meaningful results. In this thesis, we compare a variety of existing regression models and apply them to construct regulatory networks which span trancription factors and microRNAs. We also propose an extended algorithm to address the local optimum issue in finding the Maximum A Posterjorj estimator. An E. coli mRNA expression microarray data set with known bona fide interactions is used to evaluate our models and we show that our regression networks with a properly chosen prior can perform comparably to the state-of-the-art regulatory network construction algorithm. Finally, we apply our models on a p53-related data set, NCI-60 data. By further incorporating available prior structural information from sequencing data, we identify several significantly enriched interactions with cell proliferation function. In both of the two data sets, we select specific examples to show that many regulatory interactions can be confirmed by previous studies or functional enrichment analysis. Through comparing statistical models, we conclude from the project that combining different models with over-representation analysis and prior structural information can improve the quality of prediction and facilitate biological interpretation. Keywords: regulatory network, variable selection, penalized maximum likelihood estimation, optimization, functional enrichment analysis. / Science, Faculty of / Graduate

It is the purpose of this thesis to point out areas of failure and weaknesses in the Federal independent regulatory commissions, and recommendations for improvement, as seen by Louis J. Hector, James M. Landis, Emmette S. Redford, Bernard Schwartz and the Special Subcommittee on Legislative Oversight. A secondary purpose of the study is to present action taken by Congress and President Kennedy in response to recent criticisms of the commissions. The scope of the thesis is limited to the major problems of policy-making, personnel matters, and efficiency of the major independent regulatory commissions. The material presented in the thesis covers five chapters. Chapter I includes a general introductory statement, the purpose and scope of the study, and the method of organization. Chapter II is a presentation of the criticisms and recommendations of Hector, Redford, and Landis in respect to the problems of policy-making and coordination faced by the independent commissions. Chapter III examines the problems of commission personnel in respect to qualifications, turnover, and ethical conduct. Chapter IV concerns the efficiency of the independent commissions, showing examples of delay and incompetence in the performance of the functions of the CAB, the FPC, and other commissions. Criticisms and recommendations include those of Hector, the Special Subcommittee, and Landis. Chapter V, the conclusion, re-emphasizes the importance of the problems facing the commissions. Attention is given to action taken by Congress and President Kennedy to improve the efficiency of certain commissions. An analysis of the criticisms and recommendations of the sources used is presented.

Interferon regulatory factor-1 (IRF-1) is a transcription factor and tumour suppressor, involved in many diverse cellular processes including immune responses and growth regulation. An interesting feature of IRF-1 is that it can both activate and repress gene expression, possibly by acting with co-activator or co-repressor proteins. In a previous phage display assay, a homologous peptide to the known repressor protein, zinc finger 350 (ZNF350), was found to bind to the C-terminus of IRF-1. ZNF350, also known as ZBRK1 (Zinc finger and BRCA1-interacting protein with KRAB domain-1), is a member of the Krüppel-associated box (KRAB)-containing zinc finger (KZF) proteins, which is a group of the widely distributed transcriptional repression proteins in mammals. ZNF350 has previously been shown to repress the expression of a number of genes including ANG1 and GADD45A, often in complex with other proteins. This study confirms the direct interaction between IRF-1 and ZNF350 and identifies key residues, including the LXXLL repression motif within the C-terminus of IRF-1, necessary for the binding interface. The two proteins have additionally been shown to interact within a cellular environment, shown by using techniques including immunoprecipitation and a proximity ligation assay. In addition, the ZNF350/IRF-1 complex formation appears to occur in the basal state of the cell, as opposed to in response to cellular stress such as viral infection or DNA damage. On the basis of ZNF350 being a negative regulator of transcription, a novel technique was developed to identify putative targets of both ZNF350 and IRF-1. This involved an initial bioinformatics screen using candidate IRF-1 binding site data obtained from CENTIPEDE, an algorithm that combines genome sequence information, with cell-specific experimental data to map bound TF binding sites. This allowed for the identification of novel target genes that contained the ZNF350 consensus binding site, GGGxxCAGxxxTTT, within close proximity to an IRF-1 consensus site, such as the immune response gene IL-12A. Lastly, a peptide phage display screen was combined with high-throughput sequencing to identify other potential binding partners of ZNF350 and perhaps help to understand the mechanism by which transcriptional repression is controlled by complex formation.