O Problema do Multicorte Dirigido Mínimo é um problema clássico em otimização combinatória. Ele é NP-difícil mesmo para instâncias muito simples. Este trabalho faz uma análise dos algoritmos exatos e de aproximação para resolver o problema. Também implementa alguns desses algoritmos e compara seus desempenhos. / The directed multicut problem is a classical problem in combinatorial optimization. It is NP-hard even for very simple families of instances. This work makes an analysis of the exact and approximation algorithms for the problem. It also implements some of these algorithms and compares their performances.

A doença de Chagas e as leishmanioses são doenças endêmicas tropicais, que afetam milhões de pessoas, especialmente em países subdesenvolvidos, e são responsáveis por série de implicações médicas, sociais e econômicas. Seus agentes etiológicos são protozoários pertencentes à ordem Kinetoplastida, os quais provocam várias manifestações clínicas, dependendo do tipo de protozoário infectante, da imunidade do hospedeiro e da progressão destas infecções. Atualmente, os principais problemas relacionados a estas parasitoses são a carência de fármacos eficazes, a elevada toxicidade dos fármacos disponíveis na terapêutica, bem como o crescente número de casos de resistência. Neste contexto, a busca por novos e melhores quimioterápicos contra essas doenças é urgente. A latenciação é um dos processos que podem ser utilizados com vistas a esse objetivo. Por meio desse processo, o uso de micelas poliméricas como transportadoras de fármacos com a finalidade de prolongar a ação e, consequentemente, diminuir a toxicidade do fármaco, tem sido crescente. Ademais, é possível dirigir a ação dessas formas de transporte por meio de fármacos dirigidos. Face ao exposto, o presente trabalho teve por objetivo a síntese fármacos dirigidos formadores de micelas dos compostos bioativos helenalina e hidroximetilnitrofural, os quais apresentam atividade tripanomicida e leishmanicida. Pretende-se, assim, promover a liberação controlada e a consequente diminuição da toxicidade destes compostos, bem como melhorar suas características físico-químicas. A ação destes compostos será dirigida para macrófagos, no interior dos quais se encontram os parasitos, através da ligação do tiomanosídio como grupo diretor das micelas. / Chagas disease and leishmaniasis are endemic tropical diseases affecting millions of people, especially in underdeveloped countries, being responsible and they are responsible for relevant medical, social and economic matters. Etiological agents for both diseases are protozoa belonging to the Kinetoplastidae order, which cause various clinical manifestations depending on the type of protozoa infecting, the host immunity and the progression of the infection. Currently, the main problems with these parasitic diseases are the lack of effective drugs, the high toxicity of available drugs for their treatment and the growing number of cases of resistance. In this context, the search for new and better chemotherapeutic agents against those diseases is urgent. Latentiation is one of the molecular modification processes that can be used with the aim of achieving this objective. Through this process, the use of micelles as drug carriers with the objective of prolonging its action and, consequently, diminishing its toxicity has been increasing. Besides, it is possible to direct the action of those carriers thourhg the targetd drugs. This said, in this work we studied the synthesis of micelle-forming targeted drugs of the bioactive compounds helenaline and hydroxymethylnitrofurazone, which showed to be trypanomicide and leishmanicide. Thus, promoting the controlled release and the consequent decreasing of the toxicity of those compounds, besides improving their physic-chemical properties are our goal. The action of those compounds will be directed to macrophages, where the parasites, mainly leishmanias, live, by covalent binding of the directed group thiomanoside to the micelles.

Esta dissertação apresenta o desenvolvimento, a validação e a aplicação de algoritmos para inferência de conectividade neural em registros de EEG contendo potenciais evento-relacionados (ERP). Os sinais foram caracterizados via modelos auto-regressivos multivariados (MVAR) e empregou-se a coerência parcial direcionada (PDC) no estudo das relações de causalidade entre eles. Certas características dos ERPs, como sua transitoriedade intrínseca e as múltiplas repetições em experimentos, levaram ao desenvolvimento de novos algoritmos, como a estimação de modelos conjuntos a partir de vários segmentos de sinal e um procedimento em janela deslizante capaz de descrever a evolução temporal da estatística dos sinais de interesse. Ademais, mostrou-se a possibilidade de estender os resultados da análise assintótica da estatística da PDC ao caso multi-trecho, tornando possível o estudo de sua significância estatística sem recorrer a procedimentos de reamostragem. Os algoritmos foram validados em exemplos com neural mass models, modelos não-lineares capazes de gerar sinais com características muito semelhantes a sinais de EEG reais, e aplicados a uma base de dados pública contendo resultados de experimentos com ratos. / This dissertation presents the development, validation, and application of algorithms for inferring neural connectivity in EEG signals containing event-related potentials (ERP). The time series were described via multivariate auto-regressive models (MVAR) and partial directed coherence (PDC) was used to study causal relations between them. Certain features of the ERPs, such as their transitory behavior and the existence of multiple trials in an experiment, lead to the development of a new algorithm capable of estimating a joint model from multiple segments and a sliding-window procedure for describing the nonstationarity behavior of the signals of interest. Furthermore, the possibility of extending the asymptotic results for PDC\'s statistics to the multi-trial case was demonstrated, allowing, therefore, the study of its statistical significance without recurring to resampling methods. The algorithms were validated in examples with neural mass models, non-linear models capable of generating signals with features very similar to real EEG recordings, and then applied to a publicly available dataset of experiments in rats.

The strong relationship between cognitive processing and coherent behaviour and neurocognitive networks justifies the current huge interest in cortical functional connectivity modeling. This has fostered the development of connectivity estimators from the classical bivariate coherence concept to the notion of multivariate partial directed coherence (PDC) which provides information about temporal dependencies exposing cause and effect relationships. This work examines PDC performance for scalp EEG data whose research value has been subject to much debate in the light of the presence of volume conduction (VC) effects that often obscure the actual nature of cortical source dynamics. Through analytical considerations and simulations we show that even though (VC) can hinder accurate connectivity estimation, one can mitigate its effects by a judicious choice of scalp electrode configuration/ground reference. This observation allows settling the connectivity estimation adequacy debate in the presence of PDC. / A forte relação que processamento cognitivo e comportamento coerente tem com redes neurocognitivas justifica o enorme interesse atual em modelamento de conectividade cortical. Este fato tem justificado o desenvolvimento de estimadores de conectividade desde a clássica coerência bivariada até a noção multivariada de coerência parcial direcionada (PDC) que exibe informação a cerca de dependências temporais que permitem expor relações de causa e efeito. O presente trabalho examina o desempenho da PDC no contexto de EEG de escalpo cujo valor em pesquisa sob os efeitos de condução de volume (VC) tem sido objeto de uma quantidade substancial de questionamentos na medida em esta obscurece a observação da dinâmica das fontes corticais. Por meio de considerações analíticas e simulações, mostramos que é possível mitigar os erros de estimação devidos à VC através da escolha judiciosa da configuração de eletrodos e da referência de terra. Esta observação permite resolver o conflito acerca da adequabilidade da inferência cortical baseada em EEG de escalpo.

This study is conducted with the aims to develop a new ranking method for multi-criteria decision making problem with conflicting criteria. Such a problem has a set of Pareto solutions, where the act of improving a value of one solution will result in depreciating some of the others. Thus, in this type of problem, there is no unique solution. However, out of many available options, the Decision Maker eventually has to choose only one solution. With this problem as the motivation, the current study develops a compromise ranking algorithm, namely a trade-off ranking method. The trade-off ranking method able to give a trade-off solution with the least compromise compared to other choices as the best solution. The properties of the algorithm are studied in the thesis on several test cases. The proposed method is compared against several multi-criteria decision making methods with ranking based on the distance measure, which are the TOPSIS, relative distance and VIKOR. The sensitivity analysis and uncertainty test are carried out to examine the methods robustness. A critical criteria analysis is also done to test for the most critical criterion in a multi-criteria problem. The decision making method is considered further in a fuzzy environment problem where the fuzzy trade-off ranking is developed and compared against existing fuzzy decision making methods.

Inferência da força de interação nos fenômenos físicos/biológicos é objetivo comum a diversas áreas da ciência. Em particular, nas neurociências tem-se assistido a uma mudança no paradigma experimental em que a atenção tem-se voltado à compreensão da interação entre grupamentos neuronais. Em vista desta demanda surgiram naturalmente diversos métodos estatísticos de medida de dependência entre grupamentos neurais. Alguns foram desenhados para inferência de fluxo de informação, sem contudo precisar o que se entende por fluxo de informação, gerando consequentemente controvérsias na literatura. O principal objetivo deste trabalho é aplicar os conceitos da Teoria da Informação na análise de processos estacionários de segunda ordem para precisar as idéias de fluxo de informação utilizadas na literatura de forma ad hoc e obter um melhor entendimento da relação existente entre as diferentes medidas de dependência propostas. / We study the relationship between different measures of causality or information flow. We show that the concept of partial measures of dependence are related to the definition of inverse random variables.

The poultry-to-human transmission of the influenza virus and the recent H1Nl influenza pandemic have become major concerns worldwide. The nucleoprotein (NP) of influenza virus binds the RNA genome and plays essential role in transcription and replication during the virus life cycle. / The study leads to a better understanding towards the RNP organization of influenza virus and provides information for the future design of anti-influenza agents. / We have also shown, by RNP reconstitution assay and co-immunoprecipitation, that the interaction between NP and PB2 is crucial for the proper functioning of the RNP. The functional association of NP and PB2 requires either the PB2 host-determining residue lysine-627 or arginine-630 with the latter involving NP arginine-150 also. Using SPR, we have demonstrated that both residues take part in the direct protein-protein interaction, without the involvement of RNA. These results suggest a dual interaction mechanism between NP and PB2. This may confer replication advantages to the virus, as either one can give an active RNP and explains the increased virulence of avian influenza viruses carrying the E627K mutation in mammalian cells. In addition, our findings identify the NP-PB2 interacting surface, with the PB2 627/630 region facing the RNA binding groove of NP. / We have determined the 3.3 A crystal structure of H5N1 NP, which is composed of head and body domains and a tail loop. Using surface plasmon resonance (SPR), we found the basic loop (residues 73-91) and arginine-rich groove, but mostly a protruding element centering at R174 and R175, to be important in RNA binding. Ribonucleoprotein (RNP) reconstitution assay with these multiple-point and deletion mutants indicate their functional importance towards the transcription-replication activities of the virus polymerase. Single-point mutations at these concerned regions do not have a significant effect on their RNP activities, suggesting that NP mediates RNA-binding through multiple residues. / Ng, Ka Leung. / Adviser: Pang Chui Shaw. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 121-136). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

This qualitative study explores midwifery practice during the second stage of labour focusing specifically on whether midwives adopt a directed or physiological approach to maternal pushing. It was undertaken against the backdrop of research findings suggesting that there is no proven benefit to directing a woman's pushing efforts but anecdotal evidence suggests that this remains a routine and accepted part of midwifery practice in the United Kingdom (UK). Semi- structured interviews were undertaken with ten midwives who had recent experience of caring for women during the second stage of labour, ten women who had recently given birth and four obstetricians. A form of thematic analysis was undertaken. Findings were viewed through a lens of critical social theory (CST) and drew on feminist principles to provide a deeper understanding of the emergent themes. Findings indicated that a directed approach to second stage pushing was the norm in this UK Maternity Unit and was deeply embedded within the cultural context of what it meant to be a midwife that involved ' doing' rather than 'being'. Reasons explaining why midwives continue to use directed pushing were grouped into themes; ' time passing and watching the clock' 'different worlds' , 'different women', 'midwives take charge', 'growth of confidence and changing practice' and 'conflict'. When viewed from a CST perspective midwives undertaking directed pushing is seen as an example of institutionalised oppressive behaviour symbolising the way in which knowledge and rationality are disregarded in favour of a risk averse practice that is paradoxically the opposite of what evidence recommends. Midwives are identified as being oppressed by the dominant biomedical model to the extent that they do not view directed pushing as an intervention. In order to promote a more physiological approach with its' associated benefits, a return to a social model of midwifery with a focus on salutogenesis rather than pathogenesis is called for. Recommendations for midwifery education, practice and research are provided in order to support the transformational shift in midwifery culture that is needed if such a change is to become a reality.

Coenzima Q (CoQ) é uma molécula de função essencial na transferência de elétrons da cadeia respiratória mitocondrial. Em Saccharomyces cerevisiae , a CoQ é constituída por um anel de benzeno associado a uma cadeia poliprenil, com 6 unidades de repetição, sendo por isso também denominada CoQ6 ou Q6. Ao todo já foram identificados treze genes (COQ1 COQ11, ARH1 e YAH1) nucleares necessários para biossíntese da CoQ. A maioria dos produtos Coq estão fisicamente associados em um complexo biossintético ancorado na membrana mitocondrial interna. Neste projeto, tentamos descrever resíduos relevantes de Coq3p e Coq7p aliando análises de bioinformática com testes fenotípicos para balizamento funcional. Coq7p é uma proteína com dois centros de ferro com íons carboxilato e catalisa a hidroxilação de demetoxi-Q6 (DMQ6). Neste estudo, indicamos um grupo de resíduos que modulam a atividade e a estabilidade de Coq7p: D53, R57, V111 e S114. Enquanto R57, V111 e S114 são resíduos muito conservados, V111 e S114 estão correlacionados em comunidades de coevolução. Aqui, demonstramos também que o duplo mutante S114A, V111G e o mutante S114E apresentam deficiência respiratória em temperatura não permissiva, além de acumularem o intermediário DMQ6 e sintetizarem baixas quantidades de Q6, concluindo assim que o fosmimético S114E inibe a atividade Coq7p. Dessa forma, propomos que a fosforilação do resíduo S114 promove o deslocamento de uma alça entre as hélices 2 e 3, afetando assim a atividade do centro catalítico Coq7p. Por sua vez, Coq3p atua como uma metiltransferase, catalisando diferentes passos durante a biossíntese da CoQ. Aqui, identificamos resíduos que colaboram para a atividade funcional de Coq3p: E123, S125, C131, G133, G134, H165, D203, E219, K258 e S262. Mutantes carregando as alterações E123A, H165A, D203A, E219A, K258A e S62A apresentam discreto crescimento respiratório e expressão de Coq3p similares à da linhagem selvagem, além de acumularem baixas quantidades de Q6. Enquanto C131, G133 e G134 são resíduos altamente conservados, localizados em uma alça no espaço entre fitas beta, no provável sítio ativo da proteína, mutantes C131A, G133A e G134A se superexpressos apresentam crescimento respiratório em meio contendo fonte de carbono não fermentável, além de acumularem Q6 compatíveis com os níveis de expressão proteica. Propomos assim um modelo para Coq3p, tendo os resíduos C131, G133 e G134 como centro catalítico de Coq3p. / Coenzyme Q (CoQ) is a molecule of essential function in the transfer of electrons of the mitochondrial respiratory chain. In saccharomyces cerevisiae , CoQ is constituted by a benzene ring associated with a polyprenyl chain with 6 repetition units, being therefore also denominated CoQ6 or Q6. Thirteen nuclear genes have already been identified (COQ1 COQ11, ARH1 and YAH1) required for coenzyme Q biosynthesis. Most of Coq products are physically associated in a biosynthetic complex anchored at the mitochondrial internal membrane. In this project, we identified Coq3p and Coq7p residues relevant for their respective role in CoQ synthesis combining bioinformatics analyzes with phenotypic tests for functional mapping. Coq7p is a carboxylate-bridged di-iron protein that catalyzes the hydroxylation of demetoxy-Q6 (DMQ6), the last monooxygenase step in the synthesis of CoQ. In this study, we found a group of residues that modulate the activity and stability of Coq7p: D53, R57, V111 and S114. While R57, V111 and S114 are highly conserved residues, V111 and S114 are correlated in communities of coevolution. We also demonstrate that the double mutant S114A, V111G and the mutant S114E have respiratory deficiency at non-permissive temperature, in addition to accumulating of the intermediate DMQ6 and low amounts of Q6, thus concluding that phosmimetic S114E inhibits the activity of Coq7p. Hence, we propose that the phosphorylation of S114 is required to move a loop between helices 2 and 3, thus affecting the activity of the catalytic center Coq7p. For its part, Coq3p acts as a methyltransferase, catalyzing different steps during biosynthesis of CoQ. Here we identified residues that collaborate for functional activity of Coq3p: E123, S125, C131, G133, G134, H165, D203, E219, K258 and S262. Mutants E123A, H165A, D203A, E219A, K258A and S62A, have mild respiratory growth, and expression of Coq3p levels similar to the wild strain, in addition to accumulating low amounts of Q6. While C131, G133, and G134 are residues highly conserved, located in a loop in the space between beta sheets, the overexpression of the mutants C131A, G133A and G134A present respiratory growth in medium containing non-fermentable carbon source, in addition to accumulate Q6 compatible with the levels of protein expression. We propose a model for Coq3p, with residues C131, G133 and G134 as part of Coq3p catalytic center.

Neste trabalho foram estudadas algumas formas de relação entre séries temporais multivariadas. Discutiu-se, inicialmente, a função de coerência, uma função análoga a função de correlação(que é dada no domínio do tempo) calculada no domínio da freqüência. Foram estudadas também as funções de coerência parcial e coerência parcial direcionada. A função de coerência parcial mede a relação entre duas componentes de uma série multivariada, isolados os efeitos de outra série. Em linhas gerais, a Coerência Parcial Direcionada pode ser interpredata como a decomposição da coerência parcial a partir de modelos autoregressivos multivariados. Esse conceito pode ser interpretado como uma representação do conceito de causalidade de Granger no domínio da freqüência. Finalmente, foram aplicadas as funções acima em dois conjuntos de dados: um modelo VAR(1) trivariado simulado e dados de medições de eletroencefalograma. / In this work we studied relationships between multivariate time series. We discussed the coherence function, a function similar to the correlation function(calculated in time domain) in frequency domain. Next, we discussed partial coherence and partial directed coherence. The partial coherence measures the relationship between two components of a multivariate time series, after removing the influence of another time series. Generally, the partial directed coherence can be interpreted as the decompositioin of the partial coherence from multivariate autoregressive models. We can interpret this function as a representation of the Granger causality concept in frequency domain. Finally, we applied these concepts in two situations: a simulated VAR(1) model and an electroencefalogram database.