This work was aimed at developing novel tools that utilize HINT, an empirical forcefield capable of quantitating both hydrophobic and hydrophilic (hydropathic) interactions, for implementation in theoretical biology and drug discovery/design. The role of hydrophobicity in determination of macromolecular structure and formation of complexes in biological molecules is undeniable and has been the subject of research across several decades. Hydrophobicity is introduced, with a review of its history and contemporary theories. This is followed by a description of various methods that quantify this all-pervading phenomenon and their use in protein folding and contemporary drug design projects – including a detailed overview of the HINT forcefield. The specific aim of this dissertation is to introduce our attempts at developing new methods for use in the study of antibacterial drug resistance and antiviral drug discovery. Multidrug efflux is commonly regarded as a fast growing problem in the field of medicine. Several species of microbes are known to have developed resistance against almost all classes of antibiotics by various modes-of-action, which include multidrug transporters (a.k.a. efflux pumps). These proteins are present in both gram-positive and gram-negative bacteria and extrude molecules of various classes. They protect the efflux pump-expressing bacterium from harmful effects of exogenous agents by simply evacuating the latter. Perhaps the best characterized mechanism amongst these is that of the AcrA-AcrB-TolC efflux pump. Data is available in literature and perhaps also in proprietary databases available with pharmaceutical companies, characterizing this pump in terms of the minimum inhibitory concentration ratios (MIC ratios) for various antibiotics. We procured a curated dataset of 32 β-lactam and 12 antibiotics of other classes from this literature. Initial attempts at studying the MIC ratios of β-lactam antibiotics as a function of their three dimensional topology via 3D-quantitative structure activity relationship (3D-QSAR) technology yielded seemingly good models. However, this methodology is essentially designed to address single receptor-ligand interactions. Molecules being transported by the efflux pump must undoubtedly be involved in multiple interactions with the same. Notably, such methods require a pharmacophoric overlap of ligands prior to the generation of models, thereby limiting their applicability to a set of structurally-related compounds. Thus, we designed a novel method that takes various interactions between antibiotic agents and the AcrA-AcrB-TolC pump into account in conjunction with certain properties of the drugs. This method yielded mathematical models that are capable of predicting high/low efflux with significant efficiency (>93% correct). The development of this method, along with the results from its validation, is presented herein. A parallel aim being pursued by us is to discover inhibitors for hemagglutinin-neuraminidase (HN) of human parainfluenza virus type 3 (HPIV3) by in silico screening. The basis for targeting HN is explored, along with commentary on the methodology adopted during this effort. This project yielded a moderate success rate of 34%, perhaps due to problems in the computational methodology utilized. We highlight one particular problem – that of emulating target flexibility – and explore new avenues for overcoming this obstacle in the long run. As a starting point towards enhancing the tools available to us for virtual screening in general (and for discovering antiviral compounds in specific), we explored the compatibility between sidechain rotamer libraries and the HINT scoring function. A new algorithm was designed to optimize amino acid residue sidechains, if provided with the backbone coordinates, by generating sidechain positions using the Dunbrack and Cohen backbone-dependent rotamer library and scoring them with the HINT scoring function. This rotamer library was previously used by its developers previously to design a very successful sidechain optimization algorithm called SCWRL. Output structures from our algorithm were compared with those from SCWRL and showed extraordinary similarities as well as significant differences, which are discussed herein. This successful implementation of HINT in our sidechain optimization algorithm establishes the compatibility between this forcefield and sidechain rotamer libraries. Future aims in this project include enhancement of our current algorithm and the design of a new algorithm to explore partial induced-fit in targets aimed at improving current docking methodology. This work shows significant progress towards the implementation of our hydropathic force field in theoretical modeling of biological systems in order to enhance our ability to understand atomistic details of inter- and intramolecular interactions which must form the basis for a wide variety of biological phenomena. Such efforts are key to not only to understanding the said phenomena, but also towards a solid basis for efficient drug design in the future.

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隨著消費者、企業主對廣告意識的不斷提高和廣告知識的日益普及，廣告效果的研究問題是一項非常重要的課題。在以往的研究中，廣告效果可分為二種，一種是廣告的銷售效果，其方式是由銷售數字來衡量廣告效果;另一種是廣告的溝通效果，是以訊息接收者態度、行為的改變程度來衡量廣告效果。 本研究採用次級資料的分析方法，以實際產品的歷史資料做為分析的對象，並結合了廣告的銷售效果及廣告的溝通效果的理論，分別採用產品的銷售量及消費者對產品品牌的品牌態度二種指標來做為衡量廣告效果的依據，進一步地試圖比較同一產品內不同品牌間的廣告效果，以衡量廣告效果的成效。 除了廣告效果的衡量外，本研究也試圖研究台灣產業的廣告是否具有遞延效果。本研究將產品類別依產品特性、通路特性、產業集中度、廣告集中度及廣告密度進行分類，試圖研究這些分類方式的產品類別是否是影響到廣告效果，期望結果能提供廠商做一參考。 根據等級相關分析及順序迴歸分析的研究結果，本研究證實，廣告投入同時具有銷售效果與溝通效果，且大部分在廣告投入對銷售相關顯著的產品在對消費者品牌態度方面也會顯著，顯示廣告投入是同時影響銷售及消費者的品牌態度。在產品類別對廣告效果影響方面，將產品依不同產品特性、通路特性、產業集中度、廣告集中度及廣告密度進行分類檢定，所得出的結果皆為不顯著，代表沒有足夠的證據說明廣告效果會依不同產品特性、通路特性、產業集中度、廣告集中度及廣告密度等產品分類方式而有所差異。

Submitted by Pedro Silva Filho (pfsilva@ipen.br) on 2017-11-22T17:15:11Z No. of bitstreams: 0 / Made available in DSpace on 2017-11-22T17:15:11Z (GMT). No. of bitstreams: 0 / O excessivo processo de urbanização da Região Metropolitana de São Paulo resultou na perda das características naturais dos seus cursos d\'água ocasionando profundas alterações nos regimes de vazão e de qualidade. O objetivo desse estudo foi avaliar a concentração de metais tóxicos, os semi-metais As, Sb e Se e os elementos terras raras, presentes em amostras de sedimento superficiais coletadas nos Reservatórios Billings, Guarapiranga e Rio Grande. Os elementos Ag, Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Na, Ni, Pb, Sb, Se e Zn foram determinados pela técnica de Espectrometria de Emissão Ótica com Plasma Indutivamente Acoplado (ICP OES). Alguns elementos maiores, traço e elementos terras raras (Ce, Eu, La, Lu, Nd, Sm, Tb e Yb) foram determinados pela técnica de Análise por Ativação Neutrônica Instrumental (INAA). A concentração de Hg total foi determinada pela técnica Espectrometria de Absorção Atômica com Geração de Vapor Frio (CVAAS). A validação das metodologias foi realizada por meio da análise de materiais de referência certificados. Para avaliar as possíveis fontes de contaminação antrópicas foram utilizadas as ferramentas de fator de enriquecimento (FE) e o índice de geoacumulação (IGeo). Os resultados obtidos pelas técnicas foram comparados com os valores orientadores TEL e PEL estabelecidos pelo CCME (Canadian Council of Ministers of the Environment) e adotados pela CETESB. Todos os pontos analisados apresentaram valores > TEL para todos os metais e dois pontos da represa Billings (BILL02100 e 02030), valores > PEL para As, Cr, Cu, Hg, Ni, Pb e Zn, provavelmente em decorrência do recebimento das águas do Rio Pinheiros e das bacias de drenagem do ribeirão Cocaia e Bororé. Os valores de FE e IGeo calculados apontaram possíveis contaminações antrópicas para Sb e Se para os elementos determinados por ICP OES e de As, Cr, Sb e Zn, por INAA. O reservatório Billings apresentou, em geral, as maiores concentrações para os elementos analisados, indicando uma má qualidade de seus sedimentos. Este estudo confirma a necessidade de um monitoramento frequente da qualidade do sedimento nos reservatórios estudados como procedimento indispensável para avaliação periódica da qualidade das bacias, considerando sua importância no fornecimento de água para a Região Metropolitana de São Paulo. / Dissertação (Mestrado em Tecnologia Nuclear) / IPEN/D / Instituto de Pesquisas Energéticas e Nucleares - IPEN-CNEN/SP

In my thesis I analyse the development of the banking system of Ukraine and the assessment of the concentration level of the banking system in conditions of crisis 2014-2015. The theoretical part is devoted to classification and causes of the banking crisis; also, it describes the historical aspects of crisis formation in Ukraine. The practical part is focused on the evaluation of the financial security level and macroeconomic situation in Ukraine. This part emphasises problems and the specifics of functioning of domestic banks. In addition, it considers the concentration level of the banking market. The analysis performed shows that the banking crisis is the result of accumulated macroeconomic imbalances of the past and present mistakes in the implementation of anti-crisis policy. Currently the efficient functioning of most domestic banks remains at insufficient level.

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