An in silico design algorithm has been developed to design binding ligands for protein targets of known three-dimensional structure. In this method, the binding energy of a candidate ligand is used to ascribe it a probability of binding. A sample of a virtual library of candidate ligands is then used to ascribe implicit weights to all the ligands in the library. These weights are used to obtain virtual sub-libraries which collectively carry a greater probability to bind to the target. This algorithm is presented along with validation studies on the different algorithmic components, demonstrating how optimization of the design method can be best achieved.

Στα πλαίσια της διπλωματικής εργασίας μελετήθηκαν οι αλγόριθμοι και τα εργαλεία σχεδίασης Φαρμάκων με τη βοήθεια Η/Υ, που υπάρχουν στη διεθνή βιβλιογραφία. Η μελέτη αναφέρθηκε σε αλγορίθμους «εξ αρχής» σχεδιασμού φαρμακοφόρων μορίων (de novo drug design). Στόχος της διπλωματικής εργασίας ήταν η σχεδίαση ενός πλαισίου αξιολόγησης των σχετικών εργαλείων και αλγορίθμων σχεδιασμού Φαρμάκων με τη βοήθεια Η/Υ και η αναφορά πιθανών βελτιώσεων στα ανοικτά προβλήματα που προκύπτουν. / The thesis was about algorithms and tools for drug design with the use of computers, algorithms and tools which already exist in the international bibliography. The study referred to algorithms for de novo drug design. The aim of the thesis was the design of a frame for the evaluation of the relevant tools and algorithms and also the report of possible improvements to the open issues that arise.

No description available.

Stearoyl-coA desaturase-1 (SCD1) activity has been linked to the development of obesity and the metabolic syndrome (MetS) through its central role in lipid metabolism. Understanding how changes in SCD1 activity affect obesity and MetS risk biomarkers and investigating how these changes in activity affect nutrient handling in non-hepatic tissues is also important. This study investigated how acute SCD1 inhibition effected plasma lipids, skeletal muscle nutrient handling and insulin signaling in mice fed a high-carbohydrate very-low fat diet for 10 weeks. This study demonstrated that SCD1 inhibition created acute dyslipidemia, altered nutrient handling protein activity and increased the percentage of saturated fatty acids (SFA) in hepatic and muscle tissue, independent of dietary oleic acid content. However, the molecular controls of protein synthesis in the mTOR pathway were not affected by the loss of SCD1 activity. In conclusion, we observed that inhibiting hepatic SCD1 activity and subsequently changing the monounsaturated fatty acid (MUFA) to SFA ratios in tissues alters normal nutrient handling in skeletal muscle.

Hylurgopinus rufipes, the native elm bark beetle (NEBB), is the major vector of Dutch elm disease (DED) in Manitoba. Dissections of American elms (Ulmus americana), in the same year as DED symptoms appeared in them, showed that NEBB constructed brood galleries in which a generation completed development, and adult NEBB carrying DED spores would probably leave the newly-symptomatic trees. Rapid removal of freshly diseased trees, completed by mid-August, will prevent spore-bearing NEBB emergence, and is recommended. The relationship between presence of NEBB in stained branch sections and the total number of NEEB per tree could be the basis for methods to prioritize trees for rapid removal. Numbers and densities of overwintering NEBB in elm trees decreased with increasing height, with >70% of the population overwintering above ground doing so in the basal 15 cm. Substantial numbers of NEBB overwinter below the soil surface, and could be unaffected by basal spraying. Mark-recapture studies showed that frequency of spore bearing by overwintering beetles averaged 45% for the wild population and 2% for marked NEBB released from disease-free logs. Most NEBB overwintered close to their emergence site, but some traveled ≥4.8 km before wintering. Studies comparing efficacy of insecticides showed that chlorpyrifos gave 100% control of overwintering NEBB for two years as did bifenthrin: however, permethrin and carbaryl provided transient efficacy. NEBB showed a gradual increase in development rate with increasing constant temperature. Lipid content of overwintering NEBB was higher in late fall than in mid-winter, which might show that depletion of fat reserves could jeopardize survival, but could be a result of conversion to cryoprotectants.

Stearoyl-coA desaturase-1 (SCD1) activity has been linked to the development of obesity and the metabolic syndrome (MetS) through its central role in lipid metabolism. Understanding how changes in SCD1 activity affect obesity and MetS risk biomarkers and investigating how these changes in activity affect nutrient handling in non-hepatic tissues is also important. This study investigated how acute SCD1 inhibition effected plasma lipids, skeletal muscle nutrient handling and insulin signaling in mice fed a high-carbohydrate very-low fat diet for 10 weeks. This study demonstrated that SCD1 inhibition created acute dyslipidemia, altered nutrient handling protein activity and increased the percentage of saturated fatty acids (SFA) in hepatic and muscle tissue, independent of dietary oleic acid content. However, the molecular controls of protein synthesis in the mTOR pathway were not affected by the loss of SCD1 activity. In conclusion, we observed that inhibiting hepatic SCD1 activity and subsequently changing the monounsaturated fatty acid (MUFA) to SFA ratios in tissues alters normal nutrient handling in skeletal muscle.

The PMCA assay was optimized for adaptation to low level detection of PrPSc in hamster plasma. Evaluation of numerous key variables of the PMCA assay led to an optimized protocol capable of ~3 log10 amplification after 32 cycles (two 16 hour rounds). When commercially purchased normal hamster plasma was added to the PMCA reaction an accentuation in PrPSc amplification was observed (>6.75 log10 after 32 cycles). Only con-specific plasma appeared to enhance the conversion of PrPC to PrPSc, suggesting that a species-specific co-factor may be involved in assembly of protein aggregates. Serial PMCA in the presence of low level (10%) contiguous conspecific plasma resulted in the generation of de novo PrPSc after several rounds of PMCA. Although plasma significantly accentuated PrPSc amplification by PMCA, the formation of de novo PrPSc interfered with the ability of using the PMCA assay to detect prion infections in hamsters experimentally infected with 263K scrapie. / Physiology, Cell and Developmental Biology

Mestre -- Escola Nacional de Saude Publica, Rio de Janeiro, 2004.

Universiẗat, Diss., 2000--Hannover.

Universidade Federal Fluminense / Esta tese abordou como temas centrais a capacidade de extração tributária e os conflitos distributivos inerentes ao efetivo exercício da coleta de tributos pelo Estado. Nosso objetivo foi analisar os processos por trás das disputas em torno da tributação no Novo Desenvolvimentismo no Brasil (governos Luiz Inácio Lula da Silva, 2003-2010) e na Argentina (governos Néstor Kirchner, 2003-2007, e Cristina Fernández de Kirchner, 2007-2011), identificando os legados das trajetórias institucionais prévias sobre a formulação de suas agendas tributárias, bem como as estratégias empreendidas pelas coalizões governantes e opositoras para a promoção de mudanças nas instituições tributária. Para tanto, focalizamos o estudo dos conflitos em torno da CPMF, no Brasil, e das retenções às exportações, na Argentina. Sustentamos que a formação de coalizões desenvolvimentistas explica a formatação de consensos em torno do fortalecimento da capacidade de extração tributária e, por conseguinte, da capacidade de investir e de efetuar gastos sociais. As diferenças observadas nas capacidades extrativas no Brasil e na Argentina se explicam, fundamentalmente, pela construção de um duradouro consenso em torno do desenvolvimentismo, no Brasil, em contraste com a trajetória de marcada por disputas em torno das estratégias de desenvolvimento na Argentina. Ademais, a formação de coalizões de sustentação a determinadas agendas tributárias deve ser entendida no marco das disputas em torno da distribuição dos custos e dos benefícios decorrentes dessas políticas. Por isso, fez-se necessário analisar a articulação das elites econômicas dos dois países na defesa dos seus interesses: embora suas elites empresariais (industriais ou agropecuárias) apresentassem dificuldades históricas na articulação de ação coletiva em favor de agendas positivas, elas foram capazes de articularem suas ações em torno de interesses negativos, objetivando obstaculizar políticas tributárias que fossem de encontro aos seus interesses. / This thesis addressed as central themes state tax capacity and distributive conflicts inherent to the effective tax collection. We aimed at analyzing the processes behind disputes over taxation in the New Developmentist phase in Brazil (Luiz Inácio Lula da Silva government, 2003-2010) and Argentina (Néstor Kirchner, 2003-2007, and Cristina Fernández de Kirchner administrations, 2007-2011), identifying the impacts from previous institutional path legacies on the definition of their tax agendas, as well as the strategies adopted by ruling and opposing coalitions to promote changes in tax institutions. We focused our analysis on the conflicts around CPMF, in Brazil, and retenciones on exports, in Argentina. We argued that the emergence of developmentalist coalitions explains the construction of consensus around strengthening state capacity to raise taxes and thus the capacity to invest and promote social expenditures. The observed differences in tax capacity in Brazil and Argentina are explained, fundamentally, by the maintenance of a long-term consensus around developmentalism in Brazil, in contrast to a trajectory characterized by disputes around development strategies in Argentina. Furthermore, the building of coalitions that support particular tax agendas must be understood in the context of disputes around the distribution of costs and benefits associated to these policies. Therefore, we analyzed both countries economic elites articulation in the defense of their interests: even though Brazilian and Argentine business elites (industrial or agricultural) present historical difficulties in promoting collective action for positive agendas, they are capable of organizing their actions around negative interests, aiming to hinder tax policies that were against their interests.