Thesis (M.Sc. (Pathobiology))--Mahidol University, 1983.

Thesis (M.C.T.M. (Clinical Tropical Medicine))--Mahidol University, 2003.

Traditional medicines (TM) have been used for centuries to treat illnesses, but in many cases their modes-of-action (MOAs) remain unclear. Given the increasing data of chemical ingredients of traditional medicines and the availability of large-scale bioactivity data linking chemical structures to activities against protein targets, we are now in a position to propose computational hypotheses for the MOAs using in silico target prediction. The MOAs were established from supporting literature. The in silico target prediction, which is based on the “Molecular Similarity Principle”, was modelled via two models: a Naïve Bayes Classifier and a Random Forest Classifier. Chapter 2 discovered the relationship of 46 traditional Chinese medicine (TCM) therapeutic action subclasses by mapping them into a dendrogram using the predicted targets. Overall, the most frequent top three enriched targets/pathways were immune-related targets such as tyrosine-protein phosphatase non-receptor type 2 (PTPN2) and digestive system such as mineral absorption. Two major protein families, G-protein coupled receptor (GPCR), and protein kinase family contributed to the diversity of the bioactivity space, while digestive system was consistently annotated pathway motif. Chapter 3 compared the chemical and bioactivity space of 97 anti-cancer plants’ compounds of TCM, Ayurveda and Malay traditional medicine. The comparison of the chemical space revealed that benzene, anthraquinone, flavone, sterol, pentacyclic triterpene and cyclohexene were the most frequent scaffolds in those TM. The annotation of the bioactivity space with target classes showed that kinase class was the most significant target class for all groups. From a phylogenetic tree of the anti-cancer plants, only eight pairs of plants were phylogenetically related at either genus, family or order level. Chapter 4 evaluated synergy score of pairwise compound combination of Shexiang Baoxin Pill (SBP), a TCM formulation for myocardial infarction. The score was measured from the topological properties, pathway dissimilarity and mean distance of all the predicted targets of a combination on a representative network of the disease. The method found four synergistic combinations, ginsenoside Rb3 and cholic acid, ginsenoside Rb2 and ginsenoside Rb3, ginsenoside Rb3 and 11-hydroxyprogesterone and ginsenoside Rb2 and ginsenoside Rd agreed with the experimental results. The modulation of androgen receptor, epidermal growth factor and caspases were proposed for the synergistic actions. Altogether, in silico target prediction was able to discover the bioactivity space of different TMs and elucidate the MOA of multiple formulations and two major health concerns: cancer and myocardial infarction. Hence, understanding the MOA of the traditional medicine could be beneficial in providing testable hypotheses to guide towards finding new molecular entities.

Poultry meat is in the range of basic human nutrition. In human nutrition has a significant position mainly due to its composition. It is especially valuable for high-quality protein. They are very easily digested and contain all the essential amino acids. Aim of this study was a comprehensive analysis of the level of commercial properties in broiler chickens and their final hybrids. The analysis can bring about recommendations for breeders in the selection of suitable hybrid combinations in our conditions. Parental self-test forms consisted of rearing parents until the age of 154 days, the laying period of 280 days and four sub-fattening progeny tests. Rearing, laying and fattening progeny took place in the hall without windows, with deep bedding with controlled lighting and air conditioning regimen. The tests were performed 4 sub-fattening progeny tests using a load of 17.2 units chickens/1m2, length of fattening period was 35 days. The data were obtained with the consent of management of the primary data a comprehensive report of international tests and parental forms of broiler fattening sub-tests carried out in the final hybrid MTD Ústrašice for the years 1995 to 2009. These tests were made by MTD and methodology based on the guidelines for the implementation of performance tests of poultry. The data obtained were classified, summarized, and then the variation statistically using STATISTICA version 6. By comparing the results obtained from the parents and fattening tests it can be stated that, overall, the best combinations were Ross 308 and Cobb 500.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Diversos sÃo os relatos de resistÃncia in vitro de cepas de Candida spp. a fÃrmacos antifÃngicos, em especial a derivados azÃlicos. Deste modo, a prospecÃÃo de novos compostos com propriedade antifÃngica se faz necessÃria. Assim, o objetivo deste estudo foi avaliar a atividade antifÃngica do sesquiterpeno farnesol, sua aÃÃo sinÃrgica com antifÃngicos fluconazol (FLC), itraconazol (ITC), voriconazol (VRZ), anfotericina B (AMB) e caspofungina (CASP), bem como avaliar sua aÃÃo sob a atividade enzimÃtica de fosfolipases e proteases, consideradas importantes fatores de virulÃncia em Candida spp. Para tanto, foram avaliadas cepas de C. albicans (n=23), C. parapsilosis (n=16) e C. tropicalis (n=6). A concentraÃÃo inibitÃria mÃnima (CIM) foi determinada por meio da tÃcnica de microdiluiÃÃo, preconizada pelo Clinical Laboratory Standards Institute (CLSI). Em adiÃÃo, foi investigado o efeito do farnesol sobre a atividade de fosfolipase utilizando Ãgar Sabouraud suplementado com gema de ovo e a atividade de protease por tÃcnica espetrofotomÃtica. Paralelamente 14 cepas escolhidas aleatoriamente, foram prÃ-incubadas em trÃs concentraÃÃes sub-CIM de farnesol, afim de avaliar se o farnesol era capaz de causar algum dano na sensibilidade da cepa. Para as 45 cepas avaliadas, os valores de CIM para farnesol variaram de 9,37 a 150 ÂM para Candida spp. Para os derivados azÃlicos, o intervalo dos valores de CIM para fluconazol foi de 0,03125 a > 64 Âg/ml, observando-se a presenÃa de 18 cepas resistentes (CIM > 64 Âg/mL). Em relaÃÃo ao itraconazol, os valores de CIM variaram de 0,03125 a >16 Âg/mL e 35 cepas apresentaram resistÃncia a esse antifÃngico (CIM ≥1 Âg/mL). Constatou-se que das 45 cepas em estudo, 19 apresentaram resistÃncia a anfotericina B, com CIM > 1 Âg/mL. Quanto a caspofungina, os valores de CIM variaram de 0,0625 a 2 Âg/mL, com apenas seis cepas exibido resistÃncia, com CIM de 2 Âg/mL. A combinaÃÃo anfotericina B e farnesol apresentou sinergismo em 94,7% (18/19) das cepas de Candida spp. resistentes, evidenciado pelos valores de FICI ≤ 0,5. Na associaÃÃo fluconazol e farnesol, observou-se uma interaÃÃo sinÃrgica frente a todas as cepas de Candida spp. avaliadas, apresentando FICI ≤ 0,5. Trinta e seis cepas (18 C. albicans, 12 C. parapsilosis e 6 C. tropicalis) foram testadas frente à associaÃÃo de itraconazol e farnesol, observando a ocorrÃncia de sinergismo (FICI ≤ 0,5) em 94,4% dos isolados. Quanto à caspofungina todas as cepas testadas (C. parapsilosis, n=4; C. albicans, n=2) tiveram FICI ≤ 0,5, caracterizando associaÃÃo sinÃrgica com o farnesol. ApÃs constataÃÃo de que 17 das 45 cepas expressavam a enzima fosfolipase, as mesmas foram incubadas em concentraÃÃes sub-CIM de farnesol, por 24 horas, quando observouâse uma medida de Pz mÃdia de 0,73 para as cepas testadas sem contato com farnesol e valores de 0,71, 0,61, e 0,54 para aquelas incubadas em doses sub-inibitÃria de farnesol. Em relaÃÃo à produÃÃo de protease, observou-se que todas as 14 cepas produziam a enzima, em baixas concentraÃÃes, variando de 0,002 a 0,02 U/mL, e que a prÃ-incubaÃÃo com farnesol nÃo interferiu na produÃÃo enzimÃtica. No tocante a prÃ-incubaÃÃo das cepas com farnesol constatou-se que o mesmo interferi direta e indiretamente no fenÃmeno de resistÃncia das cepas. Estes resultados demonstram, em especial, o efeito do composto farnesol sobre a sensibilidade antifÃngica de Candida spp., abrindo a perspectiva de novos estudos com o intuito de determinar os mecanismos de aÃÃo desses compostos no metabolismo celular dos fungos. / There are several reports of in vitro resistance to antifungal drugs, especially azole derivatives, in strains of Candida spp. For this reason, the pursuit for new compounds that present antifungal properties is necessary. Thus, this study aimed at evaluating the antifungal activity of farnesol and its interaction with classical antifungal drugs against Candida spp., as well as evaluating its effect on the production of phospholipase and protease, which are important virulence factors for Candida species. Fourty-five strains of Candida spp. (23 C. albicans, 16 C. parapsilosis and 6 C. tropicalis) were tested through broth microdilution as described by the Clinical Laboratory Standards Institute (CLSI), document M27A2, and the minimum inhibitory concentrations (MICs) for amphotericin B (AMB), fluconazole (FLC), itraconazole (ITC), caspofungin (CAS) and farnesol (FAR) were individually determined. In addition, the effect of FAR on phospholipase activity was assessed by growing the strains on 2% Sabouraud agar, supplemented with egg yolk, and protease activity was determined through spectrophotometry. Then, 13 strains were randomly chosen, pre-incubated at three sub-inhibitory concentrations of FAR for 24 hours and re-submitted to microdilution assay. For the 45 evaluated Candida spp. strains the MIC values for FAR varied from 9.37 to 150 ÂM. For the classical antifungal drugs, MICs ranged from 0.0625 to 4 Âg/mL for AMB, with 19 resistant strains (MIC>1 Âg/mL); from 0.0125 to >64 for FLC, with 18 resistant strains (MIC> 64 Âg/mL); from 0.03125 to >16 Âg/mL for ITC, with 35 resistant strains (MIC ≥1 Âg/mL), and from 0.0625 to 2 Âg/mL for CAS, with six resistant strains (MIC≥2 Âg/mL). All resistant strains were tested against the combination of FAR with the drug to which they presented resistance. The combination of AMB and FAR was synergistic against 94.7% (18/19) of the Candida spp. isolates, as shown through the obtention of FICI≤0.5. FAR and FLC interacted synergistically against all tested strains (n=18), exhibiting FICI values of ≤0.5. The combination of FAR and ITC presented synergistic interactions (FICI≤0.5) against 94.4% of the tested isolates (33/35). Finally, FAR and CAS showed to interact synergistically (FICI≤0.5) against all tested strains. Concerning virulence factors, it was observed that 17/45 isolates produced phospholipase, with a mean Pz of 0.71. After incubating these strains at three different concentrations of FAR the mean Pz values of 0.71, 0.61 and 0.54 were obtained, after incubation at the lowest, the intermediate and the highest concentrations of FAR, respectively. In addition, it was observed that the 14 randomly chosen strains that were screened for protease activity produced low concentrations of these enzymes, varying from 0.002 to 0.02 U/mL and that FAR presented no effect on enzymatic production. Finally, it was observed that pre-incubating strains at the highest sub-inhibitory concentration of FAR reduced the MIC range of the tested antifungal drugs. These results especially show the effects of FAR on the susceptibility of Candida species to classical antifungal drugs, providing perspectives for the development of researches on the mechanisms of this compound on fungal cell metabolism

Orientador: Andreia Cristina Ribeiro / Dissertação (mestrado profissional) - Universidade Estadual de Campinas, Instituto de Matematica, Estatistica e Computação Cientifica / Made available in DSpace on 2018-08-11T11:28:46Z (GMT). No. of bitstreams: 1 Assis_LucianaMafaldaEliasde_M.pdf: 10126493 bytes, checksum: bb2628e76f90df6deb24a9011e535714 (MD5) Previous issue date: 2008 / Resumo: Neste trabalho são apresentados vários resultados importantes da Análise Combinatória com destaque para o Princípio da Inclusão e Exclusão. Relevantes aplicações deste princípio são abordadas / Abstract: In this work we present important results from enumerative combinatorics, with an emphasis on the Principle of Inclusion and Exclusion. Relevant applications of this principle are presented to illustrate its use / Mestrado / Mestre em Matemática

Introdução: A síndrome metabólica (SM) é um transtorno complexo representado por uma combinação de fatores de risco cardiometabólico relacionados à deposição central de gordura e à resistência à insulina, que aumentam diretamente o risco de doenças cardiovasculares. O crescimento na prevalência da SM acompanha o aumento do consumo de alimentos cujas combinações de nutrientes são potencialmente adipogênicas (dietas ricas em gorduras saturadas e açúcar e pobres em cereais integrais, frutas e vegetais). Esse novo padrão de consumo de alimentos em todo o mundo segue o estilo de vida ocidental moderno que é caracterizado pelo consumo excessivo de calorias e baixo gasto energético. Objetivo: Investigar a correlação entre os padrões alimentares, a SM e alguns de seus principais componentes em indivíduos adultos de ambos os sexos portadores e não-portadores da síndrome. Métodos: Estudo de delineamento transversal realizado com 267 indivíduos adultos de ambos os sexos. Foram avaliados os seguintes dados previamente coletados: demográficos (sexo e idade), antropométricos e de composição corporal (índice de massa corporal e circunferência da cintura), dietéticos (padrões alimentares detectados a partir da análise de um recordatório de 24 horas), clínicos e bioquímicos (aferição da pressão arterial, coleta de sangue após 12h de jejum para avaliação dos níveis séricos de triacilgliceróis, colesterol total, LDL-c, HDL-c e glicose de jejum). Os padrões alimentares foram identificados por meio da análise fatorial por componentes principais e subsequentemente foram realizadas análises estatísticas de correlação e comparação de médias para investigar a relação entre os padrões alimentares identificados por esse método e as características da população. Resultados: Três padrões alimentares distintos foram identificados, explicando 25,59 por cento da variabilidade da dieta da população: (i) Padrão Tradicional, representado por um alto consumo de arroz, feijão, especiarias frescas, legumes, carne branca, sucos, café e chás e açúcar, e um baixo consumo de massas; (ii) Padrão Saudável, caracterizado por alta ingestão de especiarias frescas, frutas, vegetais, laticínios com pouca gordura e pão integrais e baixa ingestão de batatas e tubérculos, carne vermelha, café e chá e açúcar; e (iii) Padrão Ocidental, representado pelo consumo elevado de óleos vegetais, carne processada, leite, pão branco, sucos, refrigerantes e baixa ingestão de laticínios de baixo teor de gordura e pão integral. Entre os indivíduos com SM, há uma correlação positiva entre o padrão saudável e HDL-c, bem como entre o padrão ocidental e circunferência da cintura e triglicerídeos séricos. Em pessoas sem SM, uma correlação positiva é observada entre o padrão saudável e colesterol total e LDL-c, e uma correlação negativa entre o padrão tradicional e LDL-c. Conclusão: Os resultados obtidos permitem concluir que os padrões alimentares podem influenciar componentes da síndrome metabólica, e reforçam a importância da abordagem nutricional na forma de combinações de alimentos para a análise da prevenção e tratamento de alterações metabólicas / Background: Metabolic Syndrome (MetS) is a complex disorder represented by a combination of cardiometabolic risk factors related to central obesity and insulin resistance, which directly increase the risk of cardiovascular disease. The growth in the prevalence of MetS follows the increase in consumption of foods whose nutrient combinations are potentially adipogenic (diets high in saturated fats and sugar and low in whole grains, fruits and vegetables). This new pattern of food consumption in the world follows the modern western lifestyle that is characterized by excessive consumption of calories and low energy expenditure. Objective: To investigate the association between dietary patterns, MetS and some of its main components in adults of both sexes carriers and non-carriers of the syndrome. Methods: Crosssectional study conducted with 267 adults of both sexes. Were evaluated the following data previously collected: demographic (age and sex), anthropometric and body composition (body mass index and waist circumference), dietary (food patterns detected from analysis of a 24-hour recall), clinical and biochemical (blood pressure measurement, blood sampling after 12h of fasting for evaluation of serum triglycerides, total cholesterol, LDL-c, HDL-c and fasting glucose). Dietary patterns (DPs) were obtained by principal component analysis and subsequent statistical analyzes of correlation and mean comparison were performed to further investigate the relationship between the dietary patterns identified by this method and the characteristics of the population. Results: Three distinct dietary patterns were identified from the principal component factor analysis, explaining 25.59 per cent of the dietary intake variance: (i) Traditional Dietary Pattern, represented by the high intake of rice, beans, fresh spice, vegetables, white meat, juices, coffee & teas and sugar, and low intake of pasta; (ii) Healthy Dietary Pattern, characterized by high intakes of fresh spice, fruits, vegetables, low-fat dairy and whole grain bread and low intake of potatoes & tubers, red meat, coffee & teas and sugar; and (iii) Western Dietary Pattern, represented by high intakes of olive & vegetable oils, processed meat, dairy, white bread, juices, sodas and low intake of low-fat dairy and whole grain bread. Among individuals with MetS, there is a positive correlation between Healthy DP and HDL-c, as well as between Western DP and waist circumference and triglycerides. In people without MetS, the positive correlation is observed between Healthy DP and total cholesterol and LDL-c, and negative correlation between Traditional DP and LDL-c. Conclusion: The present study demonstrate that dietary patterns have some influence on the components of metabolic syndrome, and reinforce that food combinations is an important strategy for the analysis of the prevention and treatment of metabolic dysregulations

Les réponses adaptatives fonctionnelles (secondaires à des modulations de la signalisation cellulaire) peuvent contribuer à la résistance des tumeurs humaines aux traitements ciblés. Ce travail vise à caractériser les changements induits par la chimiothérapie dans le phosphokinome de cellules de cancer du côlon, et à sélectionner des combinaisons de médicaments synergiques en ciblant les kinases dont l’activation est la plus importante. Nous avons créé des scripts informatiques pour l’analyse sur le logiciel de calcul R de données provenant de tests cytotoxiques avec des matrices de combinaison de doses à deux ou trois médicaments. Nous avons profilé les changements induits par différents médicaments sur des cellules de la lignée HT29 xénogreffées dans des souris immunodéprimées. Nous avons testé le 5FU, l’oxaliplatine, l’irinotecan, le cetuximab ainsi que les combinaisons de ces médicaments. Nous avons sélectionné les kinases activées par le traitement par irinotecan, notamment AKT et MEK1, et nous avons testés in vitro et in vivo des combinaisons à deux médicaments d’inhibiteurs de ces deux kinases et l’irinotecan sur 6 lignées de cancer du côlon. Enfin nous avons testés in vitro la combinaison des trois médicaments. Nous avons observé que la combinaison d’un inhibiteurs d’AKT et de MEK ainsi que la combinaison des trois médicaments étaient caractérisées par un synergisme significatif Cette étude a démontré que la chimiothérapie induit une reprogrammation des voies de signalisation intracellulaires, et fournit le rationnel pour une évaluation du profilage de la reprogrammation du phosphokinome comme outil pour développer de nouvelles combinaisons de médicaments. / Functional (i.e. due to cellular machinery modulations) adaptive responses could also contribute to human tumor resistance to targeted drugs. We hypothesized that the activation of tumor cell kinases in response to chemotherapy treatment could render the cell depending on them, and that the inhibition of these activated kinases could achieve a synergistic effect with chemotherapy agents. We compiled R scripts for analysis of data from cytotoxic tests with dose matrix combinations of 2 or 3 drugs. We evaluated phosphokinome rewiring induced by 5FU, irinotecan, oxaliplatin and cetuximab when these drugs were used alone or in combination on mice xenografted with HT29 cell line. We observed an activation of AKT and MEK1 after irinotecan treatment, and we tested two- and three drug combinations of BKM120, an AKT inhibitor, MEK162, a MEK inhibitor, and irinotecan. We showed that BKM120 and MEK162 are synergistic, as well as the combination of the three drugs. Our study shows that chemotherapy induces a significant rewiring of intracellular signaling pathways, and that profiling phosphokinome remodeling after chemotherapy treatment is useful in order to design synergistic drug combinations.

The effect of configuration changes and add-on devices on the drag reduction of a tractor-trailer is studied through wind tunnel tests using two 1/12-scale models. The configuration changes involve ground clearance, tractor-trailer gap, roof angle and back inclination while add-on devices include flow deflectors, skirts and gap seals. Moving surface boundary layer control as a means of drag reduction is also attempted. Both drag and pressure data are obtained to help identify local contributions. Results suggest that an optimum combination of configuration parameters can reduce drag up to 17% while the add-on devices resulted in a further decrease by a modest amount. The results with moving surface boundary layer control proved to be inconclusive. / Applied Science, Faculty of / Mechanical Engineering, Department of / Graduate

In this thesis I deal with the substance of the corporate mergers and its accounting treatment in relation to the Czech commercial arrangement. I compare the accounting view of mergers in the past with the solution after amendment of Act No. 125/2008 Coll., on the transformations of commercial companies and cooperatives, by Act No. 355/2011 Coll., which entered into force on 1 January 2012. I also want to point out some problems, that the new commercial arrangement of mergers brings. Finally, I deal with tax solving of mergers under current tax system in the CR, particularly the impact to the area of income tax.