Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-06-14T17:55:12Z No. of bitstreams: 1 RosaHelenaSilva.pdf: 2716670 bytes, checksum: 07dee1e77d704e91281c33c31e8c4938 (MD5) / Made available in DSpace on 2017-06-14T17:55:12Z (GMT). No. of bitstreams: 1 RosaHelenaSilva.pdf: 2716670 bytes, checksum: 07dee1e77d704e91281c33c31e8c4938 (MD5) Previous issue date: 2016-10-19 / Borreria verticillata (L.) G. Mey species known as broom vassourinha has antibacterial, antimalarial, hepatoprotective, antioxidative, analgesic and antiinflammatory activities; however, its antinociceptive action still demands more thorough investigation. The present study was to assess the antinociceptive activity of B. verticillata crude hydroalcoholic extract (EHBv) and the ethyl acetate fraction (FAc) by means of in vivo and in silico studies. In vivo assessment included the paw edema test, the writhing test, the formalin test and the tail flick test. Wistar rats and Swiss mice were divided into 6 groups and given the following treatments oral: 0.9% NaCl control group (CTL), 10 mg/kg memantine (MEM), 10 mg/kg indomethacin (INDO), 500 mg/kg EHBv (EHBv 500), 25 mg/kg FAC (FAc 25), 50 mg/kg and FAc (FAC 50). EHBv, FAc 25 and 50 treatments exhibited anti-edematous and peripheral antinociceptive effects. For in silico assessment, compounds found in FAc were subjected to molecular docking, and the leading compound was selected for molecular dynamics (MD) simulations. Ursolic acid exhibited better affinity parameters with the enzyme COX-2 and the NMDA receptor subunits GluN1a and GluN2B on molecular docking. In MD simulations, AU exhibited highly frequent interactions with residues Arg120 and Glu524 in the COX-2 active site and NMDA, whereby it might prevent COX-2 and NMDA receptor activation. Treatment with ursolic acid 10mg / Kg (AU) showed peripheral and central antinoceceptivo effect. The antinociceptive effect of B. verticillata might be predominantly attributed to peripheral actions, including the participation of anti-inflammatory components. Ursolic acid is the main active component and seems to be a promising source of COX-2 inhibitors and NMDA receptor antagonists / Borreria verticillata (L.) G. Mey espécie conhecida como vassourinha apresenta atividade antibacteriana, antimalárica, hepatoprotetora, antioxidante, analgésica e anti-inflamatória, entretanto sua atividade antinociceptiva é pouco estudada. O objetivo deste trabalho foi avaliar atividade antinociceptiva do extrato hidroalcoólico bruto (EHBv) e fração acetato de etila (FAc) de B. verticillata realizando estudos in vivo e in silico. Para avaliação in vivo, foram utilizados os testes do edema de pata, contorções abdominais, formalina e tail flick. Ratos Wistar e camundongos Swiss foram tratados via oral e divididos em 6 grupos: controle-NaCl 0.9%(CTL), memantina 10 mg/Kg (MEM), indometacina 10 mg/Kg (INDO), EHBv 500 mg/kg (EHBv 500), FAc 25 mg/Kg (FAc 25), FAc 50 mg/Kg (FAc 50). O tratamento com EHBv 500, FAc 25 e 50 apresentou efeito antiedematogênico e antinociceptivo periférico. Para avaliação in silico os compostos identificados na FAc foram submetidos a docagem molecular, o melhor composto foi selecionado para simulações de dinâmica e testado in vivo molecular. O ácido ursólico apresentou melhores parâmetros de afinidade com COX-2, GluN1a e GluN2B durante a docagem molecular. Nas simulações por dinâmica molecular, o ácido ursólico apresentou alta frequência de contatos com Arg120 e Glu524 do local ativo da COX- 2 e com o domínio LBD da Glun1a e GluN2B podendo com isso, impedir a ativação da COX-2 e do receptor NMDA. O tratamento com ácido ursólico 10mg/Kg (AU) apresentou efeito antinoceceptivo periférico e central. Sugere-se que o efeito antinociceptivo periférico de B. verticillata pode ser atribuído predominantemente à ação de compostos com ação anti-inflamatória. O ácido ursólico é o principal composto ativo, sendo um composto promissor para o desenvolvimento de fármacos inibidores da COX-2 e antagonistas dos receptores NMDA.

Many breast cancer diagnoses and second cancers are associated with BRCA gene mutations. Early detection of cancer is necessary to improve health outcomes, particularly with second cancers. Little is known about the influence of risk factors on time to diagnosis of second primary cancers after diagnosis with BRCA-related breast cancer. The purpose of this cohort study was to examine the risk of diagnosis of second primary cancers among women diagnosed with breast cancer after adjusting for BRCA status, age, and ethnicity. The study was guided by the empirical evidence supporting the mechanism of action in the mutation of BRCA leading to the development of cancer. Composite endpoint was used to define second primary cancer occurrences, and Kaplan-Meier survival curves were used to compare the median time-to-event among comparison groups and BRCA gene mutation status. Cox proportional hazards was used to examine the relationships between age at diagnosis, ethnicity, BRCA gene mutation status, and diagnosis of a second primary cancer. The overall median time to event for diagnosis of second primary cancers was 14 years. The hazard ratios for BRCA2 = 1.47, 95% CI [1.03 - 2.11], White = 1.511, 95% CI [1.18 - 1.94], and American Indian/Hawaiian = 1.424, 95% CI [1.12 -1.81] showing positive significant associations between BRCA2 mutation status and risk of diagnosis of second primary colorectal, endometrial, cervical, kidney, thyroid, and bladder cancers. Data on risk factors for development of second cancers would allow for identification of appropriate and timely screening procedures, determining the best course of action for prevention and treatment, and improving quality of life among breast cancer survivors.

Although the ‘death of God’ theology attracted considerable attention during the 1960s, in recent decades it has fallen into neglect. Nonetheless, the issues raised by the ‘death of God’ theology were important ones and it remains an interesting question whether the ‘death of God’ theologians were able to make substantial contributions to them. This thesis re-examines the work of the ‘death of God’ theologians. It argues that the popular view – that the ‘death of God’ theology represented a common tendency, or movement, towards atheism among certain prominent American Protestant theologians – is mistaken. Through a series of detailed studies of Thomas J.J. Altizer (chapters 3 and 4), William Hamilton (Chapter 5), Paul van Buren (Chapter 6), and Harvey Cox (Chapter 7), the thesis shows not only that the significance of the ‘death of God’ theologians has been widely misinterpreted, but that their work contains a number of features which have been under-emphasised or even overlooked. The aim of the thesis is to provide a more balanced contemporary reading of their work. The work of Altizer receives special attention and a case is made for the view that he should be read as a Protestant mystic of a peculiar sort.

Les études épidémiologiques longitudinales sur la qualité de vie (QdV) connaissent un essor depuis quelques années, surtout pour les maladies chroniques où aucun traitement curatif n'existe. L'objectif de ces études est la surveillance de la santé incluant la QdV et la survie. Une telle surveillance repose sur la comparaison de l'évolution longitudinale de QdV entre groupes de patients. Aussi, avons nous élaboré un test global de type log-rank pour l'évolution longitudinale de QdV par rapport à un taux de dégradation de QdV pour deux groupes de patients. <br />Généralement lors de ces études, des questionnaires de QdV sont donnés à remplir aux patients permettant de calculer leur score de QdV. L'évolution de QdV se traduit par le concept de dégradation de QdV. Un taux critique x de dégradation de QdV peut être fixé. Les patients sont considérés comme dégradés si leur score de QdV est supérieur à x. Nous étendons la statistique du score de vraisemblance partielle afin de prendre en compte un taux x de dégradation de QdV préalablement fixé et montrons que le vecteur du processus de score normalisé converge vers un processus gaussien centré. Le taux x de dégradation de QdV est ensuite supposé variable. A l'aide de la théorie des processus empiriques nous prouvons la convergence en distribution de la statistique du score normalisé vers un processus gaussien. Ces travaux ont permis de construire, lorsque le taux x de dégradation de QdV est variable, un test de type log-rank permettant de comparer l'évolution longitudinale de la dégradation de QdV pour deux goupes de patients.<br />Des simulations et une application à une cohorte de patients infectés par le VIH sont présentées.

En bloquant les deux voies majeures de métabolisation de l’acide arachidonique, les inhibiteurs mixtes 5-LOX/COX-2 sont de puissants agents anti-inflammatoires non stéroïdiens minimisant les effets secondaires gastro-intestinaux et allergiques (asthme). Par ailleurs, ils offrent de nouvelles perspectives dans le traitement préventif de certains cancers. Contrairement à la COX-2, déjà largement étudiée, le niveau de connaissances concernant la 5-LOX humaine est beaucoup plus restreint. Notre objectif a donc été de caractériser sa structure ainsi que son mode d’interaction avec des inhibiteurs de type non redox, dans le but d’aider à la conception rationnelle d’inhibiteurs mixtes 5-LOX/COX-2. Dans un premier temps, la comparaison d’inhibiteurs 5-LOX non redox de la littérature a permis de mettre en évidence un modèle de pharmacophore à 5 points. Par ailleurs, la structure 3D de la 5-LOX humaine n’étant pas encore déterminée, nous l’avons modélisée par homologie avec la 15-LOX de lapin cristallisée et nous avons étudié, par docking, le mode d’interaction d’inhibiteurs 5-LOX non redox au sein du site actif. La combinaison des approches centrées, respectivement, sur les ligands et sur la protéine, nous a permis d’affiner l’hypothèse de pharmacophore et de proposer un modèle général d’interaction au sein du site actif 5-LOX./Dual 5-LOX/COX-2 inhibitors, acting on both major arachidonic acid metabolic pathways, are potent non-steroidal anti-inflammatory agents, with a reduced gastro-intestinal toxicity and fewer allergic adverse reactions. Moreover, they are promising in the treatment of several cancers. Whereas COX-2 has already been extensively studied, little structural or mechanistic information is available regarding human 5-LOX. Therefore, we focussed on this enzyme and characterized its 3D structure as well as its interaction with non redox inhibitors in order to help the design of dual 5-LOX/COX-2 inhibitors. Firstly, comparison of non redox 5-LOX inhibitors from the literature led to the generation of a five-point pharmacophore model. The 3D structure of human 5-LOX was then modelled based on the crystal structure of rabbit 15-LOX and, the binding modes of representative ligands were investigated through docking studies. Combination of both ligand-based and target-based approaches allowed the refinement of the pharmacophore hypothesis and led to the proposal of an interaction model for non redox inhibitors inside the 5-LOX active site.

Inflammatory processes in, or in close vicinity of, the skeleton often lead to loss of bone tissue. Different cytokines have been shown to be involved as stimulators of inflammatory induced osteoclastic bone resorption. During inflammatory processes also the kallikrein-kinin system is activated, leading to production of kinins that can cause pain, vasodilation and increased permeability of vessels. Kinins can also induce bone resorption in vitro. All cytokines and kinins that stimulate bone resorption stimulate in parallell prostaglandin synthesis, and prostaglandins, per se, have also been shown to induce bone resorption. The aim of this project was to increase the knowledge about the mechanisms involved in the interactions between different inflammatory mediators (i.e. kinins, cytokines and prostaglandins) suggested to be involved in the pathogenesis of inflammatory bone resorbing diseases. Human osteoblasts (MG-63) are equipped with both kinin B1 and B2 receptors linked to prostaglandin release and the stimulation of prostaglandin release are likely mediated via separate molecular mechanisms (Paper I). Activation of B1 or B2 receptors causes synergistic stimulation of PGE2 synthesis induced by either interleukin-1b (IL-1b) or tumour necrosis factor-a (TNF-a) (Paper II). The molecular mechanism involves increased expression of cyclooxygenase-2 (COX-2) and results in synergistic potentiation of receptor activator of NF-kB ligand (RANKL) protein expression. The synergistic interaction is dependent on the activation of NF-kB and the mitogen-activated protein kinases (MAPK) p38 and JNK (Paper II). The synergistic increase in RANKL expression might be an explanation why kinins potentiate IL-1b induced bone resorption, a mechanism likely to be important in inflammation induced bone resorption in diseases such as periodontal disease and rheumatoid arthritis. The synergism between kinins and IL-1b or TNF-a might also be dependent on regulation of kinin receptors, since both IL-1b and TNF-a markedly upregulated B1 and B2 receptors, both at the mRNA level and protein level (Paper III). This upregulation is not further potentiated by the kinins, and different kinin receptor agonists do not regulate the receptors for IL-1b or TNF-a, in MG-63 cells. No other cytokines known to stimulate bone resorption regulates the expressions of B1 and B2 receptors. The IL-1b- or TNF-a-induced enhancements of B1 and B2 receptor expressions involve activation of NF-kB and MAPK. The enhancement of kinin receptors may also be an important mechanism in the synergistic interactions between the two pro-inflammatory cytokines and kinins (paper III). IL-4 and IL-13 are two cytokines that have been shown to inhibit bone resorption. We have shown that COX-2 and both B1 and B2 receptors are down-regulated by IL-4 and IL-13, via a ‘signal transducer and activator of transcription6’ (STAT6) dependent pathway, which might be an important regulatory mechanism in inflammation induced bone resorption (paper IV). In conclusion, the mechanisms behind the synergistic potentiation of prostaglandin formation and increased bone resorption caused by co-stimulation with kinins and IL-1b or TNF-a seem to involve both potentiation of COX-2 and subsequently increased levels of RANKL, as well as upregulation of B1 and B2 kinin receptors. Interestingly, IL-4 and IL-13 decreased the expressions of COX-2 and both B1 and B2 receptors. These events might be important in the regulation of inflammation induced bone resorption in diseases such as periodontitis and rheumatoid arthritis.

Pricing options quickly and accurately is a well known problem in finance. Quantum computing is being researched with the hope that quantum computers will be able to price options more efficiently than classical computers. This research extends the quantum binomial option pricing model proposed by Zeqian Chen to European put options and to Barrier options and develops a quantum algorithm to price them. This research produced three key results. First, when Maxwell-Boltzmann statistics are assumed, the quantum binomial model option prices are equivalent to the classical binomial model. Second, options can be priced efficiently on a quantum computer after the circuit has been built. The time complexity is O((N − τ)log(N − τ)) and it is in the BQP quantum computational complexity class. Finally, challenges extending the quantum binomial model to American, Asian and Bermudan options exist as the quantum binomial model does not take early exercise into account. / May 2009

In this work, the compounding of polycarbonate (PC) / poly-butylene terephthalate (PBT) blends was studied for the purpose of improving quality of products with reduced wastage and finally to satisfaction of end users. The effect of material rheological characteristics and processing conditions on compounding of PC /PBT was investigated through statistical experiments carried out on a 58 mm twin-screw extruder at SABIC Innovative Plastics Limited (formerly GE Plastics Limited) in Cobourg, Ontario. Melt Volume-Flow Rate (MVR) is the most commonly used property to monitor the quality of products of PC/PBT blends. The MVR was studied with different sampling times and correlations between product properties (melt flow) and processing conditions (screw speed, flow rates) were discussed. The rheological behavior of PC/PBT blends was investigated by dynamic and capillary rheometers. The effects of processing conditions (screw speed, feed rate) on viscosity were measured and it was found that the Cox-Merz rule is not valid for PC/PBT blends. The change of morphology of PC/PBT blends was observed under a scanning electron microscope (SEM) by using different types of samples. Those samples were (i) PC/PBT blends pellets, (ii) PC/PBT blend samples, but collected after completing the rheological tests in the parallel plate rheometer, and (iii) PC/PBT blend samples, but collected after completing the rheological tests in the capillary rheometer. There was evidence that the samples collected after completing the tests in the parallel and capillary rheometer might be degraded due to temperature and time.

In this work, the compounding of polycarbonate (PC) / poly-butylene terephthalate (PBT) blends was studied for the purpose of improving quality of products with reduced wastage and finally to satisfaction of end users. The effect of material rheological characteristics and processing conditions on compounding of PC /PBT was investigated through statistical experiments carried out on a 58 mm twin-screw extruder at SABIC Innovative Plastics Limited (formerly GE Plastics Limited) in Cobourg, Ontario. Melt Volume-Flow Rate (MVR) is the most commonly used property to monitor the quality of products of PC/PBT blends. The MVR was studied with different sampling times and correlations between product properties (melt flow) and processing conditions (screw speed, flow rates) were discussed. The rheological behavior of PC/PBT blends was investigated by dynamic and capillary rheometers. The effects of processing conditions (screw speed, feed rate) on viscosity were measured and it was found that the Cox-Merz rule is not valid for PC/PBT blends. The change of morphology of PC/PBT blends was observed under a scanning electron microscope (SEM) by using different types of samples. Those samples were (i) PC/PBT blends pellets, (ii) PC/PBT blend samples, but collected after completing the rheological tests in the parallel plate rheometer, and (iii) PC/PBT blend samples, but collected after completing the rheological tests in the capillary rheometer. There was evidence that the samples collected after completing the tests in the parallel and capillary rheometer might be degraded due to temperature and time.

Turkey has very different geomorphologic, hydrologic and climatic conditions, so the runoff coefficient should be different from one basin to another. But only one constant value, which is 0.37, is being used for all the basins in Turkey. In this thesis, monthly, seasonal and annual runoff coefficients of 48 sub-basins in western and southern part of Anatolia are determined by using synchronous and average rainfall, runoff data of 26 year record period. Their temporal and spatial distributions are investigated. The relationship between the basin parameters and the runoff coefficient are also examined. Some of the basins have unrealistic large runoff coefficients, therefore excluded from the analyses. The basin boundaries and parameters are determined by using Geograhic Information System (GIS), and areal average precipitations are found by a program written in visual basic language that uses ArcObjects. The Box-Cox transformed data are used in regression analysis. There are a number of dams in the region, which affect the natural flow. Such streams are found and their sub-basins are not used in the analyses. The results revealed that there is not a strong the relationship between the basin parameters and annual and seasonal runoff coefficients for the whole region, but there are significant relations between them for some basins.