Nous nous intéressons à l'utilisation de la technologie manycore des cartes graphiques dans le cadre de la Chimie théorique. Nous soutenons la nécessité pour ce domaine d'être capable de tirer profit de cette technologie. Nous montrons la faisabilité et les limites de l'utilisation de cartes graphiques en Chimie théorique par le portage sur GPU de deux méthodes de calcul en modélisation moléculaire. Ces deux méthodes n’intégrerons ultérieurement au programme de docking moléculaire AlgoGen. L'accélération et la performance énergétique ont été examinées au cours de ce travail.Le premier programme NCIplot implémente la méthodologie NCI qui permet de détecter et de caractériser les interactions non-covalentes dans un système chimique. L'approche NCI se révèle être idéale pour l'utilisation de cartes graphiques comme notre analyse et nos résultats le montrent. Le meilleur portage que nous avons obtenu, a permis de constater des facteurs d'accélération allant jusqu'à 100 fois plus vite par rapport au programme NCIplot. Nous diffusons actuellement librement notre portage GPU : cuNCI.Le second travail de portage sur GPU se base sur GAMESS qui est un logiciel complexe de portée internationale implémentant de nombreuses méthodes quantiques. Nous nous sommes intéressés à la méthode combinée DFTB/FMO/PCM pour le calcul quantique de l'énergie potentielle d'un complexe. Nous sommes intervenus dans la partie du programme calculant l'effet du solvant. Ce cas s'avère moins favorable à l'utilisation de cartes graphiques, cependant nous avons su obtenir une accélération. / In this research work we are interested in the use of the manycore technology of graphics cards in the framework of approaches coming from the field of Theoretical Chemistry. We support the need for Theoretical Chemistry to be able to take advantage of the use of graphics cards. We show the feasibility as well as the limits of the use of graphics cards in the framework of the theoretical chemistry through two usage of GPU on different approaches.We first base our research work on the GPU implementation of the NCIplot program. The NCIplot program has been distributed since 2011 by Julia CONTRERAS-GARCIA implementing the NCI methodology published in 2010. The NCI approach is proving to be an ideal candidate for the use of graphics cards as demonstrated by our analysis of the NCIplot program, as well as the performance achieved by our GPU implementations. Our best implementation (VHY) shows an acceleration factors up to 100 times faster than the NCIplot program. We are currently freely distributing this implementation in the cuNCI program.The second GPU accelerated work is based on the software GAMESS-US, a free competitor of GAUSSIAN. GAMESS is an international software that implements many quantum methods. We were interested in the simultaneous use of DTFB, FMO and PCM methods. The frame is less favorable to the use of graphics cards however we have been able to accelerate the part carried by two K20X graphics cards.

Despite widespread availability of effective antiretroviral therapy (ART), people living with HIV (PWH) remain at risk of developing comorbidities including HIV-associated neurocognitive impairment (H-NCI). These individuals may then be at an increased risk for treatment non-adherence, which leads to poor quality of life and early mortality. Despite this risk, there is a paucity in trained professionals in low- and middle-income countries with appropriate knowledge and skills to identify H-NCI and make appropriate referrals for additional confirmatory testing or intervention, depending on the severity and context of the screening. General medical doctors, nurses and adherence counsellors provide most HIV related healthcare services at a primary healthcare level in South Africa. However, awareness of the clinical presentation of H-NCI, and their current screening practices among these cadres, is unclear. To address these knowledge gaps this thesis set out to explore the following aims (1) examine existing H-NCI knowledge and practices among healthcare workers delivering HIV services in South Africa, (2) develop an appropriate H-NCI training programme for primary healthcare workers, and (3) lastly, pilot the H-NCI training to determine whether H-NCI screening would be feasible at a primary healthcare level in South Africa. Methods To achieve these objectives, the study was divided into two phases. In phase one, a scoping review identified and summarised published studies addressing brain and/or behaviour training approaches, including H-NCI, targeting frontline HIV healthcare workers in Africa. An online survey was developed and administered to examine existing H-NCI knowledge and current practices among healthcare workers providing HIV services in South Africa. Focus group discussions and in-depth interviews were then conducted to explore knowledge gaps, previous H-NCI training and healthcare workers' perspectives of screening at a primary healthcare level. In phase two, an H-NCI training curriculum was developed and a work-integrated H-NCI training programme targeting primary healthcare workers was piloted. The pilot training assessed knowledge of H-NCI signs and symptoms, healthcare workers' attitude toward and comfort with H-NCI screening tools and healthcare workers ability to accurately administer an H-NCI screening tool. The assessments were repeated two months post-training to evaluate retention of knowledge and skills. Results The scoping review of the existing literature suggested that there were few brain and/ or behaviour training programs targeting healthcare workers providing HIV services in Africa. Of the ten studies identified in the scoping review, one study included H-NCI in the training curriculum. The online survey found that H-NCI knowledge was limited and screening practices virtually non-existent among healthcare workers providing HIV care in South Africa. Qualitative data gathered during the focus group discussions and the in-depth interviews provided greater insight on the existing knowledge and practices gaps as well as highlighting that healthcare workers had not received training on H-NCI. The results from the qualitative investigations showed that primary healthcare workers were in favour of receiving such training. Overall, knowledge of H-NCI improved among primary healthcare workers following the work-integrated H-NCI training programme. The training demonstrated that primary healthcare workers providing clinical services, such as medical doctors or professional nurses were able to administer an H-NCI screening tool. Although knowledge of the clinical presentation of H-NCI improved among adherence counsellors, these healthcare workers experienced challenges in administering the H-NCI screening tool. Conclusion As a body of work, the findings from this thesis suggest that healthcare professionals providing HIV services in South Africa have limited knowledge to identify H-NCI, and screening practices are uncommon. Although training revealed differences between cadres in administering screening tools, healthcare workers providing clinical care, including general medical doctors and professional nurses, may be able to provide H-NCI screening at routine annual visits. Although adherence counsellors are ideally situated in the clinic flow to provide targeted screening by flagging clinical presentation of H-NCI among PWH accessing care, this cadre will require additional training, mentorship and support to successfully administer H-NCI screening tools. However, the feasibility of H-NCI screening at a primary healthcare, timing and nature of any screening remains to be explored. This body of work is a step toward increasing the availability of skilled healthcare workers with appropriate knowledge and skills to screen and identify H-NCI in low- and middle-income countries. The work presented in this thesis provides a foundation for further development of the H-NCI training module and future investigations examining targeted screening strategies at a primary healthcare level, feasibility and access to existing interventions post-screening

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The Stockholm Convention was the first global attitude trying to preserve human health and the environment of the indiscriminate use of persistent organic pollutants (POPs), especially pesticides, which are characterized by being lipophilic and can bioaccumulate in fatty tissues including breast milk. However, POPs represent only a part of the chemicals with the potential for environmental pollution and human as new substances are constantly being developed and released into the environment. In this work, the sample preparation step was optimized based on the results of the factorial design 32 varying solvents and sorbents. The method was validated for 54 compound using a mixture of hexane:acetone for extraction, clean-up by dispersible solid phase extraction (d-SPE) using activated Florisil® and determination by gas chromatography coupled to mass spectrometry using negative chemical ionization (GC-NCI-MS). The matrix effect was compensated by the use of extracted analytical curve. The validation of the method showed satisfactory results for linearity, accuracy (recovery between 71.9 and 119.8%) and precision (RSD <29%). An evaporation step of the extract concentrated the analytes enabling low detection (3 to 26 ng g-1 of fat) and quantitation (9 to 86 ng g-1 of fat) limits. The method was applied to 20 samples of breast milk collected in different regions of Rio Grande do Sul state, Brazil, all of which contained at least one of the studied compounds. With principal component analysis of the results, it was possible to relate the pesticides detected in relation to the city of origin of the samples and the number of nursing mother's pregnancies. Considering that breast milk is a complex matrix, the analytical method was effective for the determination of trace levels of POPs and pesticides in breast milk and can be applied in monitoring analysis of human exposure to these contaminants. / A Convenção de Estocolmo foi a primeira atitude mundial a tentar preservar a saúde humana e o ambiente do uso indiscriminado de agrotóxicos, especialmente os poluentes orgânicos persistentes (POPs), que se caracterizam por serem lipofílicos podendo bioacumular nos tecidos adiposos e também no leite materno. Porém, os POPs constituem apenas uma parte dos produtos químicos com potencial de contaminação ambiental e humana uma vez que novas substâncias estão constantemente sendo desenvolvidas e liberadas no ambiente. Neste trabalho a etapa de preparo de amostra foi otimizada com base nos resultados do planejamento fatorial 32 variando solventes e sorventes. O método foi validado para 54 compostos utilizando uma mistura de hexano:acetona para a extração, limpeza do extrato por extração em fase sólida dispersiva (d-SPE) empregando Florisil® ativado e determinação por cromatografia a gás acoplada à espectrometria de massas com ionização química negativa (GC-NCI-MS). O efeito matriz foi compensado pela utilização de curva analítica extraída. A validação do método apresentou resultados satisfatórios para linearidade, exatidão (recuperação entre 719-119,8%) e precisão (RSD <29%). Uma etapa de evaporação do extrato concentrou os analitos possibilitando analisar baixos limites de detecção (3 a 26 ng g-1 de gordura) e de quantificação (9 a 86 ng g-1 de gordura). O método foi aplicado em 20 amostras de leite materno coletadas em diferentes regiões do estado do Rio Grande do Sul, Brasil, das quais todas apresentaram pelo menos um dos compostos estudados. Com análise por componentes principais dos resultados foi possível relacionar os agrotóxicos detectados com relação a cidade de origem das amostras e número de gestações da nutriz. Considerando que o leite materno é uma matriz complexa, o método analítico foi eficaz para a determinação em nível de traço de POPs e agrotóxicos em leite materno, podendo ser aplicado em análise de monitoramento da exposição humana a esses contaminantes.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / In this study, was developed and validated a multi-residue method for the determination of 40 pesticides in green coffee beans. To obtain a very homogeneous sample, the coffee beans were first milled, followed by a slurry preparation of coffee and water (ratio 1:4, w/w). For the extraction procedure modifications of the QuEChERS method were developed. Acetonitrile containing 1% acetic acid and the procedure internal standard (P.I.S.) was used as extraction solvent. After the acetonitrile addition, 3 g of anhydrous magnesium sulfate were added, to promote phase separation between the organic phase (acetonitrile) and the aqueous phase. For the dispersive solid-phase extraction (dSPE) clean-up step, two sorbents were tested in separate and in different amounts and were also tested mixtures of them. Ergo the best results were obtained using 500 mg C18-bonded silica together with 600 mg of magnesium sulfate, for drying. The pesticides were determined by gas chromatography tandem mass spectrometry (GC-MS). Considering the characteristics of the pesticides and the complexity of the coffee matrix the GC-MS had to be operated in negative chemical ionization mode (NCI) and single ion monitoring mode (SIM) which provided high sensitivity and selectivity to pesticide detection. The validation was performed by analyzing spiked samples at three different concentrations (10, 20 and 50 μg kg-1), with 6 replicates (n=6) at each spike concentration. For each one of the 51 pesticides determined by GC-MS (NCI-SIM), the linearity (r) of calibration curves, accuracy (as recovery percent), instrument and method limits of detection and quantification (LOD and LOQ), precision (as RSD percent) and matrix effects (percent) were determined. From the 51 pesticides studied, approximately 76% showed average recoveries between 70-120% and 75% RSD ≤ 20% for the spike concentration of 10 μg kg-1. For the spike concentrations of 20 and 50 μg kg-1, the recoveries (%) and RSD (%) values were even better. The method LOQ was 10, 20 and 50 μg kg-1, for respectively 33, 3 and 6 pesticides, 4 pesticides could only be detected via their degradation products and 5 compounds did not presented recoveries between 70-120% and RSD ≤ 20% thus the method LOQ could not be determined for those pesticides. The matrix effect was present for all the pesticides even with the use of a clean-up step, requiring therefore matrixmatched calibration standards for application in routine analysis. / Neste estudo, foi desenvolvido e validado um método multirresidual para determinação de 40 pesticidas em grãos de café verde. Para se obter uma amostra bem homogênea, os grãos de café verde foram previamente moídos e em seguida preparou-se um slurry de café e água (razão 1:4, m/m). Para o procedimento de extração utilizou-se o método QuEChERS, no qual foram introduzidas algumas modificações. Como solvente extrator, utilizou-se acetonitrila contendo 1% de ácido acético e padrão interno do procedimento (P.I.P.). Após a adição da acetonitrila, para promover o particionamento entre as fases orgânica e aquosa, adicionou-se 3 g de sulfato de magnésio anidro. Para a purificação do extrato de café, foram testados dois adsorventes, separadamente e em diferentes quantidades e também misturas entre os dois adsorventes, em uma etapa de extração em fase sólida dispersiva (dSPE), sendo que os melhores resultados foram obtidos com a utilização de 500 mg de C18 juntamente com 600 mg de sulfato de magnésio, para remoção de água. A determinação dos pesticidas foi feita em um sistema de cromatografia gasosa acoplado a um espectrômetro de massas (GC-MS). Em função das características dos pesticidas e da complexidade da matriz, o GC-MS foi operado no modo de ionização química negativa (NCI) e monitoramento seletivo de íons (SIM), que forneceu grande sensibilidade e seletividade na determinação dos pesticidas. A validação foi realizada pela análise de amostras de café fortificado em três diferentes concentrações (10, 20 e 50 μg kg-1), com 6 replicatas (n=6) para cada concentração. Para cada um dos pesticidas, avaliou-se a linearidade da curva analítica (r), exatidão (recuperação%), limite de detecção e quantificação (LOD e LOQ) do instrumento e do método, precisão (RSD%) e efeito matriz (%). Dos 51 pesticidas estudados, aproximadamente 76% obtiveram recuperações médias entre 70-120% e 75% apresentaram RSD ≤ 20% para amostras fortificadas na concentração de 10 μg kg-1. Para as fortificações de 20 e 50 μg kg-1 os resultados foram ainda melhores. O LOQ do método foi estabelecido em 10, 20 e 50 μg kg-1, respectivamente para 33, 3 e 6 pesticidas, 4 pesticidas somente puderam ser detectados via seus produtos de degradação e 5 compostos não apresentaram recuperações entre 70-120% e RSD≤ 20%, assim o LOQ do método não pode ser estabelecido para esses pesticidas. Mesmo com a utilização de uma etapa de purificação do extrato de café o efeito matriz manteve-se presente para todos os pesticidas, dessa forma, para que o método possa ser implantado em análises de rotina, a confecção das curvas analíticas deve ser feita em matriz (matrix-matched calibration).

Submitted by Maike Costa (maiksebas@gmail.com) on 2017-06-20T14:41:46Z No. of bitstreams: 1 arquivototal.pdf: 4206052 bytes, checksum: 763f7d238671bd04ad2fa14a2f8e48c0 (MD5) / Made available in DSpace on 2017-06-20T14:41:46Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 4206052 bytes, checksum: 763f7d238671bd04ad2fa14a2f8e48c0 (MD5) Previous issue date: 2017-07-08 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The mesoionic compounds comprise a class of heterocycles with wide range of biological and technological applications. Despite many theoretical and experimental studies, some of their properties are still controversial or poorly understood; in particular: charge distribution, the nature of the chemical bonds in the mesoionic ring and the noncovalent interactions in mesoionic complexes. In this work, we sought to clarify these issues through the theoreticalcomputational study of 54 mesoionic compounds and 12 combinations of dimers. Compounds belonging to the 1,3-oxazol-5-one; 1,3-diazole-4-thione and 1,3-thiazole-5-thione rings have been evaluated by a combination of topological methods and charge models. Atomic, bond and ring properties and interactions in mesoionic dimers have been assessed. Results showed that the ring electron density and ring Laplacian were restricted to characteristic range of values for each group studied, which allows us the ring identification using those properties. The bond properties confirmed a prevalance of shared interactions in the mesoionic ring bonds, but with important charge transfers and significant and heterogeous π contribution. When individual atoms were considered, the different charge models exhibited similar qualitative results, but none of them agreed with existing mesoionic definitions. On the other hand, when net charges were considered in rings and fragments, the different models showed large differences and only one of them (QTAIM) agreed with one of the mesoionic definitions. Hence, it is unclear which of the charge models is the most suitable for these compounds. The assessment of mesoionic complexes revealed that interactions in dimers are favored at antiparallel orientations and in the presence of aromatic substituents, that suggests that charge separation and the groups bonded to the ring are paramount in those interactions. Finally, it is concluded that classical mesoionic models do not satisfactorily describe either the charge distribution or the π character of bonds in mesoionic rings. / Os compostos mesoiônicos constituem uma classe de heterociclos com ampla variedade de aplicações biológicas e tecnológicas. Apesar dos vários estudos teóricos e experimentais, algumas de suas propriedades são controversas ou mal compreendidas; em particular: a distribuição de carga, a natureza das ligações químicas no anel mesoiônico e as interações não covalentes em complexos de mesoiônicos. Neste trabalho, buscou-se elucidar esses pontos através do estudo teórico-computacional de 54 compostos mesoiônicos e 12 combinações de dímeros. Compostos das classes 1,3-oxazólio-5-ona; 1,3-diazólio-4-tiona e 1,3-tiazólio-5- tiona foram avaliados através de uma combinação de métodos topológicos e modelos de carga. Propriedades atômicas, de ligação, de anel e interações em dímeros de mesoiônicos foram avaliadas. Os resultados mostraram que a densidade eletrônica e o laplaciano de anel restringiram-se a faixas de valores características para cada grupo estudado, permitindo a identificação do tipo de anel através dessas propriedades. As propriedades de ligação apontaram uma prevalência de interações compartilhadas nas ligações do anel mesoiônico, mas com importante transferência de carga e uma contribuição significativa e heterogênea de caráter π. Considerando átomos individuais, os diferentes modelos de carga apresentaram resultados qualitativos similares, mas nenhum dos modelos corroborou as definições existentes de mesoiônicos quanto à carga. Por outro lado, quando cargas líquidas de anel e de fragmentos foram consideradas, os diferentes modelos apresentaram grandes discrepâncias e apenas um deles (QTAIM) mostrou-se de acordo com uma das definições de mesoiônicos. A avaliação dos complexos de mesoiônicos revelou que as interações em dímeros são favorecidas em orientações antiparalelas e na presença de substituintes aromáticos, sugerindo que a separação de cargas e os grupos ligados ao anel são fundamentais nessas interações. Por fim, conclui-se que os modelos clássicos de mesoiônico não descrevem de forma satisfatória nem a distribuição de carga nem o caráter π das ligações dos anéis mesoiônicos.

2,2′-Bipyridine (BPy), one of the most widely used ligands in coordination chemistry, exists naturally in the s-trans conformation but must preorganize to the s-cis conformer in order to form chelating complexes. Lower stability of the s-cis conformer was mainly attributed to steric 3,3′-hydrogen clashes and nitrogen lone pair-lone pair interactions, but recent trends in the literature suggest that these clashes might be bonding interactions in similar molecules. These close contacts are also present in metal complexes with BPy and are often used as “steric repulsions” in order to explain trends in formation constants. In the present work we investigate the CH•••HC interaction in the free ligand as well as in ZnII(BPy)n(OH2)6-2n and NiII(BPy)n(OH2)6-2n complexes. We use multiple distinct advances in theoretical chemistry in order to arrive at a consistent and coherent model describing these interactions. The Quantum Theory of Atoms in Molecules (QTAIM) reveals the presence of an atomic interaction line (a bond path) for the CH•••HC interaction. Using the Interacting Quantum Atoms (IQA) energy decomposition scheme we show that the CH•••HC interaction is attractive and quantum mechanical in nature. The Extended Transition State coupled with Natural Orbitals for Chemical Valence (ETS-NOCV) energy decomposition scheme show favorable orbital mixing, and Non-Covalent Interaction (NCI) analysis reveals that no steric (Pauli) strain exists in the valence (overlap) regions of the interaction - electron density is concentrated rather than depleted in the bonding region. We also studied various other interactions, ranging from purely repulsive (N--N interaction in the s-cis conformer of BPy), purely electrostatic (CH•••N interaction in s-trans conformer of BPy), H-bonding (CH–N and CH–O bonds in complexes) to coordination bonds and covalent bonds. Using a comparative approach, we show the similarities and differences among the interactions, and conclude that the CH•••HC interaction cannot be classified as a “steric repulsion” - the interaction is similar in properties to every studied known bonding interaction and opposite in nature to the studied known repulsions. Finally, we suggest novel interpretations and understanding of the nature of intramolecular interactions and the field of theoretical chemistry, as well as representing the first work to combine and corroborate QTAIM, IQA, NCI and ETS-NOCV findings. / Dissertation (MSc)--University of Pretoria, 2013. / gm2014 / Chemistry / unrestricted

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No / Since the development of the first cytotoxic agents, synthetic organic chemistry has advanced enormously. The synthetic and medicinal chemists of today are at the centre of drug development and are involved in most, if not all, processes of drug discovery. Recent decreases in government funding and reformed educational policies could, however, seriously impact on drug discovery initiatives worldwide. Not only could these changes result in fewer scientific breakthroughs, but they could also negatively affect the training of our next generation of medicinal chemists.