Thesis (M. Phil.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 109-144).

Thesis (M.Phil.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 109-144) Also available in print.

Abstract This study examined memory functioning from a female perspective, with the aim of determining factors that might impact performance and render the accuracy of memory measurement, particularly with advancing age, problematic. Factors investigated, among others, were the role of attention and/or engagement with the memory tasks administered, state affect (i.e., positive and negative arousal) at time of testing, subjective memory appraisal, particularly in the domain of perceived memory self-efficacy (MSE), and the use of hormone replacement therapy (HRT) by older post-menopausal women. Two experimental computer-based tests of episodic memory, Paired Associates (PA) and Serial Recall (SR), were administered to 181 female participants aged 18 to 86 years. The tasks were designed to emphasise components that make episodic memory especially difficult, and minimise the use of strategies that might assist recall. Thus, they varied the requirement for recall as opposed to recognition, the need to form an association between a pair of unrelated words, and the need to discriminate the most recent list from earlier list(s). Other measures used included a demographic survey administered to participants individually in an interview format, and a number of variables examined in this study derived from responses to items contained in this survey. The research battery also included psychometric measures of transient affective states, psychological well-being, alertness, in addition to measures of global cognitive status and metamemory (i.e., subjective memory appraisal). The overall aim was to examine a range of factors that might influence episodic memory performance in cognitively intact healthy women, and thus render the interpretation of age-related changes to memory functioning problematic. For analyses participants were assigned to three groups - young, middle-aged and older. There were 60 young adults aged 18 to 29 years, 60 middle-aged adults aged 49 to 60 years, and 61 older adults aged 61 to 86 years. Each participant was tested individually in a single session lasting approximately 3 ½ hours, with younger participants requiring less time to complete assessments. Order of test administration and instructions were standardised across the entire sample. Inferential statistics included correlation, t-test statistic, and analysis of variance (ANOVA) with Tukey post-hoc comparisons. Hierarchical multiple regression analyses were conducted to determine key correlates of memory performance outcomes. No significant differences between the cohorts were found in mean years of education. However, episodic memory recall differed significantly by age group. As expected, young adults recalled significantly more words in the memory tasks than their older counterparts, and middle-aged adults outperformed adults in the oldest cohort. Moreover, older adults’ performance deficits were more pronounced in the tasks requiring that they make an association between a pair of unrelated words. Across all cases, transient mood states were significantly related to memory scores; however, individuals in the oldest cohort were particularly vulnerable to mood fluctuations. This cohort experienced a significantly greater decline in positive affect and a significant greater increase in negative affect while undergoing memory testing, highlighting their greater vulnerability to stressors inherent in a memory testing situation. Although scores on the measure of attention were near ceiling, indicative of participants’ level of effort, motivation, and engagement with the memory tasks, the measure of attention discriminated between older and younger adults’ results, and was a key predictor of memory performance. Noteworthy is that attention scores significantly contributed to performance variability in younger and older adults but not in middle-aged adults. Across all cases, age, education, and attention were the key contributing factors to variability in memory scores. Although four lifestyle factors: (1) subjective sleep appraisal, (2) body mass index (BMI), (3) physical activity, and (4) caffeine intake were significantly associated with performance in the memory tasks, once the effects of these key variables were removed, lifestyle factor did not uniquely contribute to performance variability. Moreover, no association was found between hormone replacement therapy (HRT) and episodic memory performance across the broader sample. However, in a small subgroup of older women (n = 15, M age = 66 years), long-term users of this treatment, HRT had a significant effect on memory performance and was indicative of better recall on the memory tasks. The effect of subjective memory appraisal, MSE included, on objective performance outcomes was examined. The results showed that memory self-evaluations were not a significant contributing factor to episodic memory performance, confirming that memory self-appraisal is a poor predictor of actual memory performance, and thus does not pose a challenge to the measurement of age-related changes to memory abilities. Although there were commonalities, factors influencing memory performance differed by age cohort. For example, in young adults, positive mood, a perception of sleeping well, subjective health, and attention were significantly related to performance on the memory tasks. However, once the effect of attention was removed in the regression analysis, no other variable was predictive of episodic memory functioning in this cohort. In contrast, the single significant predictor of memory performance in middle-aged individuals was education, and neither attention, nor positive mood, or physical activity had a significant effect on this cohort’s performance. Similarly, having more years of formal education benefited older adults’ episodic memory functioning. However, high scores on global cognitive functioning and on the tasks measuring attention were equally important to episodic memory recall in this age group. In sum, the significant contribution of age to memory variability attested to the utility of the memory measures in detecting age-related changes to episodic memory functioning, which were independent of deficits in attention or level of education. Moreover, the effect of several factors (e.g., transient mood, lifestyle) on memory scores was explained by an effect on attention, and this has clear implication for the proper evaluation of long-term changes to memory functioning. Limitations of the study and suggestion for future research are discussed.

Abstract This study examined memory functioning from a female perspective, with the aim of determining factors that might impact performance and render the accuracy of memory measurement, particularly with advancing age, problematic. Factors investigated, among others, were the role of attention and/or engagement with the memory tasks administered, state affect (i.e., positive and negative arousal) at time of testing, subjective memory appraisal, particularly in the domain of perceived memory self-efficacy (MSE), and the use of hormone replacement therapy (HRT) by older post-menopausal women. Two experimental computer-based tests of episodic memory, Paired Associates (PA) and Serial Recall (SR), were administered to 181 female participants aged 18 to 86 years. The tasks were designed to emphasise components that make episodic memory especially difficult, and minimise the use of strategies that might assist recall. Thus, they varied the requirement for recall as opposed to recognition, the need to form an association between a pair of unrelated words, and the need to discriminate the most recent list from earlier list(s). Other measures used included a demographic survey administered to participants individually in an interview format, and a number of variables examined in this study derived from responses to items contained in this survey. The research battery also included psychometric measures of transient affective states, psychological well-being, alertness, in addition to measures of global cognitive status and metamemory (i.e., subjective memory appraisal). The overall aim was to examine a range of factors that might influence episodic memory performance in cognitively intact healthy women, and thus render the interpretation of age-related changes to memory functioning problematic. For analyses participants were assigned to three groups - young, middle-aged and older. There were 60 young adults aged 18 to 29 years, 60 middle-aged adults aged 49 to 60 years, and 61 older adults aged 61 to 86 years. Each participant was tested individually in a single session lasting approximately 3 ½ hours, with younger participants requiring less time to complete assessments. Order of test administration and instructions were standardised across the entire sample. Inferential statistics included correlation, t-test statistic, and analysis of variance (ANOVA) with Tukey post-hoc comparisons. Hierarchical multiple regression analyses were conducted to determine key correlates of memory performance outcomes. No significant differences between the cohorts were found in mean years of education. However, episodic memory recall differed significantly by age group. As expected, young adults recalled significantly more words in the memory tasks than their older counterparts, and middle-aged adults outperformed adults in the oldest cohort. Moreover, older adults’ performance deficits were more pronounced in the tasks requiring that they make an association between a pair of unrelated words. Across all cases, transient mood states were significantly related to memory scores; however, individuals in the oldest cohort were particularly vulnerable to mood fluctuations. This cohort experienced a significantly greater decline in positive affect and a significant greater increase in negative affect while undergoing memory testing, highlighting their greater vulnerability to stressors inherent in a memory testing situation. Although scores on the measure of attention were near ceiling, indicative of participants’ level of effort, motivation, and engagement with the memory tasks, the measure of attention discriminated between older and younger adults’ results, and was a key predictor of memory performance. Noteworthy is that attention scores significantly contributed to performance variability in younger and older adults but not in middle-aged adults. Across all cases, age, education, and attention were the key contributing factors to variability in memory scores. Although four lifestyle factors: (1) subjective sleep appraisal, (2) body mass index (BMI), (3) physical activity, and (4) caffeine intake were significantly associated with performance in the memory tasks, once the effects of these key variables were removed, lifestyle factor did not uniquely contribute to performance variability. Moreover, no association was found between hormone replacement therapy (HRT) and episodic memory performance across the broader sample. However, in a small subgroup of older women (n = 15, M age = 66 years), long-term users of this treatment, HRT had a significant effect on memory performance and was indicative of better recall on the memory tasks. The effect of subjective memory appraisal, MSE included, on objective performance outcomes was examined. The results showed that memory self-evaluations were not a significant contributing factor to episodic memory performance, confirming that memory self-appraisal is a poor predictor of actual memory performance, and thus does not pose a challenge to the measurement of age-related changes to memory abilities. Although there were commonalities, factors influencing memory performance differed by age cohort. For example, in young adults, positive mood, a perception of sleeping well, subjective health, and attention were significantly related to performance on the memory tasks. However, once the effect of attention was removed in the regression analysis, no other variable was predictive of episodic memory functioning in this cohort. In contrast, the single significant predictor of memory performance in middle-aged individuals was education, and neither attention, nor positive mood, or physical activity had a significant effect on this cohort’s performance. Similarly, having more years of formal education benefited older adults’ episodic memory functioning. However, high scores on global cognitive functioning and on the tasks measuring attention were equally important to episodic memory recall in this age group. In sum, the significant contribution of age to memory variability attested to the utility of the memory measures in detecting age-related changes to episodic memory functioning, which were independent of deficits in attention or level of education. Moreover, the effect of several factors (e.g., transient mood, lifestyle) on memory scores was explained by an effect on attention, and this has clear implication for the proper evaluation of long-term changes to memory functioning. Limitations of the study and suggestion for future research are discussed.

Orientador: Munir Salomão Skaf / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-22T05:21:38Z (GMT). No. of bitstreams: 1 Souza_PauloCesarTellesde_D.pdf: 16006519 bytes, checksum: 82d3ddc86356ae8c995467ed56947170 (MD5) Previous issue date: 2013 / Resumo: Receptores Nucleares (NRs) são proteínas que regulam a transcrição de genes, sendo alvos importantes para o desenho de fármacos. NRs são formados por quatro domínios, sendo o mais essencial deles, o Domínio de Ligação com o Ligante (LBD), responsável pelo reconhecimento seletivo de ligantes e ativação de sua função. Nesta Tese são utilizadas simulações de Dinâmica Molecular (MD) para o estudo do LBD de dois importantes NRs: Receptor do Hormônio Tireoideano (TR) e Receptor de Estrogênios (ER). Os estudos envolvendo o LBD do TR iniciaram-se pela investigação de um novo segundo sítio de ligação dos hormônios tireoideanos (T3 e T4). Foi mostrado que os hormônios se mantêm ancorados ao segundo sítio, possuindo grande mobilidade e múltiplos modos de ligação. Estimativas do DG de dissociação indicam que este novo sítio deve existir em solução aquosa, sendo T4 o hormônio com maior afinidade e candidato a ligante natural. O segundo objetivo da Tese foi a modelagem molecular da estrutura do LBD do TR sem ligantes (apo-TR) através da combinação de resultados de simulações de MD e experimentos de troca de hidrogênio/deutério. O modelo do apo-TR obtido mostra que a-hélice H12 ancora-se na H3, o que explica as mudanças de hidratação nesta região apontadas pelos experimentos. O terceiro objetivo da Tese foi elucidar os mecanismos moleculares que levam a alterações da atividade em duas mutações dos TRs: M369Ra e P452Lb. As simulações de M369Raindicam que o resíduo mutado interage com T3 no segundo sítio, o que pode explicar o aumento de sua afinidade por este ligante. As simulações de P452Lbsugeriram que esta mutação altera a posição da H12, levando a redução da cavidade de interação com co-ativadores e das interações do T3 com o primeiro sítio. O último estudo da Tese investigou uma conformação alternativa do LBD do ERb , que tem potencial para explicar como este subtipo promove repressão parcial da transcrição de genes regulada pelo ERa. Os cálculos de DG entre as conformaçõs clássica e alternativa indicam que a alternativa é estável, sendo o mínimo global de energia livre. / Abstract: Nuclear receptors (NRs) are proteins that regulate the gene transcription and thus are important targets for drug development. NRs are composed of four structural domains. The most important of them is the Ligand Binding Domain (LBD), responsible for the selective recognition of ligands and activation of NR function. In this Doctoral Thesis, Molecular Dynamics (MD) Simulation are used to study two important NRs LBD: Thyroid Hormone Receptor (TR) and Estrogen Receptor (ER). Studies involving TR began by investigating a new second binding site of thyroid hormones (T3 and T4) in the TR LBD. It has been shown that hormones remain anchored to the second site and have high mobility and multiple binding modes. Estimates of dissociation DG indicate that this new site can exist in aqueous solution. T4 has the higher affinity and may be the natural ligand of this site. The second objetive of the Thesis was the molecular modeling of the TR LBD structure without ligands (apo-TR) by combining results of MD simulations and hydrogen deuterium exchange experiments. The obtained model of apo-TR shows that H12 a-helix is anchored in H3 which explains the hydration changes in this region indicated by the experiments. The third goal was to elucidate the molecular mechanisms that lead to changes in the activity of two TR mutations: M369Ra and P452Lb. Simulations of M369Ra indicate that the mutated residue can interact directly with T3 in the second binding site, explaining the increase of its affinity. Simulations of P452Lbsuggested that this mutation changes the H12 position, leading to loss of ligand interaction with the rst binding site and reduction of coactivator cavity. The last study investigated a new alternative conformation of ERb LBD, which has the potential to explain how this subtype promotes the partial repression of ERagene transcription. Calculation of DG between classic and alternative conformations indicate that the alternative is stable and the global minimum of free energy. / Doutorado / Físico-Química / Doutor em Ciências

Submitted by Maria Medeiros (maria.dilva1@ufcg.edu.br) on 2018-07-27T13:49:44Z No. of bitstreams: 1 MARLON LEAL CABRAL MENEZES DE AMORIM - DISSERTAÇÃO (PPGECA) 2016.pdf: 1649464 bytes, checksum: a4b0872dbeecb56cc3c49eb0438ad7c7 (MD5) / Made available in DSpace on 2018-07-27T13:49:44Z (GMT). No. of bitstreams: 1 MARLON LEAL CABRAL MENEZES DE AMORIM - DISSERTAÇÃO (PPGECA) 2016.pdf: 1649464 bytes, checksum: a4b0872dbeecb56cc3c49eb0438ad7c7 (MD5) Previous issue date: 2016-08-26 / Capes / Os hormônios naturais 17β-estradiol, estrona e o hormônio sintético 17α-etinilestradiol vêm sendo detectados em águas superficiais, principalmente devido ao fato dos atuais processos de tratamento de água e esgotos serem incapazes de removê-los, sendo descarregados em corpos receptores. O monitoramento da ocorrência dessas substâncias se mostra necessário, pois suas presenças podem causar danos à saúde humana e ambiental (organismos aquáticos e terrestres). No presente trabalho, foi realizado o desenvolvimento e validação do método, por meio de cromatografia líquida de alta eficiência (HPLC) com detector com comprimento de onda variável UV/Vis, para a determinação simultânea desses hormônios em amostras de água e esgoto da região hidrográfica do médio curso do rio Paraíba. A análise cromatográfica foi realizada em modo isocrático, fase móvel acetonitrila e água (50:50), coluna C18, vazão 1 mL/min, injeção 10 μL, comprimento de onda de 200 nm, temperatura do equipamento de 40°C. O método desenvolvido apresentou uma boa resposta quanto à seletividade dos hormônios e linearidade com coeficiente de determinação (r2) entre 0,9943 e 0,9951. Os limites de quantificação estimados foram de 90,45 μg/L para o 17β-estradiol, 96,76 μg/L para o 17α etinilestradiol e 96,19 μg/L para a estrona, sendo os limites de detecção de, respectivamente, 60,27 μg/L, 65,12 μg/L e 64,16 μg/L. A precisão e a robustez apresentaram desvios padrões relativos inferiores a 5%. A metodologia proposta mostrou-se adequada para a determinação de hormônios estrogênios em amostras de águas. Com relação à análise nas amostras de água e esgoto coletada, não foi detectado a presença de hormônio em nenhuma das amostras nas concentrações mínimas de detecção e quantificação do método desenvolvido. / The natural hormones 17β - estradiol and estrone and the synthetic hormone 17α - ethinylestradiol have been detected in surface water, mainly due to the current water and wastewater treatment processes being unable to remove them, leading them to be discharged into receiving water bodies. Monitoring the occurrence of these substances in water is currently very necessary because their presence can cause harm to human health and the environment (aquatic and terrestrial organisms). This work describes the development and validation of a method for the simultaneous determination of these hormones in water samples by means of high-performance liquid chromatography (HPLC), from the simultaneous determination of these hormones in water samples and sewage from the river basin of the middle course of the river Paraíba. The chromatographic analyses were performed in an isocratic mode, being the mobile phase acetonitrile and water (50:50), using a C18 column, flow rate of 1mL/min, 10 μL-injection volume, wavelength of 200 nm and temperature of 40 °C. The method showed a good response on the hormone selectivity and linearity of calibration curves with coefficients of determination (r2) between 0.9943 and 0.9951. The estimated quantification limits were 90.45 μg/L for 17β - estradiol, 96.76 μg/L for the 17α ethinylestradiol and 96.19 μg/L for estrone, and the detection limits 60.27 μg/L, 65.12 μg/L and 64.16 μg/L, respectively. The precision and robustness presented relative standard deviations of less than 5 %. The proposed methodology was appropriate for the determination of estrogen hormones in water samples. Regarding the analysis on water collected and sewage was nor detected the presence of the hormone in any of the samples at the minimum concentrations of detection and quantification method developed.