This dissertation research study explored how registered nurses (RNs) use mobile devices as tools to support and enhance informal learning in their work settings. The mixed methods inquiry involved select Canadian practicing and regulated RNs who used mobile devices in their workplaces. A sequential explanatory research design collected quantitative and qualitative data using an online survey and semi-structured interviews. Quota sampling for the quantitative component yielded 170 usable online surveys. From the survey respondents, interview volunteers were purposively selected and ten (10) interviews were conducted. Descriptive, inferential, inductive, and integrated data analyses were conducted in order to explore strategies, processes, purposes, modes of use (individual [non-collaborative] or collaborative), and age-generational differences associated with RNs’ use of mobile devices for informal learning in the workplace. Findings indicated that the study participants primarily used their handheld devices for self-directed informal learning with non-collaborative strategies or processes in their work settings for accessing online resources for a range of reasons including: evidence-based support, new procedures/treatments, professional development, patient/client teaching, and maintaining competency. Age differences related to the use of mobile devices for informal learning were minimal. However, workplace-related influences including deficiencies in formal educational resources, Internet access, and/or employer support were relevant to the informal learning experiences. Positive perceptions of efficiencies, self-confidence, patient/client safety, patients/clients’ reactions, and the need for sanctioned resources for using mobile technologies in the healthcare workplace were articulated. The findings pointed to the significance of mobile devices as learning tools for RNs’ informal learning for construction of knowledge and meaning-making to inform professional development and continuing competence. / 2013-01

There are mounting concerns to ensure that children are prepared for the literacy demands of the 21st century. Reading inability at 9 years of age portends a lifetime of illiteracy for the majority of struggling readers. Given the greater weight placed on expository text from the junior grades onwards, children with reading disabilities become increasingly constrained by their reading deficits, putting them at risk of falling ever further behind their normally achieving peers. This ethnographic study, extending over an 8 month period and finishing on the last day of the school year, targeted older poor readers at the junior level. Less is known about their reading deficits, relative to younger struggling readers. Therefore, the first of three principal objectives aimed to extend understanding of the processes whereby older poor readers interact with expository text by providing a qualitative finer-grained assessment of their particular difficulties than presently exists. The second objective was focused on developing and implementing a cohesive program of research-based interventions that targeted critical requirements of successful interactions with expository text, including the ability to summarize, locate information, and attend to text structure. The third objective involved establishing and describing a collaborative, intensive research partnership with two classroom teachers at the junior level to implement and evaluate research-grounded interventions for their students with reading difficulties, working within the context of the regular classroom. The dual researcher role, as collaborator with the teachers and instigator of the intervention program, shaped a reconfigured model of special education, responsive to a diverse range of student needs and abilities, and situated within a content-rich, challenging curriculum. Parallel lessons afforded the opportunity to tier instruction with increasing intensity for the children with the highest needs. Results showed the critical importance of aggressively promoting self-efficacy, self-regulation, and metacognitve awareness for older struggling readers. As these children’s strategic repertoire increased, so, too, did their comprehension and comprehension-monitoring. Differentiated instruction that was tiered, flexible, and responsive supported social inclusion and social collaboration. Social context and authentic content became interwoven and instrumental in engaging the children, maintaining their motivation and sustaining their commitment to read to learn. / Thesis (Ph.D, Education) -- Queen's University, 2010-01-27 15:10:03.202

Cette thèse doctorale poursuit l’objectif de mieux comprendre le rôle joué par la profession réglementée en tant que déterminant de la détresse psychologique de la population en emploi au Québec et au Canada. Ceci, dans un contexte où plusieurs ordres professionnels représentant des professions réglementées, s’inquiètent de la santé mentale de leurs membres et de la pression considérable exercée sur eux dans une économie caractérisée par des pénuries de main-d’oeuvre importantes. Cette thèse fut également inspirée par les nombreuses limites constatées à la suite d’une revue de la littérature sur la santé mentale au travail, alors que les risques différenciés auxquels seraient soumis ces professionnels, comparativement à l’ensemble de la population en emploi, demeurent largement à documenter. La profession réglementée s’associe-t-elle directement à l’expérience de détresse psychologique? Quelles sont les conditions de travail susceptibles de conduire au développement ou à l’aggravation de la détresse psychologique pour ces professions? Dans le but de mieux comprendre le rôle joué par la profession réglementée en matière de détresse psychologique, nous avons eu recours à un modèle théorique multidimensionnel qui postule que les contraintes et les ressources découlent d’un ensemble de structures sociales incluant la profession, le travail, la famille, le réseau social hors-travail et les caractéristiques personnelles. Ce modèle découle des théories micro et macro en sociologie (Alexander et al., 1987; Ritzer, 1996), de l’approche agent-structure(Archer, 1995; Giddens, 1987) ainsi que de la théorie du stress social (Pearlin,1999). Trois hypothèses sont soumises à l’étude à travers ce modèle. La première hypothèse, est à l’effet que la profession réglementée, les conditions de travail, la famille ainsi que le réseau social hors-travail et les caractéristiques individuelles, contribuent directement et conjointement à l’explication du niveau de détresse psychologique. La seconde hypothèse induite par le modèle proposé, pose que le milieu de travail médiatise la relation entre la profession réglementée et le niveau de détresse psychologique. La troisième et dernière hypothèse de recherche, postule enfin que la relation entre le milieu de travail et le niveau de détresse psychologique est modérée par les caractéristiques individuelles ainsi que par la famille et le réseau social hors-travail. Ces hypothèses de recherche furent testées à partir des données longitudinales de l’Enquête nationale sur la santé de la population (ENSP) (cycles 1 à 7). Les résultats obtenus sont présentés sous forme de 3 articles, soumis pour publication, lesquels constituent les chapitres 5 à 7 de cette thèse. Dans l’ensemble, le modèle théorique proposé obtient un soutien empirique important et tend à démontrer que la profession réglementée influence directement les chances de vivre de la détresse psychologique au fil du temps, ainsi que le niveau de détresse psychologique lui-même. Les résultats indiquent que les professions réglementées sont soumises à des risques différenciés en termes de conditions de travail susceptibles de susciter de la détresse psychologique. Notons également que la contribution du milieu de travail et de la profession réglementée s’exerce indépendamment des autres dimensions du modèle (famille, réseau social hors-travail, caractéristiques personnelles). Les résultats corroborent l’importance de considérer plusieurs dimensions de la vie d’un individu dans l’étude de la détresse psychologique et mettent à l’ordre du jour l’importance de développer de nouveaux modèles théoriques, mieux adaptés aux contextes de travail au sein desquels oeuvrent les travailleurs du savoir. Cette thèse conclue sur les implications de ces résultats pour la recherche, et sur les retombées qui en découlent pour le marché du travail ainsi que pour le développement futur du système professionnel québécois et canadien. / This doctoral thesis aims to understand the role played by the regulated occupations as a determinant of psychological distress of the working population in Quebec and Canada. This, in a context where several professional organizations, representing regulated occupations, are concerned about the mental health of their members and the pressure exerted on them in an economy characterized by important shortages of labor. This thesis was also inspired by the many limitations observed after a literature review on work and mental health, whereas the differentiated risks which would be subjected to these professionals, compared to the total working population, remains largely undocumented. Is there a direct link between the regulated occupation and the experience of psychological distress? What working conditions contribute to the development or accentuate psychological distress for these regulated occupations? In order to better understand the role played by the regulated occupations in psychological distress, this thesis proposes a multidimensional theoretical model which postulates that the constraints and resources are generated by a set of social structures including the regulated occupation, the working conditions, family, social network outside of work and personal characteristics. This model stems from the micro and macro theories in sociology (Alexander et al., 1987; Ritzer, 1996), the agent-structure approach (Archer, 1995; Giddens, 1987) as well as the social stress theory (Pearlin, 1999). Three hypotheses are subject to analysis through the model. The first hypothesis assumes that regulated occupations, work conditions, family, social network outside the workplace, and individual characteristics contribute directly and jointly to explaining the level of psychological distress. The second hypothesis induced by the proposed model postulates that the workplace mediates the relationship between regulated occupations and psychological distress levels. The third and final research hypothesis postulates that the relationship between the workplace and psychological distress levels is moderated by individual characteristics, as well as by family and the social network outside the workplace.These hypotheses have been validated using longitudinal data from the National population health survey (NPHS) (cycles 1 to 7). The results of these analyses are presented in three articles submitted for publication, which are the chapters 5-7 of this thesis. Overall, the theoretical model gets an important empirical support and suggests that the regulated occupations directly influence the chances of living psychological distress over time as well as the level of psychological distress itself. The results also suggest that the regulated occupations are exposed to differentiated risks in terms of working conditions likely to generate psychological distress. The contribution of the workplace and regulated occupations is exercised independently of other dimensions of the model (family, social network outside of work, personal characteristics). The results also corroborate the importance in considering many dimensions of the life of an individual in the psychological distress and to put on the agenda the importance of developing new theoretical models, better suited to the realities characterizing today’s working environments in which knowledge workers work. This thesis concludes on the implications of these findings for research, and the benefits it brings to the labor market and for the future development of the professional system in Quebec and Canada.

No description available.

This research was set out to investigate the role of knowledge management as a coping strategy for PHE institutions in Botswana, especially given that they operate in a highly regulated environment. One of the major drivers of volatility in the educational sector is intensely volatile regulatory environment in which the institutions operate. Further, a large portion of the stakeholder community of these institutions hold a strong believe that these institutions offer poor quality education to maximise profit. The primary objective of this study is therefore to determine the role of knowledge management (KM) enablers in facilitating KM practices in selected PHE institutions in Botswana that operate in this highly regulated environment and to develop a model for effective KM in these institutions. The study adopted a survey research design and collected quantitative data through a structured self-administered questionnaire and document reviews. The subjects comprised all five degree-awarding PHE institutions, which were strictly regulated by the Tertiary Education Council (TEC). The population surveyed came to 670 and sample size was 350. Data was analysed through various statistical measures such as Structural Equation Modelling (SEM) in the form of Analysis of Variance (ANOVA), multiple regression analysis, and Chi-square test. The results of the study revealed that KM enablers were playing an insignificant role in facilitating KM practices in selected PHE institutions in Botswana. Results of the study can be generalised to similar institutions elsewhere operating in similar environments. In order to enhance KM practices in PHE institutions, it is recommended that the institutions adopt a systematic approach to KM, establish an organisational culture and structure that promote KM practices, and enhance the quality of their human capital including leadership. It should be noted that the state of KM in organisations operating in an uncertain environment can be enhanced if the leadership carefully controls the family-owned setting and organisational culture as these factors can detract from the organisation’s effective practising of KM. However, strategic leadership, organisational structure, and the role played by stakeholders played positive deterministic factors in ensuring an enhanced KM drive. / Business Management / D.Admin. (Business Management)

Accelerated social change emphasises knowledge and innovation, creating a need for learners to excel at learning and thinking. The study’s purpose was to replicate previous cognitive research findings, which emphasise the positive influence of learning strategies on learners’ self-efficacy and academic achievement and to verify the validity of training learners in learning strategy-use to promote learner-autonomy and accountability. The research targeted a selected primary school in a Black township in Gauteng Province using quasi-experimental and qualitative methods. The sample comprised 152 4th - 7th graders assigned by quota system to the treatment group and the control group. Learners participated in pre-tests and post-tests for learning strategies, self-efficacy and academic achievement. Only the experimental groups received strategy instruction before the post-test. The experimental group’s improved performance compared to the control group’s lower performance suggests the effectiveness of strategy-training. Subsequent learner reports of improved self-efficacy beliefs and academic achievement confirm strategy-effect on these variables. / Psychology of Education / M. Ed. (Educational Psychology)

[pt] A geração distribuída (GD) vem crescendo nos últimos anos no Brasil, particularmente a geração fotovoltaica, permitindo a pequenos e grandes consumidores ter um papel ativo no sistema elétrico, podendo investir em um sistema próprio de geração. Para os consumidores cativos, além da redução do custo de energia, o consumidor também pode ter uma redução no custo de demanda, que é calculado a partir de um contrato com a distribuidora que o atende. Assim, considerando a possibilidade de instalação de painéis fotovoltaicos, o desafio dos consumidores é estimar com maior acurácia possível sua energia, a energia gerada pelos painéis e as demandas máximas futuras de forma a determinar a quantidade ótima de painéis, bem como o contrato de demanda com a distribuidora. Nesta dissertação, propõe-se resolver este problema a partir da simulação de cenários futuros de consumo de energia, demanda máxima e correlacionando-os com cenários futuros de geração de energia. Em seguida, a partir de um modelo de otimização linear inteiro misto, calcula-se a quantidade ótima de painéis fotovoltaicos e a demanda a ser contratada. Na primeira parte da dissertação, a modelagem Box e Jenkins é utilizada para estimar os parâmetros do modelo estatístico de energia consumida e demanda combinados com a geração de energia dos painéis. Na segunda parte, é utilizado um modelo de otimização estocástica que utiliza uma combinação convexa de Valor Esperado (VE) e Conditional Value-at-Risk (CVaR) como métricas de risco para avaliar o número ótimo de painéis e a melhor contratação de demanda. Para ilustrar a abordagem proposta, é apresentado um caso de estudo real para um grande consumidor considerado na modalidade Verde A4 no Ambiente de Contratação Regulado. Os resultados obtidos mostraram que a utilização de painéis fotovoltaicos em um grande consumidor reduzem o custo anual de energia em até 20 por cento, comparado com o valor real faturado. / [en] Distributed Generation (GD) is growing up in the last years in Brazil, particularly photovoltaic generation, allowing small and large consumers play an important role in the electric system, investing in a own generation system. For the regulated consumers, besides the reduction of energy cost, they also may have a reduction in demand cost, which is computed from peak demand contract with the supply utility company. Therefore, taking into account the possibility of photovoltaic panels installation, the challenge of consumers is estimate with highest accuracy as possible its energy, the energy generation by the panels, and the future peak demand in order to estimate the optimum quantity of panels, as well as the peak demand contract with the utility. A way to solve this problem is to simulate future scenarios of energy consumption, peak demand, and correlate them with future scenarios of energy generation. After that, from a mixed integer linear stochastic optimization model, the optimum quantity of panels and peak demand to be contracted are computed. In the first part, the Box and Jenkins modelling is used to estimate the parameters of the energy consumption and peak demand by statistical model, combined with the energy generation of the panels. In the second part, a stochastic optimization model is applied using a convex combination of the Expected Value (VE) and Conditional Value-at-Risk (CVaR), which were used as risk metrics to rate the optimum number of panels and the best peak demand contract. To illustrate the proposed approach, a real case study of a large consumer presented considering the Green Tariff group A4 in the Regulated Environment. The results show that to use photovoltaic panels can reduce the annual cost by up to 20 per cent, compared with the billed real value.

O câncer de pele é um dos mais frequentes entre humanos, sendo o melanoma o tipo menos comum, mas com grande importância devido à agressividade que ele apresenta. Um dos principais agentes etiológicos deste tipo de tumor é a radiação ultravioleta proveniente da luz solar. A fração de radiação ultravioleta B (UVB) gera dano no DNA e induz alterações nas células da pele após a exposição prolongada e sem proteção. A resposta à luz UVB em melanócitos e melanomas é diferente, mostrando a importância do perfil celular. O efeito genotóxico da luz UVB pode alterar a expressão de moléculas como galectina-3 e MAPKs, desencadeando respostas UVB-dependentes. Galectina-3 é uma lectina que reconhece beta-galactosídeos e está envolvida na regulação de diversos processos celulares que modificam a viabilidade celular e a proliferação. Esta molécula é ubiquamente expressa apresentando um comportamento específico dependendo da sua localização subcelular. No presente trabalho mostramos que a distribuição de galectina-3 em melanoma e melanócitos é ampla, encontrando-se tanto no núcleo como no citoplasma, podendo ser modificada após irradiação UVB ou ainda secretada para o meio extracelular. Além disso, observamos que a luz UVB ativa a via de MAPKs, proteínas quinases ativadas por mitógenos envolvidas no crescimento, sobrevivência, diferenciação e resposta a estresse, em melanócitos e em melanomas poucos minutos após a exposição à UVB. Uma maior atividade de p38 e de ERK é evidenciada em melanomas, enquanto que em melanócitos a via de p38 é a mais ativa, corroborando a noção de que a resposta celular à luz UVB difere entre melanócitos e melanoma. As moléculas p38 e JNK são proteínas quinases ativada pelo estresse (SAPK). A via de JNK não é tão responsiva em alguns melanomas, mas ativação desta molécula parece estar envolvida com a sobrevivência celular e a translocação mitocondrial após UVB. Em adição, a inibição de JNK leva ao aumento de morte celular em linhagens melanocíticas irradiadas e não irradiadas, e em melanoma induz morte e aumenta autofagia após irradiação. Esta molécula parece interagir com galectina-3 em modelos murinos, mas não em melanomas humanos, enquanto que ERK interage fisicamente com galectina-3 em melanócitos e melanomas humanos, independente de UVB. Através do silenciamento de galectina-3 pela técnica de RNA de interferência, mostramos o aumento da ativação da via de ERK após irradiação e de proteínas downstream de ERK, promovendo a proliferação celular em melanomas nessas condições. Em melanócitos parece existir uma regulação negativa da via de ERK por galectina-3 acompanhada de uma diminuição da viabilidade celular após o silenciamento dessa lectina, independente de UVB. Estes resultados mostram que galectina-3 é uma importante reguladora de eventos associados com sobrevivência e morte celular em melanoma. Por outro lado, em melanomas a ausência de galectina-3 induz aumento da proliferação associada à ativação de ERK, evidenciando a importância do tipo celular na ação de galectina-3 / Skin cancer is the most common cancer among humans, melanoma being the least common type but very important due to its aggressive behavior. A major etiologic agent of this type of tumor is ultraviolet radiation from the sunlight. The ultraviolet B rays (UVB) cause DNA damage and induce alterations over the skin cells after prolonged exposition without protection. The UVB response in melanocytes and melanoma cells is different. This shows the importance of the cellular profile. The genotoxic effect of UVB light can alter the expression of molecules such as galectine-3 and MAPKs and also triggers multiple responses UVB-dependent. Galectin-3 is a lectin that recognizes beta-galactosides. It is involved in the regulation of many cellular processes that modify cellular viability and proliferation and presents specific behavior depending on its subcellular localization. In the present study we showed that galectine-3 distribution in melanoma cells and melanocytes is large, lying both in the nucleus and in the cytoplasm. After UVB irradiation this distribution could be modified or even galactine-3 secreted itself into the extracellular space. Moreover, we observed that UVB light activates the mitogen-activated protein kinase pathway (MAPK) involved in growth, survival, differentiation and stress-response in melanocytes and in melanoma cells just a few minutes after exposure. An increased activity of p38 and ERK was observed in melanomas, while in melanocytes just p38 pathway was highly active, supporting the notion that the cellular response to UVB light differs between melanocytes and melanoma cells. The molecules p38 and JNK are stress-activated protein kinases (SAPK). The JNK pathway is not responsive in some melanoma cells, but the activation of this molecule appears to be involved in cell survival and mitochondrial translocation after being exposed to UVB. Inhibition of JNK leads to increased cell death in irradiated and non-irradiated melanocytic lineage, but in melanoma cells induces cell death and increased autophagy only after irradiation. This molecule seems to interact with galectin-3 in mouse models but not in human melanomas, whereas ERK physically interacts with galectin-3 in human melanocytes and melanoma cells, regardless of UVB exposure. Through the knockdown of galectin-3 by siRNA, we showed increased activation of the ERK and its downstream pathway after irradiation, thus inducing cell proliferation. In melanocytes seems to be a negative regulation of the ERK pathway by galectin-3 accompanied by a decrease in cell viability after its knockdown regardless of UVB exposure. These results show that galectin-3 is an important regulatory molecule of events associated with cell death and survival in melanoma, which has different behavior depending on the cell type

My research focuses on understanding the importance of human mitochondrial Hsp70 (Grp75) chaperone machinery for the maintenance of protein quality control inside the mitochondrial matrix. The investigations carried out during this study have been addressed towards gaining better insights into the working of Grp75 chaperone folding machinery in association with its diverse set of co-chaperones residing in human mitochondria. Additionally, the research also focuses on explaining the various modes of Grp75 participation leading to multiple disease conditions. The thesis has been divided into the following sections as follows: Chapter I: An introduction to the mitochondrial import machinery and role of mitochondrial Hsp70 chaperone folding machinery for the maintenance of protein quality control: Mitochondrion is an essential organelle present in the eukaryotic cell and requires more than 1500 proteins for its proper functioning. Although, mitochondria harbour their own genome, it encodes for only 13 proteins in humans. The rest of the entire proteome is encoded by the nuclear genome and requires proper targeting of proteins to different compartments of mitochondria. Remarkably, mitochondrial matrix alone requires more than 60% of the proteome for its suitable functioning. Briefly, the mitochondrial matrix destined polypeptide passes through the outer membrane translocon; the ‘TOM’ complex and then enters the TIM23 translocon present in the inner membrane of mitochondria. The complete translocation of the polypeptide into the mitochondrial matrix side requires the assistance of mtHsp70 based motor system present on the matrix side which pulls the polypeptide into the matrix in an ATP-dependent manner and with the assistance of various co-chaperones. Subsequently, the unfolded polypeptide is to be folded back to its native state, which is ensured again by the mtHsp70 based chaperone folding machinery. Importantly, while 20% of mtHsp70 is involved in protein import, 80% of mtHsp70 is dedicated for protein folding. In addition to mtHsp70, the chaperone folding machinery consists of various soluble co-chaperones such as the J-proteins which stimulate the ATP hydrolysis rate of Hsp70. Furthermore, another co-chaperone termed as a nucleotide exchange factor ensures binding of fresh ATP molecule onto Hsp70 ensuring multiple rounds of folding cycles. To understand the relevance of mitochondrial Hsp70 chaperone folding machine in the maintenance of protein quality control, Chapter I of the thesis has been divided into multiple sections as follows: Briefly, the initial portion of Chapter I provide a glimpse of the translocon components present in mitochondria for targeting of proteins to outer membrane, inner membrane and inter-membrane space. Owing to the vast proteome size of the mitochondrial matrix, the following section describes the detailed mechanism and translocation process of the mitochondrial matrix targeted proteins. Additionally, subsequent sections of Chapter I provide a comprehensive description of each of the mtHsp70 chaperone folding components, which maintain the protein quality control in the matrix. The players that constitute the chaperone folding machines are mitochondrial Hsp70, J-proteins, nucleotide exchange factors and the newly discovered human escort protein. Essentially, the section provides information about the cellular distribution, structure and function of each of these players constituting the mtHsp70 chaperone folding machine. Loss of regulation between these players leads to defects in protein folding. Imbalance in protein homeostasis is one of the primary causes for mitochondrial dysfunction leading to various diseases. Importantly, recent literature has highlighted the involvement of mtHsp70 chaperone folding players in Parkinson’s disease (PD), Myelodysplastic syndrome (MDS) and cancer. In accordance, the last section of the Chapter I has been dedicated to describe the basic cell biology and proposed mechanisms for the above diseased states. Interestingly, in comparison to yeast and bacteria, the composition of mtHsp70 chaperone folding machinery in humans is unique and distinctly different. Owing to a lack of information about the functioning of human mitochondrial Hsp70 chaperone folding machinery and with an emphasis on understanding its role in various disease manifestations, the objectives that were laid for my PhD thesis are as follows: 1) Functional in vitro reconstitution of the human Grp75 chaperone folding machinery by purifying all the Grp75 chaperone folding machinery players namely; Grp75 (human mtHsp70), hTid-1L and hTid-1S (J-proteins), GrpEL1 (nucleotide exchange factor) and Human escort protein (Hep). 2) Dissection of the intrinsic biochemical defects associated with the variants of Grp75 reported in Parkinson’s disease (PD). 3) To understand the correlation between elevated levels of Grp75 and its contribution to malignancy. In conclusion, the current study has highlighted some of the key features of human Grp75 chaperone folding machinery and its regulation in the maintenance of human mitochondrial matrix protein quality control, failure of which leads to pathological conditions. Chapter II: Reconstitution of the human Grp75 chaperone folding machinery to understand the functional interplay between the multiple protein components: The mitochondrial Heat shock protein 70 (mtHsp70) machinery components are highly conserved among eukaryotes, including humans. However, the functional properties of human mtHsp70 machinery components have not been characterized among all eukaryotic families. To study the functional interactions, we have reconstituted the components of mtHsp70 chaperone machine (Hsp70/J-protein/GrpE/Hep) and systematically analyzed in vitro conditions for biochemical functions. We observed that the sequence-specific interaction of human mtHsp70 towards mitochondrial client proteins differs significantly from its yeast counterpart Ssc1. Interestingly, the helical lid of human mtHsp70 was found dispensable to the binding of P5-peptide as compared to the other Hsp70’s. We observed that the two human mitochondrial matrix J-protein splice-variants differentially regulate the mtHsp70 chaperone cycle. Strikingly, our results demonstrated that human Hep possesses a unique ability to stimulate the ATPase activity of mtHsp70 as well as to prevent the aggregation of unfolded client proteins similar to J-proteins. We observed that Hep binds with the C-terminus of mtHsp70 in a full-length context, and this interaction is distinctly different from unfolded client-specific or J-protein binding. In addition, we found that the interaction of Hep at the C-terminus of mtHsp70 is regulated by the helical lid region. However, the interaction of Hep at the ATPase domain of the human mtHsp70 is mutually exclusive with J-proteins, thereby promoting a similar conformational change that leads to ATPase stimulation. Moreover, we have also dissected out the inter-domain defective nature associated with the point mutant of Grp75 implicated in Myelodysplastic syndrome thus providing an explanation for the loss of function of Grp75 eventually leading to loss of protein quality control in the diseased state. Chapter III: Enhanced J-protein interaction and compromised protein stability of Grp75 variants leads to mitochondrial dysfunction in Parkinson’s disease: Parkinson’s disease (PD) is the second most prevalent progressive neurological disorder commonly associated with impaired mitochondrial function in dopaminergic neurons. Although familial PD is multi-factorial in nature, a recent proteomic screen involving PD-patients revealed two mitochondrial Hsp70 variants (P509S and R126W) that are implicated in PD-pathogenesis. However, molecular mechanisms underlying how mtHsp70 PD-variants are centrally involved in PD-progression is totally elusive. In this report, we provide mechanistic insights into the mitochondrial dysfunction associated with human mtHsp70 PD-variants. Biochemically, R126W variant showed severely compromised protein stability and was found highly susceptible to aggregation at physiological conditions. Strikingly, on the other hand, P509S variant exhibits significantly enhanced interaction with J-protein co-chaperones involved in folding and import machinery, thus altering the overall regulation of chaperone mediated folding cycle and protein homeostasis. To assess the impact of mtHsp70 PD-mutations at the cellular level, we have developed yeast as a model system by making analogous mutations in Ssc1 ortholog. Interestingly, PD-mutations in yeast (R103W and P486S) exhibit multiple in vivo phenotypes, which are associated with ‘mitochondrial dysfunction’ such as mitochondrial DNA (mtDNA) loss and increased susceptibility to oxidative stress recapitulating the cellular features of dopaminergic neurons similar to those reported in other PD-models. Together, our observations for both the variants strongly indicate a definite involvement of mtHsp70 as a susceptibility factor in Parkinson’s disease. Chapter IV: To understand the correlation between elevated levels of Grp75 and its contribution to malignancy: Multiple studies carried out by various groups have reported the presence of elevated levels of Grp75 in cancer cells. Furthermore, proteomic screens show a positive correlation with the higher levels of Grp75 and the aggressive or metastatic nature of cancer. Importantly, cancer cells also exhibit altered mitochondrial metabolism and are found to be under constant oxidative stress pressure. Moreover, Grp75 actively participates in maintenance of mitochondrial function and as well is reported to interact with many putative oncoproteins. However, there is little information available on the possible role of Grp75 in modulating the cellular niche which might favor towards increased malignant transformation of cells. To identify pathways for explaining the correlation between Grp75 and cancer, our initial attempts have focused on monitoring the multiple cellular changes influenced by elevated levels of Grp75 in a cell line based system. To our surprise, transient transfection of cells with Grp75 led to a tremendous increase in the reactive oxygen species levels. Furthermore, a strong positive correlation between the extent of increased levels of Grp75 and the amount of ROS generated in these cells was established. As expected, increased ROS levels observed in Grp75 overexpressing cells also resulted in reduced cell viability. Notably, mitochondrial superoxide generation was found to be the major source for the observed increment in ROS levels in Grp75 expressing cells. In addition, the localization profile of the exogenously expressed Grp75 protein highlighted the fact that the protein was found to be predominantly targeted to mitochondria. Strikingly, the elevated Grp75 levels led to an increase in mitochondrial mass and also displayed a higher proportion of circular and fragmented mitochondria in these cells. Together, the above preliminary observations hint towards a strong correlation between the levels of Grp75 and its influence on the redox biology of cells providing an additional and a possible explanation of the mode of participation of Grp75 in generation and progression of malignancy.

The goal of this thesis is to analyze and compare the main characteristics of Prague Stock Exchange and Warsaw Stock Exchange. At first the attention is paid to the concept of "stock exchange" in the legal system of both countries. A short summary of the history of both exchanges is followed by a description of the organizational structure and comparison of the basic conditions of exchange membership. The individual market segments are analyzed as well as conditions for admission of financial instruments to those segments. The thesis also outlines the essential characteristics of trading systems in Prague and in Warsaw together with a list of basic types of trades. The final comparative analysis is devoted to the type and volume of financial instruments traded on both exchanges and settlement of those trades.