Submitted by Claudinei Pracidelli (cpracide@ipen.br) on 2015-01-07T16:11:01Z No. of bitstreams: 0 / Made available in DSpace on 2015-01-07T16:11:01Z (GMT). No. of bitstreams: 0 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A imagem molecular oferece a perspectiva de detectar doenças bem antes de os sintomas surgirem. A vasculatura tumoral é vital no crescimento do tumor e na disseminação de metástases, sendo assim alguns radiofármacos são dirigidos para a angiogênese. O glioma, tumor cerebral de baixa incidência porém alta mortalidade, requer um diagnóstico precoce para favorecimento da abordagem terapêutica. O objetivo desse estudo foi o desenvolvimento de novo radiofármaco para diagnóstico por imagem de glioma, baseado em peptídeos angiogênicos (GX1 e GX1-RGD) marcados com o radioisótopo tecnécio-99m. O desempenho dos conjugados peptídicos mostraram-se bastante parecidos em diversas avaliações. Eles foram radiomarcados com alta pureza radioquímica (>96%) e estáveis em soro até pelo menos 4h. Ambos são hidrofílicos e com baixa ligação às proteínas plasmáticas. A biodistribuição em animais sadios demonstrou alta excreção renal e depuração sanguínea rápida para ambos os radiotraçadores. Nos estudos in vitro, o 99mTc-HYNIC-PEG4-c(GX1) apresentou picos de ligação aos 60 min e o 99mTc-HYNIC-E-[c(RGDfk)-c(GX1)]) aos 120 min, nas células endoteliais HUVEC, usadas como controle, e nas células tumorais das linhagens U87MG e T98G. A captação tumoral nos animais foi mais acentuada para células U87MG, especialmente para o 99mTc-HYNIC-E-[c(RGDfk)-c(GX1)]) (2,87 ± 0,53% DI/g) aos 60 min p.i., com boa visualização em imagens adquiridas por gama-câmara e micro-SPECT/CT. Estudos realizados com os peptídeos conjugados à nanopartículas magnéticas para visualização em ressonância magnética também demonstraram especificidade dos produtos em tecidos tumorais. O desempenho do 99mTc-HYNIC-E-[c(RGDfk)-c(GX1)]) foi superior que o do traçador GX1, quanto à captação no glioma humano, podendo ser considerado como um promissor radiofármaco para diagnóstico de gliomas. / Tese (Doutorado em Tecnologia Nuclear) / IPEN/T / Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP / FAPESP:11/12405-0

La déficience du système de réparation des mésappariements de bases aboutit à une instabilité des séquences répétées ou microsatellites (MSI) qui engendre des mutations au niveau de gènes cibles de l'oncogenèse MSI. L'objectif de ma Thèse consistait à définir les conséquences fonctionnelles des mutations d'un nouveau gène cible de la tumorigenèse colorectale MSI : le gène SMAP1 (Small ArfGAP1) qui code une protéine de la famille ArfGAP (ADP ribosylation factor GTPase Activating Protein) spécifique d'Arf6, protéine impliquée dans de nombreux mécanismes cellulaires. Les mutations de SMAP1 sont spécifiques des tumeurs MSI de différentes origines tissulaires et n'apparaissent qu'au niveau de la répétition (A10). Dans les tumeurs colorectales primaires, la fréquence de mutations de SMAP1 observées diminue au cours de la progression tumorale suggérant que les tumeurs dépourvues de mutations de SMAP1 sont plus invasives. D'un point de vue fonctionnel, les mutations de SMAP1 ont pour conséquences un défaut dans le recyclage rapide du récepteur à la transferrine, une augmentation de la prolifération cellulaire et une diminution du pouvoir invasif en maintenant les jonctions adhérentes. Ainsi, nos observations montrant que les mutations de SMAP1 augmentent le pouvoir prolifératif mais diminuent le pouvoir invasif des lignées cellulaires issues de CCR MSI pourraient expliquer certaines caractéristiques cliniques des CCR MSI, les tumeurs MSI étant en effet des tumeurs volumineuses, ayant un faible pouvoir métastatique.

Many different approaches have been proposed with the aim of facilitating sound and successful information management (IM) and knowledge management (KM) practices within business contexts. These approaches seek to identify organizational factors (e.g. culture or information technology practices) or to suggest management processes (e.g. human resources management) required to establish environments conducive to IM and KM. Most of these approaches, often presented as frameworks (as they are referred to in this study) for organizational IM or KM, are exemplified by the following features.Firstly, they have emerged as unrelated notions, with little reference to each other or to foundational studies in the area. Secondly these frameworks are not based on any theoretical foundation. Thirdly, these frameworks have tended to focus on either information or knowledge management activities but not both, even though organizational IM and KM exist in a complementary and co-dependent relationship. The usefulness of these frameworks is made problematic by muddled use of the terms 'information', 'knowledge', 'IM' and 'KM', which are often transposed or used synonymously. The situation is further complicated by the inherent complexity of the organizational environments into which practitioners attempt to introduce information and knowledge management (IKM) initiatives. Early outputs of this research are explanations of how the terminology above is used in this study and a literature review that describes current IM and KM frameworks by analyzing their components. The literature review identifies current challenges in the research domain, including the need for sound foundation (referent model) on which future IKM frameworks can be based. A suitable referent model is proposed by integrating single and double feedback loops (from systems theory) with two concepts from the IM literature: IM processes and the domains of IM activity. Then, an interpretive multi-methodological research (MMR) approach is pursued consisting of three sequential phases: action research, transition and case study. The first phase, a 3-cycle action research project accompanied by a longitudinal descriptive case study and an embedded literature analysis, was conducted over a 31 month period. The key research outcome of the action research phase was a set of candidate enablers Information and Knowledge Management (IKM) in Business Contexts for organizational IKM, while the organizational deliverables included policies, strategies, process improvement and new information systems. The information gathered in phase one was rich and deep. However, in keeping with the goal of the research to produce a practical, useful IKM framework, the researcher sought a broader view from the IKM community. To achieve this practitioner view, a second research phase was designed to bridge the gap between the detailed examinations of IKM initiatives within one organizational environment, to the examination of IKM initiatives within other organizations. Therefore phase two - a transition phase - consisted of a series of surveys and interviews with IKM practitioners that explored their perceptions of organizational IKM activities and environments. The data collected in phase two supported the findings from phase one and informed the development of the case protocols for the third - case study - phase. In the third phase, six IKM projects in three organizations were studied. Documentary and interview data were examined to understand the relationships between IKM projects, the candidate enablers identified earlier in phases one and two, and other organizational factors implicated in IKM initiatives. When analyzed, the findings from the third phase converged with the data collected in the previous two phases, and provided a rich, deep and broad collection of material. The study culminates by synthesizing the data collected in the three research phases to (1) confirm a suitable referent model on which IKM frameworks can be based and (2) develop an integrated, multidimensional IKM framework that assimilates the referent model. The referent model, which is based on previous calls for IKM frameworks to have a sound theoretical foundation, incorporates two established concepts from the IKM literature: (a) the operational, analytical and strategic domains of IKM activity and (b) double and single loop feedback loops of systems thinking applied to IKM processes. The practical and flexible IKM framework, which assimilates these concepts, has three dimensions. These dimensions are (i) domains of IKM activity and feedback loops (ii) organizational enablers (iii) project context. It is envisaged that this framework be used by practitioners to identify and manage areas of the business environment that require attention to ensure success of IKM projects or initiatives.

Universidade Federal de Uberlândia / The Electrical Discharge Machining process is very useful while machining very hard materials, which are very difficult to be machined by traditional processes, while can make complex geometries and minimum dimensions. One of the materials that are used in this process is highspeed steels, which are very hard and has a high mechanical resistance. The main objective of this work is the study of performance of different dielectric fluids used in EDM in different cut conditions in terms or metal removal rate (MMR) and wear ratio (WR) roughness parameter (Ra). A discuss of the most important factors that can produce different performance when machining with this process is presented. Five tests with different types of dielectric fluids using a cooper tool were carried out. Was noticed different performance between the fluids, which all the other conditions of operation were unchanged. According to the fluid the workpiece presented less roughness and a higher MMR in some cases. In other cases, a higher MMR produced in the other hand a recast layer less uniform. The most important conclusion of this work is about kerosene, which costs 3 times less than the specific dielectric fluids for EDM, presented worst finishing surfaces and not too high MMR as expected, despite all the risks for the operator. / O processo de Usinagem por Descargas Elétricas é muito utilizado na usinagem de materiais de elevada dureza, que são difíceis de serem usinados por processos convencionais, além de permitir a confecção de geometrias bem complexas e de dimensões diminutas. Um dos materiais que são largamente usinados por EDM (Electrical Discharge Machining) é o aço-ferramenta ABNT M2, que apresenta grande versatilidade, combinando excelente tenacidade, dureza e resistência a abrasão, muito indicado para confecção de matrizes de estampagem profundas e outras ferramentas de deformação plástica à frio. O objetivo principal deste trabalho é o estudo do desempenho de diferentes tipos de fluidos dielétricos em três regimes pré-estabelecidos com relação à rugosidade média aritmética (Ra), taxa de remoção de material (TRM), relação de desgaste (RD) e rugosidade; além de discutir e analisar os mais importantes fatores que influenciam no processo de usinagem por descargas elétricas. Os diversos fluidos dielétricos utilizados possibilitam diferentes condições de usinagem e muito pouco se sabe sobre qual o fluido mais indicado para operações de acabamento ou desbaste. Foram feitos ensaios com 5 tipos diferentes de fluidos dielétricos e com uma ferramenta de cobre. Verificou-se que há diferenças importantes quando usina-se com fluidos diferentes, mantendo-se constantes todas as demais condições de operação. Notou-se que quando utilizando-se um determinado fluido a peça apresentou uma menor rugosidade e também uma maior TRM em alguns casos. Já em outros casos, uma maior TRM ocasionou em contrapartida uma Camada Refundida menos uniforme. Porém, a maior conclusão desse trabalho foi a de que o querosene, apesar de ser até 3 vezes mais barato que os demais fluidos, apresentou piores acabamentos superficiais e TRM não tão grandes quanto o esperado, além de maiores riscos ao operador. / Mestre em Engenharia Mecânica

Introduction and Background: Measles, mumps and rubella (MMR) are infectious diseases, primarily of childhood, which cause significant mortality and morbidity globally. These infections are, however, vaccine preventable and there is potential for them to be eradicated worldwide through the strategic use of organised population immunisation programmes. Following the introduction of the MMR vaccination in the UK in 1988, uptake was initially good and a high level of population vaccination coverage was achieved. This was sustained until 1998 when a study by Dr Wakefield and colleagues was published in the Lancet suggesting the theoretical possibility of an association between MMR and Autism/bowel disease. Intense media coverage followed, uptake of MMR vaccine fell to less than 80% in Somerset, and community outbreaks of measles, which had almost been eliminated in the UK, began to reappear. The Wakefield study was subsequently discredited and was eventually retracted by the Lancet in 2010. In August 2008 the Chief Medical Officer announced a national MMR catch-up campaign, targeting all children between the age of 13 months and 18 years who had either not been vaccinated against measles, mumps and rubella, or had only partial immunisation. These children were invited again for vaccination and the campaign was completed in January 2009. This study was undertaken to explore, in depth, the quantitative data available in respect of the uptake of MMR at the time of the 2009 campaign, and also to provide new qualitative data in relation to the attitudes, beliefs and experience of MMR and immunisation services of parents who continued to decline MMR for their children after the 2009 campaign, in order to identify factors which affected parental decision-making, add to the wider knowledge base, and to use this knowledge to improve the future development of immunisation services in Somerset. Methods: The overall objective of the study was to investigate a number of social, demographic and geographic characteristics of parents and children associated with MMR uptake, to compare these characteristics within and between defined sub-sets of the Somerset population, and to explore the basis on which parents in Somerset make decisions in relation to MMR immunisation. The study design adopted was a ‘mixed methods’ approach comprising of a cross-sectional design with three sequential phases - an exploration of baseline epidemiological data; a survey conducted with parents of children who remained unimmunised after 2009; and finally, semi-structured interviews with a sub-set of these parents. Results: The key findings from the study are: Parents who decline MMR for their children are not a homogenous group, but consist of a number of sub-groups each of which have different motives, decision pathways and predicted outcomes in relation to potential to change their mind and accept MMR There are differences in geographic distribution between the two age groups investigated Whilst the ‘Wakefield’ study did, and still does have, an impact, it is not the only or most important factor in their continuing decision-making. There is evidence that health professionals have a key role in addressing parental concerns in respect of immunisation. GP practice was the most significant factor associated with uptake in the Phase 1 study, and this was further confirmed in interviews with parents. Parents make decisions through engagement, through communicating and relating to others and this offers a potential mechanism for health professionals to influence decisions through open engagement with parents. Discussion and Conclusions: Three parent sub-groups were identified (Single Vaccines; Medical Comorbidities and Natural Health). These sub-groups were further investigated and factors associated with the decision-making pathways of each group were identified. This resulted in the development of the ‘MMR Parent Engagement Framework’ as a tool for use by professionals in planning their interactions with parents to improve and encourage more open dialogue in order to positively influence parental decision-making in relation to accepting MMR or other vaccinations. From a commissioning perspective, embedding frameworks such as this in service specifications offers a more cost-effective approach to improving immunisation uptake than funding large, poorly targeted catch-up campaigns. It is therefore recommended that further research is undertaken to provide evidence of the effectiveness of the approach in practice, and to inform future commissioning decisions. Additional recommendations to improve the effectiveness and delivery of immunisation services are also made in respect of GP Practice specific factors, independent schools, ethnic minority communities, vaccine overload, media, and data validation. The study has already directly influenced changes in current practice at both a local and a national level.

Ghana is identified among the developing countries with high maternal mortality ratio in Africa. This study unpacked the Demographic and Health Survey data by examining the maternal health indicators at the district level using GIS methods. Understanding the geographic patterns of antenatal care, place of delivery, and skilled birth attendants at the small scale will help to formulate and plan for location-specific health interventions that can improve maternal health care behavior among Ghanaian women. Districts with high rates and low rates were identified. Place of residence, Gini-Coefficient, wealth status, internet access, and religious affiliation were used to explore the underlying factors associated with the observed patterns. Economic inequality was positively associated with increased use of maternal health care services. The ongoing free maternal health policy serves as a cushion effect for the economic inequality among the districts in the Northern areas. Home delivery is common among the rural districts and is more prominent mostly in the western part of Northern Region and southwest of Upper West. Educating women about the free maternal health policy remains the most viable strategy for positive maternal health outcomes and in reducing MMR in Ghana.

Organoids retain the morphological and molecular patterns of their tissue of origin, are self-organizing, relatively simple to handle and accessible to genetic engineering. Thus, they represent an optimal tool for studying the mechanisms of tissue maintenance and aging. Long-term expansion under standard growth conditions, however, is accompanied by changes in the growth pattern and kinetics. As a potential explanation of these alterations, epigenetic drifts in organoid culture have been suggested. Here, we studied histone tri-methylation at lysine 4 (H3K4me3) and 27 (H3K27me3) and transcriptome profiles of intestinal organoids derived from mismatch repair (MMR)-deficient and control mice and cultured for 3 and 20 weeks and compared them with data on their tissue of origin. We found that, besides the expected changes in short-term culture, the organoids showed profound changes in their epigenomes also during the long-term culture. The most prominent were epigenetic gene activation by H3K4me3 recruitment to previously unmodified genes and by H3K27me3 loss from originally bivalent genes. We showed that a long-term culture is linked to broad transcriptional changes that indicate an ongoing maturation and metabolic adaptation process. This process was disturbed in MMR-deficient mice, resulting in endoplasmic reticulum (ER) stress and Wnt activation. Our results can be explained in terms of a mathematical model assuming that epigenetic changes during a long-term culture involve DNA demethylation that ceases if the metabolic adaptation is disturbed.

Sufficient power supply to run GPS machinery and transmit data on a long-term basis remains to be the key challenge for wildlife tracking technology. Traditional ways of replacing battery periodically is not only time and money consuming but also dangerous to live-trapping wild animals. In this paper, an innovative wildlife tracking collar with multi-source energy harvester with advantage of high efficiency and reliability is proposed. This multi-source energy harvester entails a solar energy harvester and an innovative rotational electromagnetic energy harvester is mounted on the "wildlife tracking collar" which will extend the duration of wild life tracking by 20% time as was estimated. A feedforward and feedback control of DC-DC converter circuit is adopted to passively realize the Maximum Power Point Tracking (MPPT) logic for the solar energy harvester. A novel electromagnetic pendulum energy harvester with motion regulator is proposed which can mechanically rectify the irregular bidirectional swing motion of the pendulum into unidirectional rotational motion of the motor. No electrical rectifier is needed and voltage drops from diodes can be avoided, the EM pendulum energy harvester can provide 200~300 mW under the 0.4g base excitation of 4.5 Hz. The nonlinearity of the disengage mechanism in the pendulum energy harvester will lead to a broad bandwidth frequency response. Simulation results shows the broadband advantage of the proposed energy harvester and experiment results verified that at some frequencies over the natural frequency the efficiency is increased. / Master of Science

Les missions internationales en entreprise ne parviennent plus à retenir les talents alors même que leur coût reste très élevé. La délocalisation de l’individu apparaît donc comme une nouvelle forme d'expatriation à mi-chemin entre expatriation auto-initiée et mission internationale en entreprise. Cependant, celle-ci résonne comme une violation du contrat psychologique liant l’individu à son entreprise. En effet, le diplôme ne semble plus protéger l’employé contre la délocalisation de son poste vers des pays à coût plus bas. Cette étude de cas a aidé à identifier les facteurs influençant les talents à accepter une relocalisation sous contrat local dans un pays à moindre coût. De ce fait, cette thèse fournit aux entreprises des éléments contributifs à la gestion globale des talents dans un contexte de délocalisation. / Individual offshoring emerges as a new form of organizational-initiated expatriation which bridges self-initiated-expatriation and international assignment. The failure of IA to retain talented individuals (talent) and a growing pressure on costs leave no choice to companies but to dramatically reconsider how expatriation can develop talent globally in a different but still sustainable way.However, this new form of expatriation resonates as a breach of the psychological contract. If talent no longer expect to remain in the same company for a large part of their career, they still hold an expectation that white collar activities associated to higher degrees would protect their jobs from moving abroad. This thesis was a case study of a company offshoring some of its global talent to lower cost locations. The purpose was to understand what factors talent consider in accepting to relocate to a lower cost location under a local contract. This research contributes to talent retention and sustained talent management while offshoring ac-tivities to lower cost countries.

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