Rozprawy doktorskie na temat „MPSP”

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
A temática dos resíduos sólidos, especialmente os resíduos sólidos urbanos, é de fundamental importância para a ciência geográfica, visto que aborda variáveis pertinentes ao debate sociedade e natureza ao considerar as contradições entre o consumo, o descarte, a desigualdade social, as questões de ordem política e os impactos ao ambiente associado. Assim, demonstra-se como um campo interdisciplinar profícuo à análise ambiental dentro da Geografia. No entanto, avista-se um cenário preocupante, de ordem socioeconômica e ambiental, visto que o descarte em massa de resíduos ultrapassa 1kg.hab./dia, maior em países desenvolvidos, gerando anualmente bilhões de toneladas de resíduos em todo o mundo sendo que em grande parte dos países não há uma destinação final adequada. Tal cenário também é perceptível nos 57 municípios que fazem parte do acordo MPF/MPSP x CESP de 2009, área de análise desta pesquisa; a qual está permeada por literatura nacional e internacional, dados oficiais, produtos adquiridos por meio de geoprocessamento, trabalho de campo e entrevistas que serviram para validar ou invalidar alguns dados oficiais acerca da disposição final ambientalmente adequada. A partir de tais procedimentos, objetivou-se, de forma geral, demonstrar as falhas político-institucionais que impedem, a partir do estudo de caso regional, a implantação integral das metas e diretrizes da Lei Federal n. 12.305/2010, a qual instituiu a Política Nacional de Resíduos Sólidos (PNRS). Essa política tem se mostrado fundamental para criar um novo cenário sobre a gestão e gerenciamento de resíduos no Brasil. No entanto, em razão da sua extensão territorial, características geográficas diferenciadas, desenvolvimento socioeconômico desigual e diversidade cultural brasileira, a implantação tanto da destinação quanto da disposição final ambientalmente adequada não tem sido observada, ainda mais que depende de esforços sociopolíticos em todas as esferas – executivo, legislativo e jurídico - e escalas de poder – municipal, estadual e federal. Nesse âmbito, a tese parte da hipótese de que tanto a implantação da destinação quanto à disposição final se mostra inviável, pois demonstra falhas de ordem político-institucionais na área de estudo. Assim, para desenvolver tais prerrogativas, analisou-se de forma teórica os mecanismos da sociedade de consumo que levam ao descarte em massa, bem como as diretrizes de gestão e gerenciamento de resíduos sólidos urbanos no Brasil e no mundo. Já de modo qualitativo e quantitativo, discutiu-se a questão dos planos municipais de gestão e gerenciamento integrados e suas relações com o âmbito nacional, assim como a destinação e disposição final dos resíduos. A partir de tais leituras avistou de modo teórico um cenário de transformação de pessoas em mercadorias a partir do consumo e a evolução das diretrizes da gestão e gerenciamento, as quais visam a busca de uma destinação e disposição ambientalmente adequada para um cenário problemático em países em desenvolvimento como o Brasil. Concluiu-se que para a região estudada houve o desenvolvimento de uma política pública em prol da implementação da destinação e disposição ambientalmente adequada aos municípios contemplados pelo Acordo MPF/MPSP x CESP de 2009. Todavia, detectou-se uma incompletude dos Planos Municipais de Gestão Integrada de Resíduos Sólidos (PMGIRS), levando a precarização do planejamento da atividade no âmbito municipal. Em relação a destinação final, observou-se ainda inviabilidade geografia, pois existe uma concentração espacial das industrias recicladoras. Por fim, os mapeamentos realizados indicaram uma série de irregularidades, que colocam em xeque os dados oficiais relacionados a disposição final na região. Assim, a partir desse conjunto de falhas demonstradas na pesquisa, é possível apontar que a implementação da PNRS não tem se mostrado viável, tanto na região quanto no restante do país.
The theme of solid waste, especially urban solid waste, is of fundamental importance for geographic science, since it addresses relevant variables to the debate on society and nature since it considers the contradictions between consumption, disposal, social inequality, issues of political order and the impacts on the associated environment. Therefore, an interdisciplinary field is shown to be useful for environmental analysis within geography. However, a worrisome scenario is observed, of the socio-economic and socio-environmental order, since the massive waste disposal exceeds 1kg.hab./day, higher in developed countries, generating annually billions of tons of waste around the world being that in a large part of the countries there is no adequate final destination. This scenario is also perceptible in the 57 municipalities that are part of the MPF / MPSP x CESP agreement of 2009, the area of analysis of this research; which is permeated by national and international literature, official data, products acquired through geoprocessing, field work and interviews that served to validate or to invalidate some official data about the environmentally appropriate final disposal. Based on these procedures, the general objective was to demonstrate the political-institutional failures that prevent, from the regional case study, the integral implementation of the goals and guidelines of Federal Law n. 12,305 / 2010, which instituted the National Policy on Solid Waste (PNRS). This policy has been fundamental to create a new scenario on waste management in Brazil. However, due to its territorial extension, different geographical characteristics, unequal socioeconomic development and Brazilian cultural diversity, the implementation of both destination and environmentally adequate final disposal has not been observed, being that it depends on sociopolitical efforts in all spheres - executive, legislative and juridical - and scales of power - municipal, state and federal. In this field, the thesis is based on the hypothesis that both the implementation of the destination and the final disposition are not viable, since it demonstrates political-institutional failures in the study area. Thus, to develop such prerogatives, the mechanisms of the consumer society leading to mass discarding were analyzed theoretically, as well as the guidelines for the management of solid urban waste in Brazil and in the world. In a qualitative and quantitative way, the question of integrated municipal management plans and their relations with the national scope was discussed, as well as the destination and final disposition of the waste. Based on these readings, it was theoretically observed a scenario of people's transformation into merchandise based on consumption and the evolution of management guidelines, which point to the search for an environmentally appropriate destination and disposition for a problematic scenario as observed in developing countries like Brazil. It was concluded that, for the studied region, a public policy development was achieved in favor of the implementation of the allocation of environmentally adequate disposition in the municipalities contemplated by the MPF / MPSP x CESP Agreement of 2009. However, an incompleteness of the Integrated Solid Waste Management Municipal Plans (PMGIRS) was detected, leading to precarization of activity planning at the municipal level. Regarding the final destination, the geographycally unviability was still observed, since there is a spatial concentration of the recycling industries. Finally, the mappings indicated a series of irregularities, which put in evidence the official data related to the final disposition in the region. Thus, from this set of failures demonstrated in the research, it is possible to point out that the implementation of the PNRS has not been shown to be viable, both in the region and in the rest of the country.
La temática de los residuos sólidos, especialmente los residuos sólidos urbanos, es de fundamental importancia para la ciencia geográfica, ya que aborda variables pertinentes al debate sociedad y naturaleza al considerar las contradicciones entre el consumo, el descarte, la desigualdad social, las cuestiones de orden político y los impactos al ambiente asociado. De esta forma se muestra un campo interdisciplinario provechoso al análisis ambiental dentro de la Geografía. Sin embargo, se observa un escenario preocupante, de orden socioeconómico como socio-ambiental, puesto que el descarte masivo de residuos sobrepasa 1kg.hab./dia, mayor en países desarrollados, generando anualmente miles de millones de toneladas de residuos en todo el mundo mundo siendo que en gran parte de los países no hay un destino final adecuado. Este escenario también es perceptible en los 57 municipios que forman parte del acuerdo MPF / MPSP x CESP de 2009, área de análisis de esta investigación; la cual está permeada por literatura nacional e internacional, datos oficiales, productos adquiridos por medio de geoprocesamiento, trabajo de campo y entrevistas que sirvieron para validar o invalidar algunos datos oficiales acerca de la disposición final ambientalmente adecuada. A partir de tales procedimientos, se trazó como objetivo general demostrar las fallas político-institucionales que impiden, a partir del estudio de caso regional, la implantación integral de las metas y directrices de la Ley Federal n. 12.305 / 2010, la cual instituyó la Política Nacional de Residuos Sólidos (PNRS). Esta política se ha mostrado fundamental para crear un nuevo escenario sobre la gestión de residuos en Brasil. Sin embargo, debido a su extensión territorial, características geográficas diferenciadas, desarrollo socioeconómico desigual y diversidad cultural brasileña, la implantación tanto del destino y de la disposición final ambientalmente adecuada no ha sido observada, aún más que depende de esfuerzos sociopolíticos en todas las esferas - ejecutivo, legislativo y jurídico - y escalas de poder - municipal, estatal y federal. En este ámbito, la tesis parte de la hipótesis de que tanto la implantación del destino como la disposición final se muestra inviable, pues demuestra fallas de orden político-institucionales en el área de estudio. Así, para desarrollar tales prerrogativas, se analizó de forma teórica los mecanismos de la sociedad de consumo que llevan al descarte masivo, así como las directrices de gestión de residuos sólidos urbanos en Brasil y en el mundo. De modo cualitativo y cuantitativo, se discutió la cuestión de los planes municipales de gestión integrados y sus relaciones con el ámbito nacional, así como el destino y disposición final de los residuos. A partir de tales lecturas, observó de modo teórico un escenario de transformación de personas en mercancías a partir del consumo y la evolución de las directrices de la gestión, las cuales apuntan a la búsqueda de un destino y disposición ambientalmente adecuada para un escenario problemático en países en desarrollo como Brasil. Se concluyó que para la región estudiada hubo desarrollo de una política pública en pro de la implementación de la asignación y disposición ambientalmente adecuada a los municipios contemplados por el Acuerdo MPF / MPSP x CESP de 2009. Sin embargo, se detectó una incompletitud de los Planes Municipales de Gestión Integrada de Residuos Sólidos (PMGIRS), llevando a la precarización de la planificación de la actividad en el ámbito municipal. En cuanto a la destinación final, se observó todavía la inviabilidad geografía, pues existe una concentración espacial de las industrias recicladoras. Por último, los mapeos realizados indicaron una serie de irregularidades, que ponen en jaque los datos oficiales relacionados con la disposición final en la región. Así, a partir de ese conjunto de fallas demostradas en la investigación, es posible apuntar que la implementación de la PNRS no se ha mostrado viable, tanto en la región como en el resto del país.

Dissertação de Mestrado Integrado em Medicina Veterinária
Bovine theileriosis is a tick-borne disease caused by one or more haemoprotozoan parasites of the genus Theileria. In the past, Theileria infection in cattle in Australia was largely asymptomatic and recognized to be associated with Theileria buffeli. However, in the recent years, outbreaks of theileriosis have occurred in beef and dairy cattle in subtropical climatic regions (New South Wales) of Australia. There is also one published report of a recent theileriosis outbreak on a beef farm near Seymour in the south-eastern state of Victoria. In order to gain an improved insight into the genetic composition of Theileria populations following this outbreak, we undertook herein an integrated PCR-coupled mutation scanning-sequencing-phylogenetic analysis of sequence variation in part of the major piroplasm surface protein (MPSP) gene within and among samples from cattle involved in the outbreak. Theileria DNA was detected in 89.4% of 94 cattle on the Seymour farm; the genetic analysis showed that the ikeda and chitose genotypes representing the Theileria orientalis complex were detected in 75% and 4.8% of 84 infected cattle, respectively, and that mixed populations of these two genotypes were found in 20.2% of infected cattle. Given unpublished reports of a significant increase in the number of outbreaks in Victoria, future investigations should focus sharply on elucidating the epidemiology of Theileria to subvert the economic impact on the cattle industry in this state. Although used here to explore genetic variation within the T. orientalis complex in Australia, a mutation scanning-based approach has broad applicability to other species of Theileria in other countries.
RESUMO - ANÁLISE GENÉTICA DE POPULAÇÕES DE THEILERIA ORIENTALIS, EM BOVINOS, APÓS UM SURTO DE THEILERIOSE EM VITORIA, AUSTRÁLIA - A teileriose é uma doença transmitida por carraças e causada por hemoprotozoários pertencentes a uma ou mais espécies do género Theileria. Historicamente, a infecção de gado na Austrália, com este parasita, é considerada assintomática e associada especificamente à espécie Theileria buffeli. Contudo, nos últimos anos, surtos de teileriose têm ocorrido tanto em explorações de carne como de leite em regiões de clima subtropical da Austrália (Nova Gales do Sul). Recentemente foi publicado um relatório, correspondente a um surto de teileriose perto de Seymour, Victoria, um estado a sudeste do país. A fim de obter uma melhor compreensão sobre a composição genética das populações de Theileria envolvidas neste surto, foi levado a cabo um sistema de análise integrada de PCR - análise de mutações – sequenciação– filogenia, das variações existentes na sequência de parte do gene codificador da principal proteína de superfície do piroplasma (major piroplasm surface protein – MPSP), dentro e entre diferentes amostras provenientes de animais residentes na exploração envolvida no surto. O ADN do parasita foi detectado em 89,4% de 94 bovinos testados, na exploração de Seymour e a subsequente análise genética mostrou que os genótipos Ikeda e Chitose, representativos do complexo formado por diferentes estirpes pertencentes à espécie Theileria orientalis, foram detectados em 75% e 4,8% de 84 animais infectados, respectivamente, e que populações mistas compostas por ambos os genótipos foram detectadas em 20,2% desses mesmos animais. Dado que, relatórios não publicados apontam para um aumento significativo do número de surtos de teileriose em Victoria, futuras investigações deverão centrar-se fortemente na elucidação da epidemiologia deste parasita, a fim de avaliar o impacto económico que este poderá ter sobre a indústria bovina neste Estado. Ademais, apesar de usados neste estudo para explorar a variação genética das populações de T. orientalis na Austrália, uma abordagem baseada na análise de mutações tem ampla aplicabilidade para outras espécies de Theileria presentes em outros países.

We investigate aspects, in various contexts, of entanglement and the wave particle duality. We show that the dynamics of tripartite systems which interact via one excitation exchange leads to a direct connection between entanglement sudden death and the appearance of genuine entanglement. We also show that this is valid (not with the same generality) also for a four partite system in the context of the double JaynesCummings model. Moreover we show that the entanglement dynamics in this case can be completely expressed in geometrical terms. Using the same system we show that by performing adequate Zeno like measurements it is possible to freeze, increase, or even revive the initial entanglement. This intriguing result is also associated to entanglement sudden death. As far as wave particle duality and entanglement are concerned we studied a particle going through an interferometer equipped with a whichway device. We quantified the quality of the probe and exhibit its connection with the availability of the whichway information provided by the probe system. When the probe system information is unaccessible only the particle character will be observed. We obtain limits for a good (quantum regime) and for a bad (classical regime) whichway detector (probe system). We used our results to interpret a recent experiment set up to test the quantumclassical border where the probe covers from the quantum to the classical limit. We showed that the experimental errors influenced the conclusion inferred form the data about having achieved the classical limit. Finally we analyze the Ramsey zones from the point of view of our findings and provide for a transparent physical interpretation. In this case the classical limit of the probe system is reached due to a source plus strong dissipation dynamics, which swaps whichway information to a system containing an infinite number of degrees of freedom, making thus sure that any whichway information becomes unavailable.
Nesta tese o emaranhamento e a dualidade ondapartida são os temas principais de estudo. Para examinar alguns dos aspectos e características do emaranhamento, analisamos sistemas de três e quatro partes constituídos por átomos e pelo campo eletromagnético. A interação átomocampo é dada pelo modelo de JaynesCummings. De início mostramos que existe uma ligação direta entre o emaranhamento residual e a morte súbita de emaranhamento quando a interação entre os sistemas é do tipo troca de excitações. Como extensão, estudamos um sistema dinâmico de quatro partes e mostramos que havendo morte súbita haverá um emaranhamento que não pode ser contabilizado apenas via o emaranhamento das bipartições. Estudamos ainda os aspectos geométricos relativos à dinâmica do emaranhamento e mostramos que existe uma manifestação geométrica da morte súbita. Na sequência, neste mesmo modelo de quatro partes, ao intervir na dinâmica com medidas tipo Zeno, mostramos que a dinâmica de emaranhamento é alterada e com isso tornase possível congelar, aumentar e reviver o emaranhamento. Contudo, a possibilidade de aumentar e reviver o emaranhamento está vinculada a existência de MSE em alguma partição. Fizemos ainda uma investigação sobre a dualidade ondapartícula considerando uma partícula quântica que atravessa um interferômetro equipado com um marcador de caminho. Neste trabalho, quantificamos a qualidade da ponta de prova e mostramos sua conexão com a quantidade de informação de quecaminho que ficou disponível. Percebemos que quando a ponta de prova é incapaz de disponibilizar a informação de quecaminho então será um sistema que possui apenas comportamento tipo corpúsculo. Encontramos limites para um bom (regime quântico) ou um mal (regime clássico) discriminador de quecaminho. Aplicamos nossos resultados a um experimento de complementaridade na borda quânticoclássico onde a ponta de prova transita do regime quântico ao clássico. Mostramos que as imperfeições experimentais influem na conclusão tirada acerca do limite clássico. Em seguida, analisamos as zonas de Ramsey onde nossos resultados fornecem uma simples interpretação. Neste caso, o limite clássico da ponta de prova é alcançado mediante a dinâmica fonte+dissipação que varre a informação de quecaminho e a leva para um sistema com infinitos graus de liberdade deixandoa completamente indisponível.

Much work has been done on design of efficient coded modulation schemes since the publication of [Ungerboeck, 1982] for trellis coded modulation and [Imai & Hirakawa, 1977] for block coded modulation. Recently, increasing interest in digital mobile radio and indoor wireless systems has led to the consideration of coded modulation designs for combating fading channels. In this research, it is intended to present results of an investigation of the construction of Reed Solomon coded MPSK modulation which is robust for the Gaussian channel and a Rayleigh fading channel. Two approaches have been applied to Reed Solomon coded modulation. First, a Reed Solomon code was combined with MPSK signal set using Gray code mapping; this was called Reed Solomon coded modulation not based on set partitioning. This approach was the baseline scheme which would be compared with the proposed approach, namely Reed Solomon coded modulation based on set partitioning. The second approach to coded MPSK with M = 2m was multilevel Reed Solomon coding. In this case, each of the m bits defining an MPSK symbol was coded and decoded by different Reed Solomon codecs. The set partitioning principle was applied to define subsets with distances Deltai,-, (i = 1 to m) that were nondecreasing with i. Each of the m bits defined a subset and was decoded in multistage decoding schemes. The novel idea here was that in the receiver, we used a rotated 2m+1-PSK detector if the transmitter used a 2m-PSK modulator. The designs of Reed Solomon coded modulation schemes for the Gaussian channel and a Rayleigh fading channel (i.e. choice of the code configurations which were suitable for this channel) have been studied. The performance of Reed Solomon coded modulation based on set partitioning was compared with Reed Solomon coded modulation not based on set-partitioning, then with multilevel Reed Solomon coded modulation using Gray mapping and finally with coded modulation schemes using binary codes, Reed Muller codes. It has been shown that over the Gaussian channel and a Rayleigh fading channel, Reed Solomon coded modulation based on set partitioning is better than several alternatives, such as schemes not based on set partitioning, multistage Reed Solomon coded modulation based on Gray mapping and Reed Muller coded modulation. It was found that good codes for a Rayleigh fading channel have configurations in which all component codes have the same minimum Hamming distance because the fading phase is uniformly distributed random process. Therefore, by matching configurations of component codes with the channel characteristics, it was shown that Reed Solomon coded modulation based on set partitioning was robust for the Gaussian and a Rayleigh fading channel. Reed Solomon coded modulation schemes were applied to Orthogonal Frequency Division Multiplexing (OFDM) transmissions. The main disadvantage of OFDM systems is that they have high Peak-to-Mean Envelope Power Ratio (PMEPR). A scheme for reducing the PMEPR of OFDM systems was investigated. Multiphase complementary code pairs of length 2 are proposed to reduce the PMEPR of MPSK and QAM OFDM. Concatenated codes with Reed Solomon coded modulation as an inner code and an RS(511, 443) code as an outer code are proposed as coding schemes for OFDM systems.

Mps1 est une protéine kinase à double spécificité impliquée dans le point de contrôle du fuseau mitotique et l'alignement des chromosomes. L'augmentation de l'activité de Mps1 est corrélée avec une augmentation de son niveau de phosphorylation lors de l'entrée en mitose. Cependant, les mécanismes contrôlant cette activation sont inconnus. Nous avons donc cherché à identifier les sites de phosphorylation de Mps1 afin d'étudier leur contribution à la régulation de Mps1. Par spectrométrie de masse, nous avons identifié jusqu'à 27 sites, et nous avons choisi de mutagéniser 11 d'entre eux individuellement en acides aminés non-phosphorylables (alanine), sur la base de leur conservation entre la protéine humaine et de xenope. Nous montrons que trois de ces sites de phosphorylation (S283, T697 et T707) sont essentiels pour l'activité kinase de Mps1, et pour son rôle dans le checkpoint mitotique. Deux de ces sites (T697 et T707) sont localisés dans la boucle d'activation du domaine kinase de Mps1 et sont des sites d'autophosphorylation. La phosphorylation sur le troisième site (S283) requiert une autre kinase. S283 est localisée dans le domaine non-catalytique de Mps1 qui est peu caractérisé et est impliqué dans le recrutement de Mps1 au kinétochore. Nous montrons par immunofluorescence que l'absence de phosphate sur le site S283 ne perturbe pas significativement le recrutement de Mad2 au kinétochore. Enfin, en utilisant des inhibiteurs et l'anticorps spécifique de la phosphorylation du site S283 que nous avons développé, nous montrons que le site S283 est phosphorylé en mitose par CDK, suggérant que les fonctions de Mps1 qui sont spécifiques de la mitose soient régulées par une phosphorylation dépendante des CDKs
Mps1 is a dual-specificity protein kinase involved in the spindle assembly checkpoint and chromosome alignment. Mps1 phosphorylation state and activity increase in mitosis. However, the regulatory mechanisms underlying these observations are unknown. We therefore sought to identify Mps1 phosphorylation sites and to study their contribution to Mps1 regulation. By mass spectrometry we identified up to 27 phosphorylation sites on Mps1. We chose 11 sites that were conserved between Xenopus and human Mps1, and constructed 11 non-phosphorylatable single point mutants. We show that three phosphorylation sites (S283, T697 and T707) are essential for the kinase activity and the checkpoint signalling function of Mps1. Two of these sites (T697 and T707) are located in the activation loop of Mps1 kinase domain and are autophosphorylation sites. Phosphorylation on the third site (S283) results from the activity of an upstream kinase. S283 is located in the less characterized non-catalytic domain that is responsible for the kinetochore localization of Mps1. By immunofuorescence we show that the absence of the phosphate at S283 does not significantly perturb the kinetochore recruitment of the spindle assembly checkpoint component Mad2. Finally, using inhibitors and our developed phosphospecific antibody we demonstrate that Mps1 is phosphorylated at S283 in mitosis by cyclin-dependent kinase (Cdk), suggesting that mitosis specific functions of Mps1 kinase are regulated by Cdk-dependent phosphorylation

The spindle assembly checkpoint (SAC), a conserved surveillance system, ensures genomic stability by delaying anaphase entry until all sister chromatids are attached to the mitotic spindle. The SAC network is active at unattached kinetochores and a complex signalling cascade culminates in the production of a diffusible 'wait anaphase' signal. Regulation of protein:protein interactions by reversible phosphorylation is critical in this signalling pathway. The checkpoint kinase Mps1, a central regulator of the SAC, plays a positive role in enabling protein interactions. Mps1 builds the SAC network by phosphorylating multiple kinetochore targets and in doing so it coordinates mitotic exit with microtubule binding. Given the critical role Mps1 plays in SAC activation, precise regulation of the activity and localisation of Mps1 must be key in controlling the activation status of the SAC. Mps1 binds to unattached kinetochores and is activated by autophosphorylation of its T-loop. However, once chromosomes are attached to the spindle and the SAC is satisfied Mps1 is switched off. The mechanisms controlling the inactivation of Mps1 were unknown. Here, it is shown that phosphorylation of T676, located on the activation loop of Mps1, is important in controlling Mps1 activity and SAC signalling. A PP2A-B56 phosphatase complex opposes Mps1 activation by directly dephosphorylating its activation loop both in vitro and in vivo. The interaction of PP2A-B56 with BubR1 is essential for this dephosphorylation event. Moreover, preliminary results from experiments combining Mps1 immunoprecipitations with mass spectrometry indicate that phosphate groups are globally lost from Mps1 when the SAC is inactive. The binding of interaction partners is a common mechanism used by kinases to regulate their function. Knl1 is present in Mps1 complexes by immunoprecipitation and mass spectrometry. While these results are still preliminary it is clear from siRNA depletion that Knl1 plays a previously unidentified role in regulating the localisation of Mps1. Together, these results signify an important advance in our knowledge of how the function of Mps1 is controlled.

Des études expérimentales faites par notre laboratoire démontrent que le 17β-E₂ a des effets bénéfiques contre le MPTP. On poursuit la recherche de nouveaux composés oestrogéniques comme des agents neuroprotecteurs au cerveau pour prévenir ou combattre la maladie de Parkinson. Ce projet de recherche étudie les effets du 17β-E₂, le PPT et le DPN sur l'expression des ERs ainsi que leurs mécanismes et capacité neuroprotectrice chez la souris MPTP (modèle animal de la maladie). Les résultats démontrent que les ERs sont exprimés dans le cortex, le striatum et l'hippocampe. Les résultats examinant le striatum proposent que les traitements oestrogénique protègent contre la perte des neurones dopaminergiques. Ensuite, une augmentation de l'activité des ERK1 et ERK2 chez les souris MPTP était observé. Le traitement hormonal a normalisé cet effet dans le cas du ERK1 et le contraire est vu pour ERK2. Donc, ces mécanismes neuroprotecteurs impliquent les récepteurs oestrogéniques et la signalisation par les protéines ERK1/2

Cloud computing represents a distributed computing paradigm that gained notoriety due to its properties related to on-demand elastic and dynamic resource provisioning. These characteristics are highly desirable for the execution of workflows, in particular scientific workflows that required a great amount of computing resources and that handle large-scale data. One of the main questions in this sense is how to manage resources of one or more cloud infrastructures to execute workflows while optimizing resource utilization and minimizing the total duration of the execution of tasks (makespan). The more complex the infrastructure and the tasks to be executed are, the higher the risk of incorrectly estimating the amount of resources to be assigned to each task, leading to both performance and monetary costs. Scenarios which are inherently more complex, such as hybrid and multiclouds, rarely are considered by existing resource management solutions. Moreover, a thorough research of relevant related work revealed that most of the solutions do not address data-intensive workflows, a characteristic that is increasingly evident for modern scientific workflows. In this sense, this proposal presents MPSF, the Multiphase Proactive Scheduling Framework, a cloud resource management solution based on multiple scheduling phases that continuously assess the system to optimize resource utilization and task distribution. MPSF defines models to describe and characterize workflows and resources. MPSF also defines performance and reliability models to improve load distribution among nodes and to mitigate the effects of performance fluctuations and potential failures that might occur in the system. Finally, MPSF defines a framework and an architecture to integrate all these components and deliver a solution that can be implemented and tested in real applications. Experimental results show that MPSF is able to predict with much better accuracy the duration of workflows and workflow phases, as well as providing performance gains compared to greedy approaches.
A computação em nuvem representa um paradigma de computação distribuída que ganhoudestaque devido a aspectos relacionados à obtenção de recursos sob demanda de modo elástico e dinâmico. Estas características são consideravelmente desejáveis para a execução de tarefas relacionadas a fluxos de trabalho científicos, que exigem grande quantidade de recursos computacionais e grande fluxo de dados. Uma das principais questões neste sentido é como gerenciar os recursos de uma ou mais infraestruturas de nuvem para execução de fluxos de trabalho de modo a otimizar a utilização destes recursos e minimizar o tempo total de execução das tarefas. Quanto mais complexa a infraestrutura e as tarefas a serem executadas, maior o risco de estimar incorretamente a quantidade de recursos destinada para cada tarefa, levando a prejuízos não só em termos de tempo de execução como também financeiros. Cenários inerentemente mais complexos como nuvens híbridas e múltiplas nuvens raramente são considerados em soluções existentes de gerenciamento de recursos para nuvens. Além destes fatores, a maioria das soluções não oferece mecanismos claros para tratar de fluxos de trabalho com alta intensidade de dados, característica cada vez mais proeminente em fluxos de trabalho moderno. Neste sentido, esta proposta apresenta MPSF, uma solução de gerenciamento de recursos baseada em múltiplas fases de gerenciamento baseadas em mecanismos dinâmicos de alocação de tarefas. MPSF define modelos para descrever e caracterizar fluxos de trabalho e recursos de modo a suportar cenários simples e complexos, como nuvens híbridas e nuvens integradas. MPSF também define modelos de desempenho e confiabilidade para melhor distribuir a carga e para combater os efeitos de possíveis falhas que possam ocorrer no sistema. Por fim, MPSF define um arcabouço e um arquitetura que integra todos estes componentes de modo a definir uma solução que possa ser implementada e utilizada em cenários reais. Testes experimentais indicam que MPSF não só é capaz de prever com maior precisão a duração da execução de tarefas, como também consegue otimizar a execução das mesmas, especialmente para tarefas que demandam alto poder computacional e alta quantidade de dados.

L’altération génétique et/ou fonctionnelle de p53 est très répondue dans les cancers humains et est répertoriée dans plus d’un cas sur deux. Les traitements et molécules utilisés en chimiothérapie anticancéreuse induisent pour la plupart l’apoptose dépendante de p53 ce qui confère une résistance particulière aux tumeurs p53 déficientes. Nous avons développé des techniques se basant sur la vidéomicroscopie à haut débit et l’utilisation de cellules fluorescentesTP53+/+ et TP53-/- pour mettre en évidence des agents chimiques qui ciblent les cellules p53 déficientes. Nous avons identifié SP600125, un inhibiteur de kinases dont MPS1, Aurora A et Aurora B, et qui tue préférentiellement les cellules tumorales TP53-/- . Cette cytotoxicité sélective a été confirmée sur de nombreux modèles de cellules déficientes en p53 in vitro et in vivo sur des xénogreffes TP53+/+ et TP53-/- injectés à des souris nudes. Nous avons utilisé une autre molécule qui a un spectre d’inhibition semblable à SP600125, la reversine, et nous avons aussi trouvé qu’elle a une cytotoxicité sélective envers les cellules p53 déficientes.L’analyse vidéomicroscopique des cellules traitées nous révèle que la mort préférentielle des cellules P53 déficientes est intimement liée à un mécanisme de polyploïdisation. En effet, les cellules TP53-/- (contrairement à celles TP53+/+) traitées effectuent des mitoses aberrantes sans karyokinèse ni cytokinèse qui ne sont pas contrôlées par un arrêt du cycle cellulaire. Ces cellules succombent par catastrophe mitotique après activation de la voie mitochondriale de l’apoptose.Cette observation concorde avec le fait que l’inhibition des protéines anti-apoptotiques de la famille Bcl-2 sensibilise les cellules traitées alors que l’inhibition des protéines BAX, APAF-1 et les caspases protège les cellules TP53-/- de l’effet cytotoxique de SP600125 et la reversine.Ces résultats nous permettent d’envisager ces drogues (ou dérivées) dans la prévention des cas de tumeurs pré malignes et/ou dans le traitement des cas de cancers p53 déficients
The genetic and/or functional alterations of p53 are highly prevalent in cancer and are reported for more than a half of all human cancers. Classic chemotherapy leads p53 mediated apoptosis conferring a drug resistance for p53 deficient cells. We developed in the laboratory a technique based on high-content videomicroscopy and fluorescent TP53+/+ and TP53-/- cells for the screening of molecules that targets p53 deficient cells. We discovered that SP600125, a kinase inhibitor, including MPS1, Aurora A and Aurora B, kills p53-deficient cells more efficiently than their p53-proficient counterparts. This selective cytotoxicity was confirmed in vivo in mice carrying p53-deficient and -proficient human xenografts. Than after we used an another inhibitor with a similar broad-spectrum kinase, reversine, and we found that this molecule have a selective toxicity for TP53-/- cells and this result was confirmed in vitro for both molecule.Videomicroscopy-based cell fate profiling revealed that the p53-deficient cell death is coupled to hyperploïdy mechanism. Indeed, TP53-/- (but not TP53+/+) undergo successive round of abortive mitosis and failed to arrest the cell cycle in response to treatment and cells became polyploidy and progressively succumbed to mitochondrial apoptosis. In line with this notion, the depletion of anti-apoptotic proteins of the BCL-2 family sensitized TP53-/- cells to the toxic effects of SP600125 and reversine. Moreover, the knockdown of BAX or APAF-1, as well as the chemical inhibition of caspases, limited the death of TP53-/- cells.Hence, SP600125 or reversine (and its analogues/derivatives) might be used for cancer chemoprevention (for eliminating pre-malignant cells that have inactivated p53) or chemotherapy of p53-deficient cancers

International Telemetering Conference Proceedings / October 28-31, 1996 / Town and Country Hotel and Convention Center, San Diego, California
It is always desirable to transmit several data signals simultaneously. This paper discusses how one transmitter can transmit several data signals to several receivers at the same time in a Point to Multipoint communication system. Two novel schemes are proposed. One is communication with Multiple Phase Shift Keying(MPSK,e.g.8PSK),another is communication with Direct-Sequence Spread-Spectrum Multiple-Access(DS/SSMA). Their models are presented and their operations are illustrated. It is proved theoretically that the communication properties of DS/SSMA are better than those of another.

The aim of the thesis is to evaluate the system of procurement at the Ministry of Labour and Social affairs between 2011-2015. The first part defines important terms in the issue of public procurement from different points of view. The second part deals with internal legislation regulating procurement at the Ministry of Labour and Social affairs and the procurement system analysis of over-threshold (below-threshold) procurement and small-scale public contracts. The last part analyzes the data of public contracts between 2011-2015. The right system adjustment of procurement at the Ministry of Labour and Social affairs is questioned.

Tesis para optar al Grado de Magíster en Química área de especialización en Química de Materiales y Memoria para optar al Título de Químico
En el presente trabajo de tesis se han sintetizado y caracterizado fases bimetálicas derivadas del sistema MnPS3. Las fases bimetálicas obtenidas son cuatro: Zn0,2Mn0,8PS3•0,25 H2O, Cu0,2Mn0,8PS3 • 0,25 H2O, Ni0,2Mn0,8PS3 • 0,25 H2O y Co0,2Mn0,8PS3 • 0,25 H2O, las cuales fueron obtenidas mediante el método de síntesis asistida por microondas, a partir del precursor de potasio K0,4Mn0,8PS3 • H2O. Además, se sintetizaron, usando el mismo método, compositos intercalados con iones trivalentes de lantánidos (GdIII, TbIII y EuIII) del tipo Ln0,03K0,3Mn0,8PS3 • 0,85H2O. La fase prístina de manganeso(II) es estable térmicamente hasta los 400 °C, que al compararse con las fases bimetálicas, resulta ser una de las más estables térmicamente a excepción de la fase bimetálica de NiII, la cual presenta una mayor estabilidad térmica que la fase prístina. Queda en evidencia así, la influencia del ion divalente insertado en la fase sobre el comportamiento térmico de estos sistemas. En cuanto a los compositos intercalados con iones Ln III, Ln0,03K0,3Mn0,8PS3 • 0,85H2O se observó que tales compositos también son más estables térmicamente que la fase precursora de potasio. Esto confirma que los iones lantánidos (III) influyen en la estabilidad térmica de estas fases laminares, aun cuando existe una pequeña cantidad de éstos iones trivalentes en el espacio interlaminar del sistema. Al realizar el estudio de las propiedades ópticas de las fases bimetálicas se observó un desplazamiento del borde de absorción a valores de menor energía respecto a la fase precursora de potasio K0,4Mn0,8PS3 • H2O. Se observó que el borde de absorción de los tres compositos con iones lantánidos, Ln0,03K0,3Mn0,8PS3 • 0,85H2O también se desplazó a valores de menor energía respecto a la fase precursora de potasio K0,4Mn0,8PS3 • H2O. En cuanto a las propiedades de emisión de los compositos a temperatura ambiente, no fue posible observar emisión en ninguno de los tres compositos intercalados con iones Ln"
This thesis presents the synthesis, and characterization of bimetallic phases, based on the pristine MnPS3 phase. The obtained bimetallic phases were Zn0,2Mn0,8PS3•0,25 H2O, Cu0,2Mn0,8PS3 • 0,25 H2O, Ni0,2Mn0,8PS3 • 0,25 H2O y Co0,2Mn0,8PS3 • 0,25 H2O. These phases were prepared by a microwave assisted method, staring from the potassium precursor, K0.4 Mn0.8PS3• H2O. Using the same method, three intercalated phases were obtained by the cationic exchange method, where part of the potassium ions located in the interlamellar space was substituted by lanthanide(III) ions (Ln = GdIII, TbIII y EuIII), producing composites of general stoichiometry, Ln0,03K0,3Mn0,8PS3 • 0,85H2O. The pristine manganese(II) phase is thermally stable till 400 °C, while the bimetallic phases were less stable than the pristine phase, with the exception of the bimetallic NiII phase. In this way, the influence on the thermal stability of the secondary bivalent metal ion becomes evident. Besides, the intercalated composites with lanthanide(III) ions, are also more stable than the corresponding potassium precursor. This fact confirms that the lanthanide ions influence the thermal stability of these composites, even though only a small quantity of these trivalent ions is exchanged with the interlamellar potassium ions. The study of the optical properties of the bimetallic phases showed that the absorption edge of the solid state spectra of the bimetallic phases was at lower energy values than that of K0,4Mn0,8PS3 • H2O. When the Ln0,03K0,3Mn0,8PS3 • 0,85H2O phases were studied a similar optical phenomenon was observed. The absorption edge of these composites was also at lower energy values, as compared to that of the potassium precursor. With respect to the luminescent properties the spectra of these composites at room temperature did not show emission
Conicyt; Fondecyt; CEDENNA

Företag och organisationer har sedan industrialismens första år arbetat med att försöka effektivisera produktionen. Effektiv produktion leder till billigare produkter, som i sin tur leder till ökad försäljning. Ett bra hjälpmedel för att uppnå denna effektivisering är införande av ett MPS-system. Systemet hjälper till att planera, organisera, samordna, styra och kontrollera materialflödet i företaget.

Införandet av detta system är dock inte alldeles trivialt. Många experter säger att implementering av MPS-system är svårare än att introducera en ny produkt eller att etablera sig på en helt ny marknad. Det finns många kritiska faktorer för att införandet skall bli lyckat. Några av de viktigaste är att det måste finnas klart uttalade mål med implementationen, engagemanget hos företagsledningen och de anställda, noggrann analys av företagets behov, tillvägagångssättet vid val av system, samarbetet med leverantören samt utbildning av personalen.

Denna uppsats har gjorts i syfte att undersöka hur företag har behandlat dessa olika faktorer vid införandet av deras MPS-system. Hur man går tillväga vid införandet påverkar i mycket hög grad hur nöjd man skall bli med systemet. Med nöjd menas här att systemet skall leva upp till de förväntningar som fanns på det före införandet. För att undersöka hur nöjda företag är med sina system har jag gjort en enkätundersökning. Utifrån den kan konstateras att många har slarvat med de faktorer som nämndes ovan och då framför allt analysen av företagets behov. Som en följd av detta har de blivit mer eller mindre missnöjda med sina system.

Orientador: Dionei Ramos
Resumo: Introdução: O tabagismo, bem como a abstinência deste, traz uma série de mudanças físicas e psicológicas. Na literatura a escala The Mood And Physical Symptoms Scale (MPSS) e a Wisconsin Smoking Withdrawal Scale (WSWS) são semelhantes e avaliam sintomas da abstinência do tabagismo, porém somente a WSWS é validada para o Brasil, sendo necessária a validação transcultural da MPSS. Além disso, é necessário verificar em momentos diferentes da abstinência, a responsividade das duas escalas a fim de quantificar corretamente os sintomas relacionados à Síndrome de Abstinência Tabagística (SAT). Objetivos: Verificar se MPSS é um instrumento válido e reprodutível para avaliar a presença de sintomas da SAT em tabagistas brasileiros e, determinar a diferença mínima clinicamente importante (DMI) da MPSS e WSWS após cessação. Métodos: Para a validação, 112 tabagistas responderam a escala MPSS e (WSWS) da seguinte forma: basal (avaliador 1 – MPSS e WSWS), após 30 minutos (avaliador 2 - MPSS) e após 15 dias (avaliador 1 - MPSS). Para a DMI foram avaliados 33 tabagistas após 24 horas e terceira semana após a cessação do tabagismo. Para reprodutibilidade na aplicação, e reaplicação da MPSS, o coeficiente de correlação intraclasse (CCI) foi utilizado, assim como o teste de Wilcoxon, para verificar se houve diferença entre as aplicações. A consistência interna da escala foi avaliada por meio do coeficiente alfa de Cronbach. A validade de constructo da MPSS em relação a WSWS foi avaliada por meio... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Introduction: Smoking, as well as this abstinence, brings a series of physical and psychological changes. In the literature, The Mood and Physical Symptoms Scale (MPSS) and The Wisconsin Smoking Withdrawal Scale (WSWS) are similar and evaluate smoking cessation symptoms, but only the WSWS is validated for Brazil, requiring cross-cultural validation of the MPSS. In addition, it is necessary to verify at different times of abstinence the responsiveness of the two scales in order to correctly quantify the symptoms related to the Smoking Abstinence Syndrome (SAS). Aim: Verify if MPSS scale is a valid and reproducible instrument to evaluate the presence of SAT symptoms in Brazilian smokers and to determine the Minimal Detectable Change (MDC) of MPSS and WSWS after cessation of smoking. Methods: For validation, 112 smokers answered to the MPSS and WSWS as follows: baseline (appraiser 1 - MPSS and WSWS), after 30 minutes (appraiser 2 - MPSS) and after 15 days evaluator 1 - MPSS). For MDC, 33 smokers were assessed after 24 hours and third week after cessation of smoking. For reproducibility in the application and reapplication of the MPSS, the intraclass correlation coefficient (ICC) was used and the Wilcoxon test, to verify if there was a difference between the applications. The internal consistency of the scale was evaluated using the Cronbach alpha coefficient. The construct validity of the MPSS in relation to the WSWS was evaluated by means of the Spearman correlation coefficient... (Complete abstract click electronic access below)
Mestre

Thesis (Honors)--Ohio State University, 2007.
Title from first page of PDF file. Document formatted into pages: contains v, 31 p.; also includes graphics. Includes bibliographical references (p. 31). Available online via Ohio State University's Knowledge Bank.

BACKGROUND:We have further characterized floral organ-localized gene expression in the inflorescence of Arabidopsis thaliana by comparison of massively parallel signature sequencing (MPSS) data. Six libraries of RNA sequence tags from immature inflorescence tissues were constructed and matched to their respective loci in the annotated Arabidopsis genome. These signature libraries survey the floral transcriptome of wild-type tissue as well as the floral homeotic mutants, apetala1, apetala3, agamous, a superman/apetala1 double mutant, and differentiated ovules dissected from the gynoecia of wild-type inflorescences. Comparing and contrasting these MPSS floral expression libraries enabled demarcation of transcripts enriched in the petals, stamens, stigma-style, gynoecia, and those with predicted enrichment within the sepal/sepal-petals, petal-stamens, or gynoecia-stamens.RESULTS:By comparison of expression libraries, a total of 572 genes were found to have organ-enriched expression within the inflorescence. The bulk of characterized organ-enriched transcript diversity was noted in the gynoecia and stamens, whereas fewer genes demonstrated sepal or petal-localized expression. Validation of the computational analyses was performed by comparison with previously published expression data, in situ hybridizations, promoter-reporter fusions, and reverse transcription PCR. A number of well-characterized genes were accurately delineated within our system of transcript filtration. Moreover, empirical validations confirm MPSS predictions for several genes with previously uncharacterized expression patterns.CONCLUSION:This extensive MPSS analysis confirms and supplements prior microarray floral expression studies and illustrates the utility of sequence survey-based expression analysis in functional genomics. Spatial floral expression data accrued by MPSS and similar methods will be advantageous in the elucidation of more comprehensive genetic regulatory networks governing floral development.

Une des premières caractéristiques reconnues dans les cellules cancéreuses fut l’observation d’aberrations chromosomiques au cours de la division cellulaire. Parmi ces aberrations, on retrouve l’aneuploïdie, une mutation génétique définie par un nombre de chromosomes anormal de la cellule. Première cause associée aux fausses couches et au retard mental, l’aneuploïdie participe également à la progression tumorale. Plusieurs mécanismes sont mis en place par la cellule pour parer à ces aberrations chromosomiques. Le « spindle assembly checkpoint » (SAC) fait partie de ces mécanismes qui assurent la ségrégation précise des chromosomes au cours de la mitose. La kinase à double spécificité MPS1 codée par le gène TTK est une composante critique du SAC. La régulation de l’activité et de la localisation de MPS1 reste encore incomprise dans son ensemble. La localisation de MPS1 aux kinétochores (KT, structure des centromères permettant la mise en place du SAC) nécessite une région d’environ 50 acides aminés appelée NTE (N-Terminal Extension) qui ne possède pas de domaine fonctionnel clairement défini. Des données récentes ont montré que la région N-Terminale de MPS1 est impliquée dans la régulation de son activité. L’objectif principal de ces travaux est de comprendre dans quelle mesure la région NTE participe à la régulation de l’activité kinase et à la localisation de MPS1. Mettant en place une approche basée sur l’hypothèse que la conservation de la structure à travers l’évolution peut correspondre à une fonction, nous avons mis en évidence que la région NTE de MPS1 contribue à sa localisation et son activation par 2 modules indépendants. Nous avons démontré que les résidus 19-29 sont absolument requis pour la localisation de MPS1 déterminant ainsi plus précisément une région responsable de sa localisation. Cette région est également nécessaire pour diminuer l’interaction entre MPS1 et sa protéine partenaire ARHGEF17/TEM4 qui participe à son recrutement au KT, régulant de ce fait la localisation de MPS1. Le second module concerne les résidus 40-49 et c’est en particulier la phosphorylation de cette région qui contribue à l’activation de la kinase, vraisemblablement par la relâche d’un mécanisme d’auto-inhibition de la kinase. Ce mécanisme, participant à la régulation de l’activité kinase de MPS1, semble se produire successivement avec la dimérisation, puis la phosphorylation initiale de la région NTE et est enfin suivie de la trans-autophosphorylation de la boucle d’activation du domaine kinase. L’importance de la région NTE dans l’accomplissement des fonctions de MPS1 au cours de la mitose a été démontrée ainsi que la nécessité de ces deux régions particulières de la NTE requises indépendamment pour le fonctionnement optimal et le maintien de la robustesse du SAC. Ainsi, cette thèse apporte des informations supplémentaires et indispensables à la compréhension des mécanismes régulant l’activité kinase et la localisation au kinétochore de MPS1 par l’intermédiaire de sa région NTE.
One of the first recognized characteristics in cancer cells was the observation of chromosomal aberrations during cell division. Among these aberrations, there is aneuploidy, a genetic abnormality defined by having an incorrect number of chromosomes in the cell. As the leading cause of miscarriages and mental retardation, aneuploidy also contributes to tumor progression. Several mechanisms are established by the cell to counter these chromosomal aberrations. The "spindle assembly control point" (SAC) is one of these mechanisms which ensures accurate segregation of chromosomes during mitosis. The dual specificity kinase MPS1 coded by the TTK gene is a critical component of the SAC. The regulation of the activity and the localization of MPS1 is still not wholly understood. The localization of MPS1 to the kinetochores (KT, structure of the centromeres allowing SAC organization) requires a region of approximately 50 amino acids called NTE (N-Terminal Extension) which does not exhibit a known functional domain. Recent data have demonstrated that the N-Terminal region of MPS1 is involved in the regulation of its activity. The main objective of this project is to understand to what extent the NTE region participates in the regulation of the kinase activity and the localization of MPS1. Using a structure-based approach, we have demonstrated that the NTE region of MPS1 contributes to its localization and activation by 2 independent modules. We demonstrated that residues 19-29 are absolutely required for the localization of MPS1, thus defining more accurately the region responsible for its localization. This region is also necessary to decrease the interaction between MPS1 and its partner protein ARHGEF17/TEM4, which participates in its recruitment to the KT thereby regulating the localization of MPS1. The second module concerns the residues 40-49, especially the phosphorylation of this region which contributes to the activation of the kinase, presumably by the release of a mechanism of auto-inhibition of the kinase. This mechanism, which participates in the regulation of the MPS1 kinase activity, appears to occur successively with dimerization then the initial phosphorylation of the NTE region and finally followed by trans-autophosphorylation of the activation loop of the kinase domain. The importance of the NTE region in performing the functions of MPS1 during mitosis has been demonstrated as well as the need for these two particular regions of the NTE which are independently required for optimal functioning and maintaining the robustness of the SAC. Thus, this thesis provides additional and indispensable information for understanding the mechanisms regulating the kinase activity and the kinetochore localization of MPS1 via its NTE region.

Diploma thesis is focused on the analysis of expenditure of the state budget of the Ministry of labour and social affairs in the years 2000 to 2010. This thesis explores the changing structure of those expenses and tries to answer the question whether the political cycle and the power of coalitions significant impact on spending in this chapter. It also addresses the issue of sustainability of public finances.

Tillverkande företag har under de senaste åren ställts inför en förändrad marknadssituation, vilket innebär att de fått förändra sitt arbetssätt från en produktionsorienterad syn till en kundorienterad syn. Den kundorienterade synen innebär att företag snabbt måste kunna ställa om sin produktion för att tillfredsställa kundens behov.

MPS-system (Material- och ProduktionsStyrningssystem) är mycket effektiva hjälpmedel vid snabba beslut och omplaneringar, de ger dessutom möjlighet att ge kunder direkt besked om orderstatus. MPS-system tenderar att bli stora och komplexa, de har kontaktytor mot nästan alla delar i företagen.

Många företag idag köper MPS-system. Stora företag byter gamla föråldrade system och allt fler små och medelstora företag inför MPS-system. Kommande milleniumskiftet är också en orsak till att flera företag byter sina MPS-system idag.

Med detta väcktes intresset för att undersöka om företag som investerar i dyra MPS-system verkligen får ut det de förväntar sig av dem. Det är intressant att se om den utbildning som de blivande användarna får är tillräcklig för att de ska nyttja sina MPS-system som det var tänkt.

Undersökningen visar att MPS-leverantörerna ansåg att utbildningen var tillräcklig för att företagen ska kunna nyttja sina MPS-system till den grad de önskar, men att MPS-systemen ändå inte nyttjas till den grad som är möjlig. Företagsledning och de systemansvariga på företag som köpt MPS-system tyckte att utbildningen var tillräcklig. Användarna i produktion ansåg däremot att utbildningen inte var tillräcklig, de hade önskat en mer helhetsbild över MPS-systemet. Hur utbildningen bedrevs var viktigare än antalet timmar. Allmän datorutbildning visade sig vara en viktig del för att användarna ska kunna nyttja sina MPS-systemet.

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Este trabalho apresenta uma proposta que objetiva contribuir com a compreensão do Modelo de Referência MPS para Software (MR-MPS-SW), facilitando a sua implantação, principalmente em micros, pequenas e médias empresas (mPME) produtoras de software. Outro objetivo é contribuir com a uniformização do conhecimento do MR-MPS-SW entre todos os envolvidos nos processos de implantação, consultoria e avaliação do modelo. O MR-MPS-SW possui sete níveis de maturidade, de A (maior nível) a G (menor nível). A proposta trata de uma nova forma de organizar o conhecimento do MR-MPS-SW através da definição de uma ontologia empresarial implementada em OWL para os níveis G e F. Esses níveis requerem grandes desafios na mudança da cultura organizacional, bem como no gerenciamento de projetos, garantia da qualidade e medições. Para apoiar o usuário com uniformização dos termos de Gerência de Projetos, foram associados conceitos e terminologia do PMBOK (Project Management Body of Knowledge). Indicadores do modelo BSC (Balanced Scorecard) foram integrados ao modelo MR-MPS-SW para facilitar futuras iniciativas de alinhamento com o planejamento estratégico da empresa e modelo de negócios. Para isso, este trabalho providenciou uma sistemática para avaliação de uma versão alpha da ontologia, através de técnicas usadas em testes de usabilidade na Engenharia de Software. Essa avaliação mostrou como a ontologia facilitou o entendimento de usuários com diferentes níveis de conhecimento no MR-MPS-SW. Também proporcionou recomendações para melhorias na ontologia. Uma versão beta foi disponibilizada em repositórios gratuitos para ser avaliada por mPME e pessoas interessadas no modelo MPS-SW
This work presents a proposal that aims to contribute to the understanding of MPS Reference Model for Software (MPS-SW), facilitating its deployment, especially in micro, small and medium enterprises (MSME) of software development. Another goal is to contribute to the standardization of the knowledge of the MPS-SW among stakeholders in the process of implantation, consulting and evaluation of the model. The MPS-SW has seven levels of maturity, from A (highest level) to G (lower level). This proposal is a new way of organizing knowledge of the MPS-SW through the definition of an enterprise ontology in OWL for G and F levels. These levels require great efforts in changing organizational culture, as well as project management, quality assurance and measurements. . Terminology and concepts of the PMBOK (Project Management Body of Knowledge) were associated to the ontology, in order, to support the user in terms of standardization of project management. Indicators of the BSC Model (Balanced Scorecard) were integrated into the MPS-SW model to facilitate future initiatives for alignment with the strategic planning and business model. For this purpose this work provided a systematic evaluation of an alpha release of the ontology using techniques of usability testing in Software Engineering. The evaluation showed how ontology facilitated the understanding of users with different levels of knowledge on the MRMPS-SW. It also provided the definition of recommendations for improvements in the ontology. A beta version was made available in free ontology repositories to be evaluated by MSME and people interested in the MPS-SW model

Orientador: Hilda Carvalho de Oliveira
Banca: Kechi Hirama
Banca: João Porto
Resumo: Este trabalho apresenta uma proposta que objetiva contribuir com a compreensão do Modelo de Referência MPS para Software (MR-MPS-SW), facilitando a sua implantação, principalmente em micros, pequenas e médias empresas (mPME) produtoras de software. Outro objetivo é contribuir com a uniformização do conhecimento do MR-MPS-SW entre todos os envolvidos nos processos de implantação, consultoria e avaliação do modelo. O MR-MPS-SW possui sete níveis de maturidade, de A (maior nível) a G (menor nível). A proposta trata de uma nova forma de organizar o conhecimento do MR-MPS-SW através da definição de uma ontologia empresarial implementada em OWL para os níveis G e F. Esses níveis requerem grandes desafios na mudança da cultura organizacional, bem como no gerenciamento de projetos, garantia da qualidade e medições. Para apoiar o usuário com uniformização dos termos de Gerência de Projetos, foram associados conceitos e terminologia do PMBOK (Project Management Body of Knowledge). Indicadores do modelo BSC (Balanced Scorecard) foram integrados ao modelo MR-MPS-SW para facilitar futuras iniciativas de alinhamento com o planejamento estratégico da empresa e modelo de negócios. Para isso, este trabalho providenciou uma sistemática para avaliação de uma versão alpha da ontologia, através de técnicas usadas em testes de usabilidade na Engenharia de Software. Essa avaliação mostrou como a ontologia facilitou o entendimento de usuários com diferentes níveis de conhecimento no MR-MPS-SW. Também proporcionou recomendações para melhorias na ontologia. Uma versão beta foi disponibilizada em repositórios gratuitos para ser avaliada por mPME e pessoas interessadas no modelo MPS-SW
Abstract: This work presents a proposal that aims to contribute to the understanding of MPS Reference Model for Software (MPS-SW), facilitating its deployment, especially in micro, small and medium enterprises (MSME) of software development. Another goal is to contribute to the standardization of the knowledge of the MPS-SW among stakeholders in the process of implantation, consulting and evaluation of the model. The MPS-SW has seven levels of maturity, from A (highest level) to G (lower level). This proposal is a new way of organizing knowledge of the MPS-SW through the definition of an enterprise ontology in OWL for G and F levels. These levels require great efforts in changing organizational culture, as well as project management, quality assurance and measurements. . Terminology and concepts of the PMBOK (Project Management Body of Knowledge) were associated to the ontology, in order, to support the user in terms of standardization of project management. Indicators of the BSC Model (Balanced Scorecard) were integrated into the MPS-SW model to facilitate future initiatives for alignment with the strategic planning and business model. For this purpose this work provided a systematic evaluation of an alpha release of the ontology using techniques of usability testing in Software Engineering. The evaluation showed how ontology facilitated the understanding of users with different levels of knowledge on the MRMPS-SW. It also provided the definition of recommendations for improvements in the ontology. A beta version was made available in free ontology repositories to be evaluated by MSME and people interested in the MPS-SW model
Mestre

In order to study the subcellular localization of the protein-tyrosine phosphatase MPTP, indirect immunofluorescence microscopy experiments were performed. The enzyme was thereby determined to localize almost exclusively to the nucleus. The nuclear localization signal was mapped by further immunofluorescence experiments performed with deletion mutants and $ beta$-galactosidase fusion constructs. The sequence $ rm sp{345}RKRIRED sp{351}$ was found to be capable and sufficient to localize MPTP and unrelated proteins to the nucleus, and a secondary domain was identified that is likely involved in mediating the nuclear retention of MPTP. To determine the in vivo functions of MPTP, its substrate specificity was analyzed. Dephosphorylation assays of cellular proteins identified a preferred substrate of an approximate molecular weight of 40 kiloDaltons (kDa) and an isoelectric point (pI) of 4.9. This and another substrate of approximately 43kDa and a pI of 4.8 were identified in a trapping assay using a catalytically inert mutant of MPTP as an affinity reagent, and could be isolated from two independent cell lines. Taken together, these data provide significant advances towards the identification of the signal transduction pathways in which MPTP is involved.

Our search for protein tyrosine phosphatases (PTPases) that are involved in murine development led to the isolation of a novel PTPase called MPTP-PEST. To elucidate the function of MPTP-PEST, several biological aspects of the protein were investigated. It was determined that the MPTP-PEST enzyme is a stable cytosolic protein tyrosine phosphatase of 112 kDa that is ubiquitously expressed both in the adult and in the embryo. MPTP-PEST is composed of a single amino-terminus catalytic domain which is active against phosphorylated substrates in vitro. The gene structure and chromosomal localization of MPTP-PEST were determined using a series of $ lambda$ phage clones isolated from a mouse genomic library. Analysis of the MPTP-PEST locus indicated that the gene spans over 90 kb of the mouse genome and is composed of 18 exons, 10 of which constitute the catalytic phosphatase domain. Fluorescence in situ hybridization with MPTP-PEST genomic DNA defines the map position of MPTP-PEST to mouse chromosome 5 region A3-B. To gain mechanistic insights into the function of MPTP-PEST, the association of proteins with MPTP-PEST was investigated using several different in vitro and in vivo binding assays. It was shown that the proto-oncoprotein SHC and the adaptor protein Grb2 associate with MPTP-PEST through specific carboxy-terminus sequences. In addition, the SHC/MPTP-PEST association was shown to be mediated by a novel type of protein-protein interaction. Both SHC and Grb2 function downstream of receptor type and cyloplasmic protein tyrosine kinases and have been shown to mediate several signal transduction events. The association of MPTP-PEST with these signaling proteins may therefore represent a function for MPTP-PEST in signaling events.

Tableau d'honneur de la Faculté des études supérieures et postdorales, 2014-2015
Les études chez l’humain et les modèles animaux ont montré que les œstrogènes exercent des effets bénéfiques importants sur le risque de développer la maladie de Parkinson. Bien que les œstrogènes soient neuroprotecteurs, leurs actions périphériques limitent actuellement leur utilisation pour le traitement ou la prévention de maladies neurodégénératives, d’où l’importance de trouver des stratégies alternatives qui reproduisent les effets favorables des œstrogènes mais minimisent les effets indésirables. Lors de cette thèse, nous avons montré que l’activation du récepteur membranaire des œstrogènes couplé aux protéines G (GPER1), un récepteur non-féminisant, est aussi puissante que le 17β-estradiol à protéger les neurones dopaminergiques de la toxicité du MPTP chez des souris mâles, un modèle de la maladie de Parkinson. La neuroprotection par le 17β-estradiol est perdue lorsque le GPER1 ou les récepteurs des œstrogènes (ER) α/β sont bloqués, montrant que les ERα/β et le GPER1 sont requis dans la protection des neurones dopaminergiques par le 17β-estradiol. Ces résultats suggèrent une potentielle interaction entre les ERα/β et le GPER1. Utilisant une approche pharmacologique, nos résultats montrent que le ERα interagit avec le GPER1 pour augmenter la signalisation d’Akt ainsi que les niveaux de Bcl-2 et du BDNF, et protéger les neurones dopaminergiques de l’effet toxique du MPTP. L’effet neuroprotecteur du GPER1 se fait indépendamment des ERα/β, quoique le GPER1 requière la collaboration des ERα/β pour augmenter les niveaux du BDNF. L’investigation du mécanisme d’action du raloxifène, un modulateur sélectif des récepteurs des œstrogènes utilisé en clinique, a révélé que le raloxifène agit par le GPER1 pour activer Akt, augmenter les niveaux de Bcl-2 et du BDNF, et protéger les neurones dopaminergiques et les niveaux plasmatiques d’androgènes. La progestérone, un stéroïde non-féminisant, possède également des propriétés neuroprotectrices chez les souris MPTP. De plus, nos résultats montrent que la progestérone, lorsqu’administrée après le MPTP, permet la récupération partielle des neurones dopaminergiques. Lors de cette thèse, nous avons montré l’effet neuroprotecteur de plusieurs composés qui pourraient servir de stratégies alternatives à l’utilisation des œstrogènes. L’investigation des récepteurs oestrogéniques impliqués dans la neuroprotection fournissent d’importantes informations pour le développement de nouvelles thérapies.
Studies in humans and animal models have shown that estrogens exert significant beneficial effects on the risk to develop Parkinson's disease. Although estrogens are neuroprotective, their peripheral actions currently limit their use for the treatment or prevention of neurodegenerative diseases, hence the importance of finding alternative strategies that mimic the beneficial effects of estrogen but minimize adverse effects. In this thesis, we have shown that activation of the membrane G protein-coupled estrogen receptor (GPER1), a non-feminizing receptor, is as potent as 17β-estradiol to protect dopaminergic neurons against MPTP toxicity in male mice, a model of Parkinson's disease. Neuroprotection by 17β-estradiol is lost when the GPER1 or estrogen receptors (ER) α/β are blocked, indicating that both ERα/β and GPER1 are required for the protection of dopaminergic neurons by 17β-estradiol. These results suggest a potential interaction between ERα/β and GPER1. Using a pharmacological approach, our results show that ERα interacts with GPER1 to increase Akt signaling, as well as the levels of Bcl-2 and BDNF, and protect dopaminergic neurons from the toxic effect of MPTP. However, the neuroprotective effect of GPER1 is independent of ERα/β, while GPER1 requires collaboration with ERα/β to increase BDNF levels. Investigation of the mechanism of action of raloxifene, a selective estrogen receptor modulator used in the clinic, has revealed that raloxifene acts through GPER1 to activate Akt, increasing the levels of Bcl-2 and BDNF, and protects dopaminergic neurons and plasma androgen levels. Progesterone, a non-feminizing steroid, has neuroprotective properties in MPTP mice. In addition, our results show that progesterone, when administered after MPTP, has rescued effects on dopaminergic neurons. In this thesis, we have shown the neuroprotective capacity of several compounds that could serve as alternative strategies to the use of estrogen. Investigation of estrogen receptors involved in neuroprotection provides important information for the development of new therapies.

Vilka funktionskrav ställs på MPS-system för plastindustrin? Vad är det för faktorer som medför att existerande standardiserade MPS-system inte kan användas inom processindustrin? Det är dessa frågeställningar ligger till grund för denna rapport.

Rapporten inleds med en genomgång av hur kravspecifikationer bör utformas, vad material- och produktionsstyrning innebär samt en introduktion till process- och plastindustrin. I de fallstudier som presenteras diskuteras processen från order till leverans med avseende på material- och produktionsstyrning.

De funktionskrav, som identifieras som viktigast för ett MPS-system för plast-industrin, kan innefattas i följande punkter:

· Prognoshantering som kan omvandla försäljningsprognos till leveransplan.

· Verktygshantering som klarar en koppling mellan produkt och verktyg.

· Materialbehovsberäkning som kan hantera ingöt kontra produkt.

· Spårning vid felsökning.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Atualmente, devido ao grande avanço tecnológico o uso dos métodos de partículas vêm ganhando espaço nas simulações de escoamento de fluido. O primeiro método de partículas a ser desenvolvido foi o Smoothed Particle Hydrodynamics (SPH) que se mostrou bastante eficiente para problemas de escoamento compressível, mas ineficiente para escoamento incompressível. Desta forma, surgiu algumas estratégias para resolver problemas de escoamento incompressível como o Incompressible Smoothed Particle Hydrodynamics (ISPH) e o Moving Particle Semi-Implicit (MPS); em ambos os métodos a pressão é atualizada por um equação de Poisson. Portanto para obter uma boa aproximação das equações de Navier-Stokes é necessário antes ter uma boa aproximação da equação de Poisson. Neste trabalho são abordados os métodos de partículas Smoothed Particle Hydrodynamics (SPH) e Moving Particle Semi-Implicit (MPS). A discretização dos operadores diferenciais por esses métodos é feita por meio da aproximação do núcleo e também por partículas. Um estudo comparativo entre discretização foram efetuadas. Afim de saber se os parâmetros utilizados na literatura dos métodos de partículas SPH e MPS dão uma boa solução para equação de Poisson foram realizados vários testes variando os parâmetros com e sem o tratamento de fronteira. Neste trabalho também foi proposta uma estratégia para resolver o problema de oscilação na solução da equação de advecção com descontinuidade nas condições iniciais e os resultados foram bem satisfatório
Currently, due to the technological advances the use of particle methods is gaining ground in the simulations of fluid flow. The first particle method to be developed was the Smoothed Particle Hydrodynamics (SPH) that was very efficient for compressible flow problems, but inefficient for incompressible ones. Thus, there was some strategy to solve incompressible flow problems as the incompressible Smoothed Particle Hydrodynamics (ISPH) and the Moving Particle Semi-Implicit (MPS); in both methods the pressure is updated by a Poisson equation. For an approximation of the Navier-Stokes equations it is first needed a good approximation for the Poisson equation. This paper discusses the following particles methods: Smoothed Particle Hydrodynamics (SPH) and Moving Particle Semi-Implicit (MPS). The discretization of differential operators by these methods is done through the approximation of the kernel and also by particles. A comparative study of different discretizations were made. In order to know if the parameters used in the literature for the SPH and MPS methods provide a good solution for Poisson equation, have been performed several tests by varying the parameters with and without the borders treatment. This work also proposed a strategy to solve the oscillation problem in advection equation with discontinuity in the initial conditions and the results were very satisfactory

Orientador: Messias Meneguette Junior
Banca: Gilcilene Sanchez de Paulo
Banca: Afonso Paiva Neto
Resumo: Atualmente, devido ao grande avanço tecnológico o uso dos métodos de partículas vêm ganhando espaço nas simulações de escoamento de fluido. O primeiro método de partículas a ser desenvolvido foi o Smoothed Particle Hydrodynamics (SPH) que se mostrou bastante eficiente para problemas de escoamento compressível, mas ineficiente para escoamento incompressível. Desta forma, surgiu algumas estratégias para resolver problemas de escoamento incompressível como o Incompressible Smoothed Particle Hydrodynamics (ISPH) e o Moving Particle Semi-Implicit (MPS); em ambos os métodos a pressão é atualizada por um equação de Poisson. Portanto para obter uma boa aproximação das equações de Navier-Stokes é necessário antes ter uma boa aproximação da equação de Poisson. Neste trabalho são abordados os métodos de partículas Smoothed Particle Hydrodynamics (SPH) e Moving Particle Semi-Implicit (MPS). A discretização dos operadores diferenciais por esses métodos é feita por meio da aproximação do núcleo e também por partículas. Um estudo comparativo entre discretização foram efetuadas. Afim de saber se os parâmetros utilizados na literatura dos métodos de partículas SPH e MPS dão uma boa solução para equação de Poisson foram realizados vários testes variando os parâmetros com e sem o tratamento de fronteira. Neste trabalho também foi proposta uma estratégia para resolver o problema de oscilação na solução da equação de advecção com descontinuidade nas condições iniciais e os resultados foram bem satisfatório
Abstract: Currently, due to the technological advances the use of particle methods is gaining ground in the simulations of fluid flow. The first particle method to be developed was the Smoothed Particle Hydrodynamics (SPH) that was very efficient for compressible flow problems, but inefficient for incompressible ones. Thus, there was some strategy to solve incompressible flow problems as the incompressible Smoothed Particle Hydrodynamics (ISPH) and the Moving Particle Semi-Implicit (MPS); in both methods the pressure is updated by a Poisson equation. For an approximation of the Navier-Stokes equations it is first needed a good approximation for the Poisson equation. This paper discusses the following particles methods: Smoothed Particle Hydrodynamics (SPH) and Moving Particle Semi-Implicit (MPS). The discretization of differential operators by these methods is done through the approximation of the kernel and also by particles. A comparative study of different discretizations were made. In order to know if the parameters used in the literature for the SPH and MPS methods provide a good solution for Poisson equation, have been performed several tests by varying the parameters with and without the borders treatment. This work also proposed a strategy to solve the oscillation problem in advection equation with discontinuity in the initial conditions and the results were very satisfactory
Mestre

A doença de Parkinson (DP) é uma doença neurodegenerativa caracterizada pela progressiva depleção dos neurônios dopaminérgicos da substância negra (pars compacta). A DP não ocasiona apenas uma desordem motora, mas também pode provocar uma disautonomia cardiovascular. A DP com sintomas similares aos que ocorrem em humanos pode ser experimentalmente induzida em ratos e camundongos com a administração das neurotoxinas 1-metil-1-4-fenil-1,2,3,6-tetrahidropirimidina (MPTP), 6-hidroxidopamina (6-OHDA) e rotenona. Mais, na década de 90, camundongos transgênicos que expressam altos níveis de alfa-sinucleína mutante humana têm sido produzidos e utilizados para investigar a possível relação entre a agregação da proteína alfa-sinucleína e a DP, uma vez que em humanos, a alta expressão dessa proteína está relacionada ao desenvolvimento do parkinsonismo associado à desnervação cardíaca simpática. No entanto, a desnervação cardíaca e suas conseqüências no miocárdio na DP não estão claramente caracterizadas, pois na literatura os métodos quantitativos empregados para tal finalidade têm sua confiabilidade e acurácia questionáveis. Desta forma, avaliou-se, no modelo de indução neurotóxico (MPTP), o miocárdio de camundongos C57/BL aplicando-se métodos morfoquantitativos tridimensionais (estereológicos). Neste trabalho, observamos que o volume da parede ventricular, o volume e a densidade de volume do interstício cardíaco foram, respectivamente, 0,8%, 5,3% e 2,4% maior no grupo MPTP. O volume do lúmen ventricular, o volume ventricular, o volume das fibras musculares cardíacas e a sua densidade de volume foram, respectivamente, 11,7%, 0,9%, 2,3% e 1,7% maior no grupo controle. O número total de núcleos de cardiomiócitos foi 14,8% menor no grupo MPTP bem como o número total de cardiomiócitos que foi 19% menor também neste grupo. Houve diferença estatística significativa entre os grupos para o parâmetro número de cardiomiócitos. Não houve, porém, diferença estatística significativa para os outros parâmetros avaliados.
Parkinson´s disease (PD) is a neurodegenerative disorder mostly characterised by a profound reduction of dopamine in the striatum due to a dramatic loss of dopaminergic neurons in the substantia nigra (pars compacta). The disease is not only characterised by a motor disorder but also present cardiovascular dysautonomia. The disease has been chemically induced in rats and mice using neurotoxins such as 1-metyl-1-4-phenyl-1,2,3,6-tetrahydropyrimidina (MPTP), 6-OHDA and rotenone. In the nineties, transgenic α-synuclein mice have recently been used as a model of PD and alpha-synuclein aggregation, because the overexpression of this protein is related to the development of parkinsonism associated to the sympathetic cardiac denervation. Although, the cardiac denervation in PD and its consequences in myocardium is not well defined because the literature reports no reliable quantitative methods. Therefore, the myocardium of the C57/BL mice was investigated in the neurotoxin animal model (MPTP) applying tridimensional morphoquantitative methods (stereological). In this study, we observed an increase of 0,8%, 5,3% and 2,4% in ventricular wall volume, in cardiac interstitial volume and in cardiac interstitial volume density, respectively, in the MPTP group. The lumen ventricular volume, the ventricular volume, the cardiac muscle fibre and their volume density were, respectively, 11,7%, 0,9% , 2,3% and 1,7% larger in control group. The total number of cardiomyocyte nuclei was 14,8% lower in MPTP group as well as the total number of cardiomyocyte that was 19% lower for this group too. Significant difference was observed between the groups to the total number of cardiomyocyte. No significant difference, however, was detected for the others estimated parameters.

Parkinson's disease (PD) is a neurodegenerative Lewy body disorder characterized by severe motor deficits, followed by cognitive dysfunction with progression of the disease. Environmental exposure has been suggested as a possible contributor to the development of PD and this view is linked to the discovery of the nigrostriatal neurotoxin MPTP. MPTP can induce dopamine specific degeneration within the basal ganglia often resulting in motor deficits similar to PD. MPTP used in the C57BL/6 mouse is a widely used animal model of PD. The pyrethroid permethrin (PM), and the organophosphate chlorpyrifos (CPF), can produce changes in dopaminergic nigrostriatal neurons, the primary target of PD and MPTP-induced neurotoxicity. Such insecticide induced changes in the basal ganglia could exacerbate the onset or severity of PD. Chronic exposure to the metal manganese (Mn) can damage the globus pallidus (GP) of the BG, and produce motor deficits similar to PD. Since the GP is part of the BG circuitry essential for motor control, and is synaptically integrated with the nigrostriatal pathway, Mn may exacerbate MPTP-induced neurotoxicity. Because the BG is disynaptically linked to the mesocortical pathway, a dopaminergic pathway that is important for cognition, Mn induced damage in the BG could indirectly affect the mesocortical pathway as well. This study investigated the pesticides, permethrin and chlorpyrifos, and the heavy metal, manganese as possible environmental compounds that could exacerbate PD in the MPTP treated C57BL/6 mouse. The first part of this dissertation used immunohistochemistry to examine insecticide induced effets on MPTP-induced neurotoxicity in the dorsolateral striatum of the C57BL/6 mouse, the principal target of the nigrostriatal pathway. Tyrosine hydroxylase (TH) was used as a marker for loss of dopaminergic neuropil and glial fibrillary acidic protein (GFAP) was used as a marker of glial activation in the striatum. Three experiments assessed effects of 1) PM (200 mg/kg), 2) CPF (50 mg/kg) & 3) PM + CPF, on MPTP (30 mg/kg) neurotoxicity. Immunohistochemistry revealed a decrease in TH staining and an increase in GFAP staining with MPTP (30 mg/kg). A main effect increase in GFAP was observed for PM (200 mg/kg), but not for CPF (50 mg/kg) or PM+CPF. Insecticides, alone or combined, did not alter MPTP-induced toxicity. . However, the absence of the PM-induced increase in GFAP staining following combined insecticide treatment suggests a neuroprotective effect. The next set of experiments in this dissertation looked at the effect of Mn on MPTP-induced neurotoxicity in the nigrostriatal and mesocortical dopaminergic pathways of the C57BL/6 mouse. Inductively Coupled Plasma atomic emission spectrometry revealed striatal Mn levels were significantly increased with multiple dose 100, 50, and 25 mg/kg MnCl2. Administration of Mn (MnCl2 s.c., Days 1, 4, & 7) in the MPTP (20 mg/kg i.p., Day 8) treated C57BL/6 mouse revealed Mn and MPTP interactions for locomotor activity, grip strength, and repeated measures of learning. Mn attenuated the effect of MPTP on striatal DOPAC, and facilitated the effect of MPTP on cortical DA and DOPAC. Mn also attenuated the MPTP induced decrease in cortical DAT. While these data support the notion that insecticides can produce tissue damage in the nigrostriatal pathway, in this case, these insecticide induced changes were not found to be strong enough to facilitate PD-like tissue damage. While Mn did not always facilitate MPTP neurotoxicity in the mesocortical and nigrostriatal dopaminergic pathways, these results demonstrate Mn and MPTP can interact in a complex way to alter dopaminergic function as well as motor and cognitive behavior. Differences in brain uptake mechanisms and metabolism of Mn and MPTP, could explain why combined administration of Mn and MPTP differentially affect dopaminergic activity in the nigrostriatal and mesocortical pathways.
Ph. D.

Mps1 est une protéine kinase conservée qui, pendant la mitose, corrige les attachements inappropriés entre kinétochores et microtubules, assurant ainsi la bi-orientation des chromosomes. Cependant, ses cibles critiques dans ce processus restent largement inconnues. Mps1 contrôle également le « spindle assembly checkpoint » (SAC), qui arrête la ségrégation des chromosomes en métaphase jusqu'à ce que la bi-orientation soit atteinte. Son rôle dans l'activation du SAC est antagonisé par la phosphatase PP1 et implique la phosphorylation de la protéine d’échafaudage au kinétochore KNL1/Spc105, qui à son tour recrute la kinase Bub1 pour favoriser l'assemblage des complexes effecteurs du SAC. Une question cruciale est si la correction des erreurs et l'activation du SAC font partie d'une seule et même voie ou des voies séparables.Au cours de ma thèse, j'ai caractérisé un nouveau mutant thermosensible, mps1-3, qui est défectueux dans la bi-orientation des chromosomes et la signalisation du SAC. La mutation mps1-3 change une sérine conservée dans le domaine kinase en phénylalanine et, de façon surprenante, la protéine Mps1-3 a une activité catalytique accrue par rapport à la protéine sauvage. Inversement, la protéine ne se localise pas aux kinétochores, ce qui suggère que les défauts mitotiques du mutant mps1-3 proviennent du manque de phosphorylation des cibles critiques aux kinétochores.Grâce à un crible génétique, j'ai identifié des mutations qui supprimaient la thermosensibilité du mutant mps1-3 en affectant l'interaction entre la protéine du kinétochore Spc105/KNL1 et la phosphatase PP1, et j’ai démontré que des niveaux réduits de PP1 aux kinétochores sous-tendent la suppression. Remarquablement, les suppresseurs restauraient à la fois la signalisation du SAC et la bi-orientation des chromosomes, ce qui suggère que Mps1 contrôle les deux processus par le même mécanisme moléculaire. Nous avons proposé que la phosphorylation de Spc105/KNL1, qui conduit au recrutement de Bub1 aux kinétochores et est antagonisée par la phosphatase PP1, est une fonction cruciale de Mps1 dans la correction des liaisons inappropriées kinétochores-microtubules comme pour l'activation du SAC. De façon cohérente, la phosphorylation de Spc105 et la localisation de Bub1au kinétochore étaient affectées dans les cellules mps1-3 et restaurées dans les suppresseurs susmentionnés. De plus, le recrutement artificiel de Bub1 à Spc105 supprimait les défauts de ségrégation des cellules mutantes mps1-3. Ainsi, une conclusion principale de mon travail de thèse est que le SAC et la correction d'erreurs sont déclenchés par un seul dispositif sensoriel impliquant Mps1 et antagonisé par PP1.Grâce au même crible génétique ci-dessus, j'ai également trouvé des suppresseurs portant des mutations dans la protéine F-box Grr1, qui fait partie du complexe ubiquitine-ligase SCF. Mes données préliminaires indiquent que Grr1 se localise aux kinétochores, suggérant que le complexe SCFGrr1 pourrait être un nouvel acteur dans le contrôle de la bi-orientation des chromosomes. Enfin, j'ai pu isoler des suppresseurs intragéniques, qui portent une seconde mutation dans MPS1 et restaurent les fonctions mitotiques de la protéine Mps1-3. Les données recueillies jusqu'à présent indiquent que cette classe de mutations, contrairement aux suppresseurs extragéniques ci-dessus, rétablit la localisation de Mps1 au kinétochore. Étant donné que Mps1 régule son propre turnover aux kinétochores par autophosphorylation, nous avions émis l’hypothèse que les suppresseurs puissent rétablir la localisation de Mps1-3 au kinétochore en diminuant son activité catalytique. Étonnamment, bien que la plupart des mutations suppressives réduisaient la capacité de Mps1-3 à phosphoryler une cible exogène, elles n'affectaient pas de façon significative l'autophosphorylation, ce qui suggère que la phosphorylation dépendante de Mps1 d'une protéine non identifiée au kinétochore pourrait influencer le turnover de Mps1
Mps1 is a conserved protein kinase that during mitosis corrects improper kinetochore–microtubule attachments, thereby ensuring chromosome biorientation and balanced chromosome segregation. Yet, its critical phosphorylation targets in this process remain largely elusive. Mps1 also controls the spindle assembly checkpoint (SAC), which halts chromosome segregation in metaphase until biorientation is attained. Its role in SAC activation is antagonised by the PP1 phosphatase and involves phosphorylation of the kinetochore scaffold Knl1/Spc105, which in turn recruits the Bub1 kinase to promote assembly of SAC effector complexes. A crucial question is whether error correction and SAC activation are part of a single or separable pathways.During my PhD thesis, I characterized a novel temperature sensitive mutant, mps1-3, that is defective in chromosome biorientation and SAC signaling. The mps1-3 mutation changes a conserved serine in the kinase domain to phenylalanine, and, surprisingly, the Mps1-3 protein has enhanced catalytic activity compared to the wild type protein. Conversely, the protein does not localize at kinetochores, suggesting that the mps1-3 mitotic defects stem from the lack of phosphorylation of critical kinetochore substrates.Through an unbiased screen for spontaneous suppressors of the temperature-sensitivity of the mps1-3 mutant, I found suppressing mutations that affected the interaction between the kinetochore protein Spc105/KNL1 and the phosphatase PP1, suggesting that reduced levels of PP1 at kinetochores underlie the suppression of the temperature-sensitivity of mps1-3 cells. Importantly, the suppressors restored both SAC signaling and proper chromosome bi-orientation, suggesting that the same molecular mechanism underlies the role of Mps1 in both processes. We have proposed that phosphorylation of Spc105/KNL1, which leads to Bub1 kinetochore recruitment and is antagonized by the phosphatase PP1, is a crucial function of Mps1 in the correction of improper kinetochore-microtubule attachments as it is for SAC activation. Consistently, Spc105 phosphorylation and Bub1 kinetochore localization were affected in mps1-3 cells and restored in the aforementioned suppressors. Moreover, artificial recruitment of Bub1 to Spc105 suppressed the chromosome segregation defects of mps1-3 mutant cells.Thus, a main conclusion of my thesis work is that SAC and error correction are triggered by a single sensory device involving Mps1 and antagonized by PP1.Through the same genetic screen, I also found suppressors carrying mutations in the F-box protein Grr1 that is part of the SCF ubiquitin-ligase complex. My preliminary data indicate that Grr1 might localize at kinetochores, suggesting that the SCFGrr1 complex could be a novel player in the control of chromosome bi-orientation at kinetochores. Finally, I could isolate intragenic suppressors, carrying a second mutation in MPS1 that restored the mitotic functions of the Mps1-3 protein. The data gathered so far indicate that this class of suppressing mutations, unlike the extragenic suppressors above, re-establish Mps1 kinetochore localization. Since Mps1 regulates its own turnover at kinetochores by autophosphorylation, we postulated that the elevated kinase activity of the Mps1-3 mutant protein might be responsible for its displacement from kinetochores and the suppressors might re-establish kinetochore localization of Mps1-3 by decreasing its kinase activity. Surprisingly, although most of the suppressing mutations reduced the ability of Mps1-3 to phosphorylate an exogenous substrate, they did not significantly affect autophosphorylation, suggesting that Mps1-dependent phosphorylation of an unidentified kinetochore protein could influence Mps1 residence time

In this work the structure of the electrochemical metal-liquid interface is determined through use of quantum mechanics, molecular simulation, and experiment. Herein are profiled the molecular dynamics details and results of solid-liquid interfaces at flat non-specific solid surfaces and copper metal electrodes. Ab initio quantum-mechanical calculations are reported and define the interatomic potentials in the simulations. Some of the quantum-mechanical calculations involve small copper clusters interacting with 3-mercaptopropanesulfonic acid (MPSA), sodium, chloride, bisulfate and cuprous ions. In connection with these I develop the electrode charge dynamics (ECD) routine to treat the charge mobility in a metal. ECD bridges the gap between small-scale metal-cluster ab initio calculations and large-scale simulations of metal surfaces of arbitrary geometry. As water is the most abundant surface species in aqueous systems, water determines much of the interfacial dynamics. In contrast to prior simulation work, simulations in this work show the presence of a dense 2D ice-like rhombus structure of water on the surface that is relatively impervious to perturbation by typical electrode charges. I also find that chloride ions are adsorbed at both positive and negative electrode potentials, in agreement with experimental findings. Including internal modes of vibration in the water model enhances the ion contact adsorption at the solid surface. In superconformal filling of copper chip interconnects, organic additives are used to bottom-up fill high-aspect ratio trenches or vias. I use molecular dynamics and rotating-disk-electrode experiments to provide insight into the function of MPSA, one such additive. It is concluded that the thiol head group of MPSA inhibits copper deposition by preferentially occupying the active surface sites. The sulfonate head group participates in binding the copper ions and facilitating their transfer to the surface. Chloride ions reduce the work function of the copper electrode, reduce the binding energy of MPSA to the copper surface, and attenuate the binding of copper ions to the sulfonate head group of MPSA.