<p>Cellular biophysics deals with, among other things, transport processes within cells. This thesis presents two studies where mathematical models have been used to explain how two of these processes occur.</p><p>Cellular membranes separate cells from their exterior environment and also divide a cell into several subcellular regions. Since the 1970s lateral diffusion in these membranes has been studied, one the most important experimental techniques in these studies is <i>fluorescence recovery after</i> <i>photobleach</i> (FRAP). A mathematical model developed in this thesis describes how dopamine 1 receptors (D1R) diffuse in a neuronal dendritic membrane. Analytical and numerical methods have been used to solve the partial differential equations that are expressed in the model. The choice of method depends mostly on the complexity of the geometry in the model.</p><p>Calcium ions (Ca²⁺) are known to be involved in several intracellular signaling mechanisms. One interesting concept within this field is a signaling microdomain where the inositol 1,4,5-triphosphate receptor (IP₃R) in the endoplasmic reticulum (ER) membrane physically interacts with plasma membrane proteins. This microdomain has been shown to cause the intracellular Ca²⁺ level to oscillate. The second model in this thesis describes a signaling network involving both ER membrane bound and plasma membrane Ca²⁺ channels and pumps, among them store-operated Ca²⁺ (SOC) channels. A MATLAB^® toolbox was developed to implement the signaling networks and simulate its properties. This model was also implemented using<i> Virtual cell.</i></p><p>The results show a high resemblance between the mathematical model and FRAP data in the D1R study. The model shows a distinct difference in recovery characteristics of simulated FRAP experiments on whole dendrites and dendritic spines, due to differences in geometry. The model can also explain trapping of D1R in dendritic spines.</p><p>The results of the Ca²⁺ signaling model show that stimulation of IP3R can cause Ca²⁺ oscillations in the same frequency range as has been seen in experiments. The removing of SOC channels from the model can alter the characteristics as well as qualitative appearance of Ca²⁺ oscillations.</p> / <p>Cellulär biofysik behandlar bland annat transportprocesser i celler. I denna avhandling presenteras två studier där matematiska modeller har använts för att förklara hur två av dess processer uppkommer.</p><p>Cellmembran separerar celler från deras yttre miljö och delar även upp en cell i flera subcellulära regioner. Sedan 1970-talet har lateral diffusion i dessa membran studerats, en av de viktigaste experimentella metoderna i dessa studier är fluorescence recovery after photobleach (FRAP). En matematisk modell utvecklad i denna avhandling beskriver hur dopamin 1-receptorer (D1R) diffunderar i en neural dendrits membran. Analytiska och numeriska metoder har använts för att lösa de partiella differentialekvationer som uttrycks i modellen. Valet av metod beror främst på komplexiteten hos geometrin i modellen.</p><p>Kalciumjoner (Ca2+) är kända för att ingå i flera intracellulära signalmekanismer. Ett intressant koncept inom detta fält är en signalerande mikrodomän där inositol 1,4,5-trifosfatreceptorn (IP3R) i endoplasmatiska nätverksmembranet (ER-membranet) fysiskt interagerar med proteiner i plasmamembranet. Denna mikrodomän har visats vara orsak till oscillationer i den intracellulära Ca2+-nivån. Den andra modellen i denna avhandling beskriver ett signalerande nätverk där både Ca2+-kanaler och pumpar bundna i ER-membranet och i plasmamembranet, däribland store-operated Ca2+(SOC)-kanaler, ingår. Ett MATLAB®-verktyg utvecklades för att implementera signalnätverket och simulera dess egenskaper. Denna modell implementerades även i Virtual cell.</p><p>Resultaten visar en stark likhet mellan den matematiska modellen och FRAP-datat i D1R-studien. Modellen visar en distinkt skillnad i återhämtningsegenskaper hos simulerade FRAP-experiment på hela dendriter och dendritiska spines, beroende på skillnader i geometri. Modellen kan även förklara infångning av D1R i dendritiska spines.</p><p>Resultaten från Ca2+-signaleringmodellen visar att stimulering av IP3R kan orsaka Ca2+-oscillationer inom samma frekvensområde som tidigare setts i experiment. Att ta bort SOC-kanaler från modellen kan ändra karaktär hos, såväl som den kvalitativa uppkomsten av Ca2+-oscillationer.</p>

Molecular dynamics simulations were performed on the influenza A non-structural protein 1 (NS1) RNA binding domain (RBD), a homodimer. Fourteen simulations were performed at 298K, nine ionized with 0.1M KCl and five with no ions. Several analysis techniques were employed to study RBD residue flexibility. The focus of the study was the RNA binding cavity formed by side chains of helix 2 (chain A) and helix 2’ (chain B) and cavity intermonomeric salt bridges. Opening of the salt bridges D29–R46’ and D29’–R46 was observed in several of the trajectories. The RNA binding cavity has large flexibility, where the dimension and shape change during the dynamics. One pair of residues surrounding the cavity and necessary for RNA binding, residues R38 and R38’, have motions during the simulations which cover the top of the cavity. There is correlation between the salt bridge breaking, flexibility of R38 and R38’, and the cavity size and shape changes. Possible RBD small molecule drug targets are these two salt bridges and the pair R38 and R38’. Disrupting the events that occur around these areas could possibly inactivate RNA binding function of the domain. These results could have implications in searching for potential molecules that effectively treat influenza A.

In this thesis, computer simulations are used to study the properties of new colloidal systems with structured interactions. These are pair interactions that include both attraction and repulsion. Structured colloids differ from conventional colloids in which the interactions between particles are either strictly attractive or strictly repulsive. It is anticipated that these novel interactions will give rise to new microscopic structure and dynamics and therefore new material properties. Three classes of structured interactions are considered: radially structured interactions with an energetic barrier to pair association, Janus surface patterns with two hemispheres of different surface charge, and striped surface patterns. New models are developed to capture the structured interactions of these novel colloid systems. Dynamical computer simulations of these models are performed to quantify the effects of structured interactions on colloid properties. The results show that structured interactions can lead to unexpected particle ordering and novel dynamics. For Janus and striped particles, the particle order can be captured with simpler isotropic coarse-grained models. This relates the static properties of these new colloids to conventional isotropically attractive colloids (e.g. depletion attracting colloids). In contrast, Janus and striped particles are found to have substantially slower dynamics than isotropically attractive colloids. This is explained by the observation of longer-duration reversible bonds between pairs of structured particles. Dynamical mapping methods are explored to relates the dynamics of these structured colloids to isotropically attractive colloids. These methods could also facilitate future nonequilibrium simulation of structured colloids with computationally efficient coarse-grained models.

Skyline analysis is important for multi-criteria decision making applications. The data in some of these applications are inherently uncertain due to various factors. Although a considerable amount of research has been dedicated separately to efficient skyline computation, as well as modeling uncertain data and answering some types of queries on uncertain data, how to conduct skyline analysis on uncertain data remains an open problem at large. In this thesis, we tackle the problem of skyline analysis on uncertain data. We propose a novel probabilistic skyline model where an uncertain object may take a probability to be in the skyline, and a p-skyline contains all the objects whose skyline probabilities are at least p. Computing probabilistic skylines on large uncertain data sets is challenging. An uncertain object is conceptually described by a probability density function (PDF) in the continuous case, or in the discrete case a set of instances (points) such that each instance has a probability to appear. We develop two efficient algorithms, the bottom-up and top-down algorithms, of computing p-skyline of a set of uncertain objects in the discrete case. We also discuss that our techniques can be applied to the continuous case as well. The bottom-up algorithm computes the skyline probabilities of some selected instances of uncertain objects, and uses those instances to prune other instances and uncertain objects effectively. The top-down algorithm recursively partitions the instances of uncertain objects into subsets, and prunes subsets and objects aggressively. Our experimental results on both the real NBA player data set and the benchmark synthetic data sets show that probabilistic skylines are interesting and useful, and our two algorithms are efficient on large data sets, and complementary to each other in performance.

In regions with hot and humid tropical climate, as Maceió-AL, the use of daylight, natural ventilation and shading should be thought from the initial stages of the project. To enhance shading, architectural elements as brises-soleil, perforated blocks and balconies are essential to buildings. In the case of balconies, today we see the use of random on environmental issues. As a consequence, and solution for the discomfort caused by the absence of appropriate elements of weather, the use of artificial means to ensure the thermal and visual comfort is intensified contributing to wasted energy. Given this context, this study aims evaluat the use of balconies in vertical multifamily residential apartments buildings located in Ponta Verde, Maceió-AL, as shading and daylighting. To achieve this, the methodology was a comparative analysis of recurring types of balconies on the shading and daylight devices, through the techniques of data collection, generation of shadow masks and simulations in the program Sketchup and Tropilux. The analysis of results provided an understanding of the behavior of shading and daylighting in the typologies examined and also the comparison between the simulation results of heatstroke and the results of simulation of daylighting. Since opting for a better strategy of shading, using the balconies, it is not always achieved a good result in the performance of daylight indoors. Finally, the use of balconies in residential buildings of Maceió, that can be worked to achieve better results in environmental comfort and to enrich the formal aspect of the buildings, should be considered at an early stage of the architectural design / Fundação de Amparo a Pesquisa do Estado de Alagoas / Nas regiões de clima tropical quente e úmido, como é o caso de Maceió-AL, o aproveitamento das fontes de iluminação e ventilação naturais e o uso do sombreamento devem ser pensados desde as etapas iniciais do projeto. Para favorecer o sombreamento, elementos como brises, cobogós e varandas são indispensáveis às edificações. No caso das varandas, atualmente, percebe-se a sua utilização de forma aleatória quanto às questões ambientais. Como consequência disso e para sanar o desconforto gerado pela ausência de elementos adequados ao clima, intensifica-se o uso de meios artificiais para garantir o conforto nos ambientes, contribuindo para o desperdício de energia. Diante desse contexto, esse trabalho tem como objetivo geral avaliar o uso de varandas em apartamentos de edifícios residenciais verticais multifamiliares localizados no bairro de Ponta Verde, em Maceió-AL, quanto ao sombreamento e à iluminação natural. Para alcançá-lo, a metodologia utilizada consistiu de uma análise comparativa entre tipologias recorrentes de varandas, quanto ao sombreamento e a iluminação natural, através das técnicas de levantamento de dados, geração de máscaras de sombra e simulações nos programas computacionais Sketchup e Troplux. As análises dos resultados possibilitaram a compreensão do comportamento do sombreamento e da iluminação natural nas tipologias examinadas e ainda a análise comparativa entre os resultados das simulações de insolação e da iluminação natural. Constatou-se que, uma vez optando por uma melhor estratégia de sombreamento, utilizando as varandas, nem sempre será obtido um bom resultado no desempenho luminoso dos ambientes internos. Enfim, o uso de varanda nos edifícios residenciais de Maceió pode ser trabalhado para alcançar melhores resultados no conforto ambiental e para enriquecer o aspecto formal dos edifícios, devendo ser pensado desde a fase inicial do projeto arquitetônico

Nesta tese estudamos o espectro de absorção da Merocianina de Brooker (MB) e três derivados em solventes com diferentes polaridades. O interesse no estudo desses sistemas se dá pela presença de algumas propriedades particulares das merocianinas, por exemplo, apresentam um grande deslocamento solvatocrômico devido à mudança na polaridade do meio. Nós apresentamos os resultados teóricos obtidos para o espectro de absorção das moléculas considerando diferentes estruturas para o estado fundamental: formas trans, cis, zwiteriônica (zw), protonada (MBH+) e dímero(MB2). O efeito do solvente foi considerado utilizando diferentes modelos de solvatação: (i) modelo contínuo polarizável (PCM), (ii) através de uma configuração eletrostática média do solvente (ASEC), (iii) incluindo algumas moléculas explícitas do solvente juntamente com um ambiente eletrostático gerado pelas demais moléculas do solvente. Como uma investigação adicional, apresentamos nossos resultados de medidas experimentais para o espectro de absorção da MB em vários solventes variando acidez e concentração. Vimos, através de cálculos quânticos, que as formas cis/trans apresentam a excitação eletrônica na mesma região, e que a deformação estrutural gerada pela forma zw provoca um deslocamento para o vermelho na excitação eletrônica. Os nossos resultados teóricos e experimentais mostram que a forma MBH+ apresenta um solvatocromismo pequeno, com deslocamento de 20 nm provocado pela mudança água-clorofórmio. Realizando medidas experimentais através da titulação espectroscópica nós obtivemos o pKa associado ao processo de desprotonação/protonação da MB em água e metanol. Em água obtivemos um valor de 8.7, em boa concordância com valores da literatura. Apresentamos um valor inédito do pKap da MB em metanol, 9.9. Conseguimos uma boa descrição teórica para a excitação eletrônica da MB em solventes com alta polaridade, na região entre 430-500 nm, utilizando o método quântico TD-DFT com funcionais B3LYP e CAM-B3LYP e conjunto de funções base 6-311+G**, porém a excitação em solventes de baixa polaridade, que ocorre na região entre 550-650 nm, não é corretamente descrita considerando a MB nos solventes. Nós vimos, através de estudos experimentais, que a sonda MB pode agregar em solventes de baixa polaridade. Os cáculos teóricos para dímeros em solução mostraram a existência de uma excitação eletrônica de baixa intensidade nesta região. Adicionalmente, os espectros experimentais em solventes de baixa polaridade mostraram 2 bandas, onde a segunda se assemelha com a banda observada para a forma MBH+. Para explicar essas 2 bandas experimentais para a MB, apresentamos uma proposta teórica onde ocorre uma transferência de prótons (H+) entre os monômeros do dímero formado, gerando uma estrutura desprotonada (MBH-) e uma protonada (MBH+). Cálculos teóricos para a forma MBH- mostram que essa forma apresenta uma excitação eletrônica de intensidade moderada na região entre 550-650 nm. Com essa hipótese nós conseguimos descrever, através de cálculos teóricos, o solvatocromismo anômalo observado experimentalmente para o espectro eletrônico de absorção da MB nas duas regiões de polaridade dos solventes: alta polaridade, sendo descrita pela forma MB, e baixa polaridade, descrita pela forma MBH-. / In this thesis we studied the absorption spectrum of merocyanine Brooker (MB) and three derivatives in solvents with different polarities.The interest in this system is given by the presence of some particular properties of this molecule, for example, it presents a large solvatochromic shift due to the change in the polarity of the medium. We present the results for the absorption spectrum of the molecules considering different structures to the ground state: forms trans, cis, zwitterionic (zw), protonated MBH+ and dimer (MB2). The solvent effect was treaty by different ways: (i) continuous model using the PCM polarizable, (ii) by an average electrostatic configuration of solvent, ASEC, (iii) including some explicit solvent molecules with an electrostatic environment generated by other solvent molecules. As an additional investigation, we present results of experimental measurements in the thesis. We have seen, through quantum calculations, that the forms cis/trans have the electronic excitation in the same region and the structural deformation generated in the zw form causes a red shift. Our theoretical and experimental results show that the MBH+ form has a small solvatochromism, with displacement of 20 nm caused by water-chloroform change. Performing spectroscopic titration we got the pKa associated with the process of deprotonation/protonation of MB in water and methanol. In water we obtained a value of 8.7, in good agreement with the values reported in the literature. We present a unpublished pKap for the MB in methanol, 9.9. We got a good theoretical description for electronic excitation of MB in solvents with high polarity, in the region between 430-500 nm, using a method quantum TD-DFT B3LYP and CAM-B3LYP functional whit basic functions set 6-311+G** but the excitation in low polarity solvents, which occurs in the region between 550-650 nm, is not properly described considering the MB form in the solvents. We have seen, through experimental studies that the MB probe can aggregate in low polarity solvents. Theoretical calculations for dimer in solution showed the existence of a low intensity electron excitation in this region. Additionally, the experimental spectra in low polarity solvents showed 2 bands, where in the second band is similar to the observed to MBH+ form. To explain these two experimental bands for MB, we present a theoretical proposal where there is a proton transfer (H+) between the monomers of the dimer, generating a deprotonated structure (MBH-) and a protonated (MBH+). Theoretical calculations for the MBH- show that this form presents an electronic excitation of moderate intensity in the region between 550-650 nm. With this assumption we can describe, through theoretical calculations, the anomalous solvatochromism for the electronic absorption spectrum of MB in the two polarity regions of solvents: high polarity is described by the MB form, and low polarity, described by the MBH- form.

Computer simulations have become a great tool to assist the medical field. The present work is a study of a non-invasive patient-specific methodology to evaluate the hemodynamic importance of coronary stenosis using computer simulations. The severity of the lesion is evaluated by the Fractional Flow Reserve, calculated by the pressure gradient before and after the lesion. The geometry models are obtained from medical images of Computed Tomography Angiography exams, and the simulations considers the pulsatile flow and the blood as a non-Newtonian fluid. The governing equations of the blood flow are solved by using Finite Element Method applied to the numerical method called Incremental Pressure Correction Scheme, and with the aid of the libraries from the open-source software FEniCS. Computer simulations of three different patients are performed and the results are compared with the invasive FFR measurements. The methodology proposed shows to be feasible in the study and analysis of stenosed coronaries. / Simulações computacionais tornaram-se uma excelente ferramenta para auxiliar a área médica. O presente trabalho é um estudo de uma metodologia não invasiva para avaliar a importância hemodinâmica de artérias coronárias com estenose através do uso de simulações computacionais. A severidade da lesão da artéria é avaliada através do Fractional Flow Reserve, calculado pelo gradiente de pressão antes e depois da lesão. Os modelos geométricos computacionais foram obtidos a partir de imagens médicas de exames de Angiografia por Tomografia Computadorizada e as simulações consideram o fluxo pulsátil e as propriedades não-Newtonianas do sangue. As equações governantes do fluxo de sangue são resolvidas utilizando o Método dos Elementos Finitos aplicado ao método numérico chamado Incremental Pressure Correction Scheme, e com o uso de bibliotecas do programa em código aberto FEniCS. Foram realizados simulações de três pacientes e os resultados foram confrontados com as medidas invasivas do FFR. A metodologia proposta mostrou-se viável para o estudo e análise de coronárias com estenose.

As variáveis biológicas de muitos seres vivos apresentam ritmos diários, em paralelo ao dia e à noite do ambiente. A maioria desses ritmos não é uma mera reação aos estímulos cíclicos do ambiente: eles são ritmos circadianos gerados endogenamente por um temporizador interno - o oscilador circadiano - que sustenta uma ritmicidade com período diferente de 24 horas na ausência de pistas ambientais, mas se sincroniza para um período de 24 horas quando exposto ao ambiente cíclico. Em mamíferos, o oscilador circadiano se localiza no cérebro e pode ser sincronizado pelo ciclo diário de claridade e escuridão (ciclo CE) do dia e da noite transmitido através das retinas. Animais subterrâneos passam boa parte do tempo abaixo da terra, onde as condições ambientais variam menos que na superfície. Em razão disso, questiona-se até que ponto estes animais mantêm ritmos circadianos e se seus osciladores circadianos se baseiam no ciclo CE para se sincronizar com o ambiente. Procuramos responder essas questões nos roedores subterrâneos da espécie Ctenomys cf. knighti (tuco-tucos). Em campo, realizamos observações visuais diretas para registrar o padrão temporal de exposição à luz. Em laboratório, construímos a Curva de Resposta de Fase (CRF), que consiste em medir indiretamente a resposta do oscilador circadiano a estímulos luminosos em diferentes momentos do dia. Por fim, recorremos a simulações computacionais de um modelo matemático de oscilador, para integrar os dados anteriores. Verificamos, em campo, que os tuco-tucos se expõem, diariamente, a pulsos de luz irregularmente distribuídos nas horas claras do dia levantando alguns questionamentos sobre sua capacidade como sincronizador dos ritmos em campo. Contudo, a CRF nos indicou que o sistema circadiano dos tuco-tucos responde a estímulos luminosos de forma semelhante aos animais não-subterrâneos. Nós verificamos 3 hipóteses: ou a informação da exposição à luz em campo é suficiente para sincronizar o oscilador circadiano, apesar da aparente irregularidade; ou a CRF do tuco-tuco possui alguma característica que facilita a sincronização pelo regime observado de exposição à luz; ou seu sistema circadiano se baseia em outra pista temporal do ambiente para se manter sincronizado. Nossas simulações computacionais indicaram que a primeira hipótese é a mais provável, visto que os padrões de exposição à luz simulados, como aqueles observados em campo, com o mínimo de informação temporal, ainda assim são suficientes para sincronizar os osciladores. Em conjunto, nossos dados indicam que o ciclo claro-escuro tem um papel importante na sincronização dos ritmos circadianos dos tuco-tucos na natureza. / Daily rhythms are found in the biological variables of many organisms, in parallel to the environmental day and night. Most of those rhythms are not mere reactions to the cyclic stimulus of the environment. They are actually circadian rhythms, endogenously generated by an internal timer, the circadian oscillator, which sustains a non-24-hour rhythm under constant conditions, but is synchronized to a 24-hour period when exposed do a cyclic environment. In mammals, this oscillator is located in the brain, and can be synchronized by the daily light-dark cycle (LD cycle) of day and night. Subterranean animals remain most of the time in an underground habitat, where environmental conditions vary less markedly than aboveground. Therefore, there are doubts whether these animals maintain circadian rhythms and whether their circadian oscillators rely on the LD cycle for environmental synchronization. We attempted to answer those questions in subterranean rodents of the species Ctenomys cf. knighti (tuco-tucos). In the field, we performed direct visual observations to assess their temporal pattern of light-exposure. In the lab, we build the Phase Response Curve (PRC), which consists in an indirect measurement of the circadian oscillator responses to light stimuli applied at different times of the day. Finally, computer simulations of an oscillator model were used to integrate these previous data. We verified that tuco-tucos expose themselves to light pulses that are irregularly distributed through day-light hours, raising some questions about its validity as an environmental synchronizer. However, the PRC results indicated that the tuco-tucos circadian system responds to light stimuli in a way similar to non-subterranean animals. We then verified three hypothesis: either the light-exposure temporal information was enough for the synchronization of the circadian system, despite its apparent irregularity; or the tuco-tuco\'s PRC present some feature that facilitates the synchronization by the observed light-exposure regimen; or the tuco-tuco\'s circadian system rely on another environmental temporal cue to maintain its synchronization. Our computer simulations support the first hypothesis, given that the simulated regimens, despite being little informative in the temporal sense, were still sufficient to synchronize the simulated oscillators. Together, our data indicate that the light-dark cycle plays an important role in the synchronization of the tuco-tucos\' circadian rhythms in nature.

Orientador: Gilberto Francisco Martha de Souza / Dissertação (mestrado profissional) - Universidade Estadual de Campinas, Faculdade de Engenharia Mecânica / Made available in DSpace on 2018-08-18T21:07:39Z (GMT). No. of bitstreams: 1 Braggio_LuisAugustoMaia_M.pdf: 3144133 bytes, checksum: 5fa55e10f11ae3f05c70aaa00d52d26e (MD5) Previous issue date: 2011 / Resumo: Esse trabalho busca, através da administração estratégica da manufatura, estabelecer as prioridades competitivas e, utilizando a ferramenta de simulação de evento discreto, implementá-las. A simulação é uma ferramenta poderosa, pois se executa experimentos virtualmente, diminuindo os riscos de implementação de soluções pouco testadas e alcançando, na maioria das vezes, a melhor solução, além da possibilidade inerente de avaliar sistemas complexos e considerar seu comportamento dinâmico. Apesar das vantagens da ferramenta de simulação, na manufatura a mesma ainda não é uma ferramenta comumente estabelecida no mercado. Nesse trabalho, além da simulação abordam-se também os requisitos e as restrições de um projeto em simulação de evento discreto. Foi elaborado um estudo de caso em uma empresa fabricante de motores diesel, onde foi realizado um mapeamento da manufatura identificando a estratégia de negócio e a prioridade competitiva, caracterizando-se respectivamente por diferenciação e flexibilidade, para cumprir à necessidade do aumento de capacidade das linhas de usinagem. Definiu-se então uma linha de usinagem para aplicar a ferramenta de simulação. Dentro do modelo de simulação, verificou-se a influência das variáveis de troca de ferramenta e quebra de máquina na capacidade de produção da linha. O software utilizado para a construção do modelo de simulação foi o Automod e a execução dos experimentos foi realizada no software AutStat. Os resultados obtidos demonstraram que houve um aumento da capacidade de produção, apenas quando alterado as variáveis de quebra de máquina das operações determinadas como críticas. Atingindo o ganho de 5% necessário para atender o volume de produção previsto. Como o modelo de simulação está validado e nesse trabalho não foram esgotadas todas as alternativas de melhoria, ainda é possível realizar outros experimentos para obtenção dos resultados ainda melhores. A ferramenta de simulação de evento discreto mostrou-se eficiente ao realizar experimentos sem o comprometimento dos recursos alocados na linha. Também se observou que para obter um resultado satisfatório deve-se possuir na empresa uma estrutura para execução do projeto sem deixar o processo de desenvolvimento moroso / Abstract: This thesis aims through the manufacturing strategic management to establish the competitive priorities and using discrete event simulation tool to implement them. The simulation is a powerful tool because it executes experiments virtually, reducing implementation risks and achieving, in most cases, the best solution, besides the inherent possibility to evaluate complex systems and consider their dynamic behavior. Despite of these advantages, the manufacturing simulation is not a usual tool in the market, therefore in this work, the discrete event simulation requirements and constraints were analyzed. A case study was elaborated in a diesel engine manufacturer company, wherein was done a manufacturing mapping to identify the business strategy and competitive priorities, characterized respectively by differentiation and flexibility, to perform the increased capacity of machining lines. Then, it was defined a machining line to apply the simulation tool. The simulation model has been designed to check the influence of machining tools change and downtime machine variables in line production capacity. The software used to build the simulation model was Automod and experiments execution was done by AutoStat software. The results showed an increase in production capacity, only, when the downtime machine variables of critical operations were changed. Achieving gain 5% needed to attend the foreseen production volume. As the simulation model is validated and not all improvement alternatives were exhausted, it is still possible to realize other experiments to obtain even better results. The discrete-event simulation tool presented to be efficient when performing experiments without compromising the resources allocated at the line. Then, it was noted that to obtain a satisfactory result, the company should have a structure to execute the simulation project without a lengthy development process / Mestrado / Manufatura / Mestre em Engenharia Automobilistica

Absence epilepsy is a neurological disorder that commonly occurs in children. Some studies have shown that absence seizures predominantly originate either in the thalamus or the cerebral cortex. Some cerebellar nuclei (CN) neurons project to these brain areas, as explained further in Fig. 2.6 in Chapter 2. Also, some CN neurons have been observed to show modulation during the absence seizures. This indicates that they somehow participate in the seizure and hence are referred to as "participating neurons" in this thesis. In this research, I demonstrate how machine learning techniques and computer simulations can be applied to investigate the properties and the input conditions present in these participating neurons. My investigation found a sub-group of CN neurons, with similar interictal spiking activity, spiking activity between the seizures, that are most likely to participate in seizures. To investigate the input conditions present in the CN neurons that produce this type of interictal activity, I used a morphologically realistic conductance based model of an excitatory CN projection neuron [66] and optimised the input parameters to this model using an Evolutionary Algorithm (EA). The results of the EA revealed that these participating CN neurons receive a synchronous and bursting input from Purkinje cells and bursting input with long intervals(approx. 500ms) from mossy fibre. The same interictal activity can also be produced when the Purkinje cell input to the CN neuron is asynchronous. The excitatory input in this case also had long interburst intervals but there is a decrease in excitatory and inhibitory synaptic weight. Surprisingly, a slight change in these input parameters can change the interictal spiking pattern to an ictal spiking pattern, the spiking pattern observed during absence seizures. I also discovered that it is possible to prevent a participating CN neuron from taking part in the seizures by blocking the Purkinje cell input.