<p>The inverse problem of modeling biochemical processes mathematically from measured time course data falls into the category of system identification and parameter estimation. Analyzing the time course data would provide valuable insights into the model structure and dynamics of the biochemical system. Based on the types of biochemical reactions, such as metabolic networks and genetic networks, several modeling frameworks have been proposed, developed and proved effective, including the Michaelis-Menten equation, the Biochemical System Theory (BST), etc. One bottleneck in analyzing the obtained data is the estimation of parameter values within the system model.</p> <p>As most models for molecular biological systems are nonlinear with respect to both parameters and system state variables, estimation of parameters in these models from experimental measurement data is thus a nonlinear estimation problem. In principle, all algorithms for nonlinear optimization can be used to deal with this problem, for example, the Gauss-Newton iteration method and its variants. However, these methods do not take the special structures of biological system models into account. When the number of parameters to be determined increases, it will be challenging and computationally expensive to apply these conventional methods.</p> <p>In this research, several methods are proposed for estimating parameters in two classes of widely used biological system models: the S-system model and the linear fractional model (LFM), by utilizing their structure specialties. For the S-system, two estimation methods are designed. 1) Based on the two-term structure (production and degradation) of the model, an alternating iterative least squares method is proposed. 2) A separation nonlinear least squares method is proposed to deal with the partially linear structure of the model. For the LFM, two estimation methods are provided. 1) The separation nonlinear least squares method can also be adopted to treat the partially linear structure of the LFM, and moreover a modified iterative version is included. 2) A special strategy using the separation principle and the weighted least squares method is implemented to turn the cost function into a quadratic form and thus the estimates for parameters can be analytically solved. Simulation results have demonstrated the effectiveness of the proposed methods, which have shown better performance in terms of estimation accuracy and computation time, compared with those conventional nonlinear estimation methods.</p>

A modelagem farmacocinética permite prever a concentração de medicamentos em diferentes tecidos do organismo humano. O desenvolvimento de modelos matemáticos é importante para verificar a adequação de certos procedimentos realizados na administração de medicamentos. O objetivo deste trabalho é o desenvolvimento de um modelo farmacocinético capaz de prever a concentração plasmática de drogas no organismo para diversas formas de infusão. Foram utilizados dois tipos de abordagem. Inicialmente, na abordagem monocompartimental, considerou-se que a droga adentra ao organismo diretamente no compartimento sanguíneo, que representa todo o corpo humano. Já na abordagem bicompartimental foram considerados os seguintes compartimentos: um representando o meio pelo qual a droga é infundida no organismo (podendo ser via gastrointestinal, transdermal ou pulmonar) e outro representando o plasma sanguíneo. Em ambos os casos, foi considerada a hipótese de concentração homogênea da droga nos compartimentos em questão. O modelo foi estruturado na forma de diagramas de blocos e a solução foi feita com a utilização da Transformada de Laplace. Foi feita a validação dos modelos e verificou-se que os resultado gerados foram muito próximos dos resultados presentes na literatura. A utilização do modelo monocompartimental permitiu comparar os resultados da administração da mesma quantidade de droga por infusão constante e por infusão periódica. A análise dos resultados gerados pelo modelo mostrou que as concentrações atingidas pelos dois métodos não são as mesmas. O modelo bicompartimental permitiu simular administrações orais e transdermais, e inalação. Foi possível prever a concentração sanguínea após a interrupção da terapia com anti-concepcionais e anti-depressivos e foi verificado o tempo necessário para que esta concentração seja atingida novamente. Foram propostos métodos para que esta concentração fosse atingida em um menor período de tempo. Outra aplicação foi na comparação entre o tratamento com comprimidos inteiros e tomados pela metade em um intervalo menor de tempo. Verificou-se que a concentração atingida é diferente mesmo que a massa ingerida seja a mesma. O modelo também foi utilizado para calcular a concentração de nicotina após o consumo de cigarros e verificou-se que, o indivíduo que fuma a cada três horas não consegue eliminar totalmente a nicotina de seu organismo. Além disso, foi possível simular a sobredosagem de um anti-inflamatório e verificar o tempo em que a concentração fica acima do nível terapêutico. Foi proposto um método para obtenção do parâmetro farmacocinético relacionado à absorção, que pode ser obtido facilmente a partir de dados presentes nas bulas dos medicamentos. Este método é muito mais simples e preciso do que e proposto na literatura, que utiliza análise gráfica e dados clínicos que não são obtidos com tanta facilidade. / The pharmacokinetic modeling can predict the concentration of drug in different tissues of the human body. The development of mathematical models is an important tool to verify the appropriateness of certain procedures performed in medication administration. The objective of this work is to develop a pharmacokinetic model able to predict the plasma concentration of drug in the body after various forms of infusion. Two approaches were used. Initially, in the one-compartment approach it was considered that the drug enters the body directly into the blood compartment, which represents the entire human body. In the two-compartment approach it was considered the following compartments: one representing the means by which the drug is infused into the body (either via the gastrointestinal tract, lung, or transdermal) and one representing the blood plasma. In both cases, it was considered homogeneous concentration of the drug in the compartments. The model was built by using block diagrams and the solution was obtained using the Laplace Transform. The model was validated by comparing its results to literature data, with very good agreement. The model allowed comparing the one-compartment constant infusion of drug in the body with the periodic infusion. The analysis of the results generated by the model showed that the concentrations achieved by these methods are not the same. The two-compartment model allowed simulating oral and transdermal administration, and inhalation. It was possible to predict blood concentration after interruption of therapy with anti-depressants and anti-conceptional drugs. The model was able to verify the time it takes to reach the former level. Methods have been proposed to achieve the same concentration in a shorter period of time. Another application was the comparison of the treatment with whole tablets and taken by half in a smaller interval of time. It was found that the concentration achieved is different even though the same mass is ingested in both cases. The model was also used to calculate the concentration of nicotine after cigarette smoking and it was found that the individual who smokes every three hours, nicotine is not entirely eliminated from body. Furthermore, it was possible to simulate overdose of an anti-inflammatory and the period of time when the concentration is above the therapeutic level. It has been proposed a method to obtain pharmacokinetic parameter related to absorption, which can be easily obtained based on data present in the drug bull. This method is much simpler and more accurate than the method proposed in the, which uses graphical analysis and clinical data that are not so easy to be obtained.

No description available.

Over the years, data management has diversified and moved into multiple directions, mainly caused by a significant growth in the application space with different usage patterns, a massive change in the underlying hardware characteristics, and-last but not least-growing data volumes to be processed. A solution matching these constraints has to cope with a multidimensional problem space including techniques dealing with a large number of domain-specific data types, data and consistency models, deployment scenarios, and processing, storage, and communication infrastructures on a hardware level. Specialized database engines are available and are positioned in the market optimizing a particular dimension on the one hand while relaxing other aspects (e.g. web-scale deployment with relaxed consistency). Today it is common sense, that there is no single engine which can handle all the different dimensions equally well and therefore we have very good reasons to tackle this problem and optimize the dimensions with specialized approaches in a first step. However, we argue for a second step (reflecting in our opinion on the even harder problem) of a deep integration of individual engines into a single coherent and consistent data management ecosystem providing not only shared components but also a common understanding of the overall business semantics. More specifically, a data management ecosystem provides common “infrastructure” for software and data life cycle management, backup/recovery, replication and high availability, accounting and monitoring, and many other operational topics, where administrators and users expect a harmonized experience. More importantly from an application perspective however, customer experience teaches us to provide a consistent business view across all different components and the ability to seamlessly combine different capabilities. For example, within recent customer-based Internet of Things scenarios, a huge potential exists in combining graph-processing functionality with temporal and geospatial information and keywords extracted from high-throughput twitter streams. Using SAP HANA as the running example, we want to demonstrate what moving a set of individual engines and infra-structural components towards a holistic but also flexible data management ecosystem could look like. Although there are some solutions for some problems already visible on the horizon, we encourage the database research community in general to focus more on the Big Picture providing a holistic/integrated approach to efficiently deal with different types of data, with different access methods, and different consistency requirements-research in this field would push the envelope far beyond the traditional notion of data management.

Ce projet de thèse, dans le cadre d’une collaboration entre le LIMOS et le LPC, s’inscrit dans une démarche de recherche permettant la mise en synergie des domaines de la biologie, de la physique et de l’informatique par la proposition d’une démarche de simulation permettant la réalisation d’expériences in silico. Pour cela, nous nous proposons de développer une plateforme logicielle dédiée à la modélisation multiéchelle des systèmes biologiques qui pourra par la suite être interfacée avec les outils de simulation de physique des particules. Nous proposons également un modèle individu-centré de cellule biologique paramétrable à l’aide de données obtenues d’expériences in vitro. Nous présentons l’élaboration de cette plateforme et une démarche de validation de ses fonctionnalités à travers l’implémentation de modèles d’automates cellulaires de la littérature. Nous présentons ensuite la construction du modèle de cellule biologique en prenant le temps d’expliquer comment est pris en compte le système biologique, comment nous le modélisons puis comment nous paramétrons le modèle. Nous modélisons les processus internes de la cellule, dont les caractéristiques sont liées à l’information génétique qu’elle porte. Ce modèle de cellule permet de reproduire le comportement d’une cellule isolée, et à partir de là, d’un ensemble de cellules via l'automate. Le modèle est ensuite utilisé pour retrouver les courbes de croissance d'une population de bactéries Escherichia coli. Des valeurs de données de fluxomique ont été exploitées et ont permis la reproduction in silico des expériences in vitro dont elles étaient issues. / This PhD thesis project is part of a research program in the fields of biology, physics and computer science aiming to propose a simulation approach for performing experiments in silico. For this, we propose to develop a software platform dedicated to multi-scale modeling of biological systems that can be combined with particle physics simulation tools. We also propose a general individual-based model of biological cell in which data obtained from in vitro experiments can be used. We present the development of this platform and the validation process of its functionalities through the implementation of cellular automata from the literature. We then present the design of the biological cell model by giving the hypothesis we made, how we model and how we parameterize the model. Starting from a simple biological system, bacteria, observed in liquid culture, our model uses a multi-scale middle-out approach. We focus on the cell and we model internal processes, assuming that all their properties come from genetic information carried out by the cell’s genome. This model allows to consider the cell behavior, and then to obtain the behavior of a cell population. Data from fluxomic experiments have been used in this model to parameterize the biochemical processes. The results we obtain allow us to consider the model as validated as simulation results match the experimental data.

Este trabalho teve por objetivo investigar a degradação de lipídios em três sistemas anaeróbios de tratamento: um reator anaeróbio de fluxo horizontal de leito fixo (RAHLF) , um sistema combinado composto por um reator enzimático de leito expandido invertido (RELI) seguido por um RAHLF e um reator anaeróbio de manta de lodo (UASB). Os sistemas foram monitorados em uma câmara com temperatura controlada a 30,0 ± 0,5°C e alimentados com substrato sintético a base de lipídios, com concentração, em termos de demanda química de oxigênio (DQO) de 8748 ± 711 mg/L e concentração de óleos e graxas de 1820 ± 512 mg/L, O reator RAHLF foi operado com tempo de detenção hidráulica (TDH) de 24 horas por 100 dias e apresentou eficiências médias de remoção de DQO e de lipídios de 98,9 ± 0,4% e 94,9 ± 3,2%, respectivamente. O sistema combinado (reator enzimático / reator anaeróbio) apresentou eficiências médias de remoção de DQO e de lipídios de 99,0 ± 0,3% e 94,2 ± 2,8%, respectivamente, operado com TDH de 30 min no reator enzimático e 24 h no reator microbiológico. Posteriormente, o reator RAHLF foi submetido à diminuição do TDH de 24 para 8 h. As eficiências médias de remoção de DQO e lipídios foram de 87,0 ± 3,2% e 90,5 ± 2,7% verificadas para o menor TDH aplicado (8 h). O modelo cinético baseado em reações paralelas e em série, de primeira ordem, indicaram que a velocidade de reação aumenta com o aumento da velocidade superficial no reator RAHLF. Este comportamento pode ser atribuído à diminuição contínua da resistência à transferência de massa da fase líquida. O reator UASB apresentou baixa eficiência devido à flotação de 85% da manta de lodo granular, após 18 dias de operação. Os resultados obtidos neste trabalho permitem concluir que o reator RAHLF pode ser utilizado como unidade única no tratamento de efluentes com alta concentração de lipídios, devido a ter apresentado performance similar à observada no sistema integrado enzimático-anaeróbio. / The aim of this work was the investigation of the lipid degradation in three anaerobic treatment systems: a horizontal-flow anaerobic immobilized biomass (HAIB) reactor, a combined system composed by an inverted expanded-bed enzymatic reactor (EIBE) followed by a HAIB reactor and an up-flow anaerobic sludge blanket (UASB) reactor. The systems were monitored in a chamber under controlled temperature of 30 ± 0.5°C and fed with lipid-based synthetic wastewater, with chemical oxygen demand (COD) of 8748 ± 711 mg/L and 1820 ± 512 mg/L of oil and grease concentration. The HAIB reactor was operated with hydraulic detention time (HDI) of 24 hours for 100 days and it presented average COD and lipids removal efficiencies of 98.9 ± 0.4% and 94.9 ± 3.2%, respectively. The combined system (enzymatic/anaerobic reactors) presented COD and lipids removal efficiencies of 99.0 ± 0.3% and 94.2 ± 2.8%, respectively, operating with a HDI of 30 min in the enzymatic reactor and 24 h in the microbiological one. Afterwards, the HAIB reactor was subjected to decreasing HDI values from 24 to 8 h. Average COD and the lipids removal efficiencies of 87.04 ± 3.2% and 90.5 ± 2.7%, respectively, were achieved for the lower HDI applied (8 h). A kinetic model, based on first-order series and parallel reactions, indicated that the lipids reaction rate increased as the liquid superficial velocity was increased in the HAIB reactor, since the liquid-phase mass transfer resistance decreased continuously. The UASB reactor presented a poor performance, presenting flotation of the 85% of the granular sludge bed after 18 days of operation. The results obtained in this work permit the potential indication of HAIB reactor as the sole unit to treat lipid-rich wastewater, since the performance of the HAIB reactor was similar to that observed for the integrated hydrolytic-anaerobic system.

In this PhD thesis, the utilisation of interactive simulation in a higher education e-learning classroom environment was explored and its effectiveness was experimentally evaluated by engaging university students in a classroom setting. Two case studies were carried out for the experimental evaluation of the proposed novel interactive simulation e-learning tool. In the first case study, the use of interactive agent-based simulation was demonstrated in teaching complex adaptive system concepts in the area of ecology to university students and its effectiveness was measured in a classroom environment. In a lab intervention using a novel interactive agent-based simulation (built in NetLogo). For the purpose of teaching complex adaptive systems such as the concept of spatially-explicit predator prey interaction to undergraduate and postgraduate students in the University of Stirling. The effectiveness of using the interactive simulation was investigated by using the NetLogo software and compared with non-interactive simulation built using R programming language. The experimental evaluation was carried out using a total of 38 students. Results of this case study demonstrates that the students found interactive agent-based simulation to be more engaging, effective and user friendly as compare to the non-interactive simulation. In the second case study, a novel interactive simulation game was developed (in NetLogo) and its effectiveness in teaching and learning of complex concepts in the field of marine ecology was demonstrated. This case study makes a twofold contribution. Firstly, the presentation of a novel interactive simulation game, developed specifically for use in undergraduate and postgraduate courses in the area of marine ecology. This novel interactive simulation game is designed to help learners to explore a mathematical model of fishery population growth and understand the principles for sustainable fisheries. Secondly, the comparison of two different methods of using the interactive simulation game within the classroom was investigated: learning from active exploration of the interactive simulation game compared with learning from an expert demonstration of the interactive simulation game. The case study demonstrated the effectiveness of learning from passive viewing of an expert demonstration of the interactive simulation game over learning from active exploration of the interactive simulation game without expert guidance, for teaching complex concepts sustainable fishery management. A mixed methods study design was used, using both quantitative and qualitative methods to compare the learning effectiveness of the two approaches, and the students’ preferences. The investigation was carried out by running interventions with a mixture of undergraduate and postgraduate students from the University of Stirling in a classroom environment. A total of 74 participants were recruited from undergraduate and postgraduate level for both case studies. This thesis demonstrated through two case studies effectiveness of the proposed novel interactive simulation in university e-learning classroom environment.

Este trabalho teve por objetivo investigar a degradação de lipídios em três sistemas anaeróbios de tratamento: um reator anaeróbio de fluxo horizontal de leito fixo (RAHLF) , um sistema combinado composto por um reator enzimático de leito expandido invertido (RELI) seguido por um RAHLF e um reator anaeróbio de manta de lodo (UASB). Os sistemas foram monitorados em uma câmara com temperatura controlada a 30,0 ± 0,5°C e alimentados com substrato sintético a base de lipídios, com concentração, em termos de demanda química de oxigênio (DQO) de 8748 ± 711 mg/L e concentração de óleos e graxas de 1820 ± 512 mg/L, O reator RAHLF foi operado com tempo de detenção hidráulica (TDH) de 24 horas por 100 dias e apresentou eficiências médias de remoção de DQO e de lipídios de 98,9 ± 0,4% e 94,9 ± 3,2%, respectivamente. O sistema combinado (reator enzimático / reator anaeróbio) apresentou eficiências médias de remoção de DQO e de lipídios de 99,0 ± 0,3% e 94,2 ± 2,8%, respectivamente, operado com TDH de 30 min no reator enzimático e 24 h no reator microbiológico. Posteriormente, o reator RAHLF foi submetido à diminuição do TDH de 24 para 8 h. As eficiências médias de remoção de DQO e lipídios foram de 87,0 ± 3,2% e 90,5 ± 2,7% verificadas para o menor TDH aplicado (8 h). O modelo cinético baseado em reações paralelas e em série, de primeira ordem, indicaram que a velocidade de reação aumenta com o aumento da velocidade superficial no reator RAHLF. Este comportamento pode ser atribuído à diminuição contínua da resistência à transferência de massa da fase líquida. O reator UASB apresentou baixa eficiência devido à flotação de 85% da manta de lodo granular, após 18 dias de operação. Os resultados obtidos neste trabalho permitem concluir que o reator RAHLF pode ser utilizado como unidade única no tratamento de efluentes com alta concentração de lipídios, devido a ter apresentado performance similar à observada no sistema integrado enzimático-anaeróbio. / The aim of this work was the investigation of the lipid degradation in three anaerobic treatment systems: a horizontal-flow anaerobic immobilized biomass (HAIB) reactor, a combined system composed by an inverted expanded-bed enzymatic reactor (EIBE) followed by a HAIB reactor and an up-flow anaerobic sludge blanket (UASB) reactor. The systems were monitored in a chamber under controlled temperature of 30 ± 0.5°C and fed with lipid-based synthetic wastewater, with chemical oxygen demand (COD) of 8748 ± 711 mg/L and 1820 ± 512 mg/L of oil and grease concentration. The HAIB reactor was operated with hydraulic detention time (HDI) of 24 hours for 100 days and it presented average COD and lipids removal efficiencies of 98.9 ± 0.4% and 94.9 ± 3.2%, respectively. The combined system (enzymatic/anaerobic reactors) presented COD and lipids removal efficiencies of 99.0 ± 0.3% and 94.2 ± 2.8%, respectively, operating with a HDI of 30 min in the enzymatic reactor and 24 h in the microbiological one. Afterwards, the HAIB reactor was subjected to decreasing HDI values from 24 to 8 h. Average COD and the lipids removal efficiencies of 87.04 ± 3.2% and 90.5 ± 2.7%, respectively, were achieved for the lower HDI applied (8 h). A kinetic model, based on first-order series and parallel reactions, indicated that the lipids reaction rate increased as the liquid superficial velocity was increased in the HAIB reactor, since the liquid-phase mass transfer resistance decreased continuously. The UASB reactor presented a poor performance, presenting flotation of the 85% of the granular sludge bed after 18 days of operation. The results obtained in this work permit the potential indication of HAIB reactor as the sole unit to treat lipid-rich wastewater, since the performance of the HAIB reactor was similar to that observed for the integrated hydrolytic-anaerobic system.