The response of cells to their environment is driven by a variety of proteins and messenger molecules. In eukaryotes, their distribution and location in the cell are regulated by the vesicular transport system. The transport of aquaporin 2 between membrane and storage region is a crucial part of the water reabsorption in renal principal cells, and its malfunction can lead to Diabetes insipidus. To understand the regulation of this system, we aggregated pathways and mechanisms from literature and derived three models in a hypothesis-driven approach. Furthermore, we combined the models to a single system to gain insight into key regulatory mechanisms of Aquaporin 2 recycling. To achieve this, we developed a multiscale computational framework for the modeling and simulation of cellular systems. The analysis of the system rationalizes that the compartmentalization of cAMP in renal principal cells is a result of the protein kinase A signalosome and can only occur if specific cellular components are observed in conjunction. Endocytotic and exocytotic processes are inherently connected and can be regulated by the same protein kinase A signal.

There is an increasing need for accurate models describing the electrical behaviour of individual biological cells exposed to electromagnetic fields. In this area of solving linear problem, the most frequently used technique for computing the EM field is the Finite-Difference Time-Domain (FDTD) method. When modelling objects that are small compared with the wavelength, for example biological cells at radio frequencies, the standard Finite-Difference Time-Domain (FDTD) method requires extremely small time-step sizes, which may lead to excessive computation times. The problem can be overcome by implementing a quasi-static approximate version of FDTD, based on transferring the working frequency to a higher frequency and scaling back to the frequency of interest after the field has been computed. An approach to modeling and analysis of biological cells, incorporating the Hodgkin and Huxley membrane model, is presented here. Since the external medium of the biological cell is lossy material, a modified Berenger absorbing boundary condition is used to truncate the computation grid. Linear assemblages of cells are investigated and then Floquet periodic boundary conditions are imposed to imitate the effect of periodic replication of the assemblages. Thus, the analysis of a large structure of cells is made more computationally efficient than the modeling of the entire structure. The total fields of the simulated structures are shown to give reasonable and stable results at 900MHz, 1800MHz and 2450MHz. This method will facilitate deeper investigation of the phenomena in the interaction between EM fields and biological systems. Moreover, the nonlinear response of biological cell exposed to a 0.9GHz signal was discussed on observing the second harmonic at 1.8GHz. In this, an electrical circuit model has been proposed to calibrate the performance of nonlinear RF energy conversion inside a high quality factor resonant cavity with known nonlinear device. Meanwhile, the first and second harmonic responses of the cavity due to the loading of the cavity with the lossy material will also be demonstrated. The results from proposed mathematical model, give good indication of the input power required to detect the weakly effects of the second harmonic signal prior to perform the measurement. Hence, this proposed mathematical model will assist to determine how sensitivity of the second harmonic signal can be detected by placing the required specific input power.

Les nanomatériaux sont de plus en plus utilisés dans de nombreusesapplications, que cela soit pour la catalyse, la coloration, l’optique, etc. Pour optimiser leurutilisation, il est nécessaire de mieux comprendre les réactions et interactions ayant lieu à ceséchelles. Cette thèse se propose d’essayer d’explorer les liens entre conditions de synthèse,morphologie de particules, et propriétés de celles-ci. En particulier, nous avons opté pourl’étude d’un matériau modèle : l’oxyde de cérium (IV). Les nanoparticules de CeO2 ont étéobtenues par voie de synthèse solvothermale assistée par chauffage micro-ondes. Lesmorphologies des nanoparticules de CeO2 étudiées ont été : les cubes, les octaèdres et lesbâtonnets, et nous avons essayé de fournir une explication à leur obtention par la voie desynthèse utilisée. De l’or a ensuite été déposé en surface des ces nanoparticules de CeO2 etétudié par une combinaison d’études par Microscopie Électronique en Transmission et demodélisations numériques. / Nanomaterials are more and more used in various situations, such as catalysis,color, optics, etc. To optimize their use, it is necessary to better understand reactions andinteractions taking place at these scales. This PhD thesis aims at exploring the links betweensynthesis conditions, particle morphology and their properties. In particular, we chose a tostudy a model-material: cerium (IV) oxide. CeO2 nanoparticles have been obtained bymicrowave-heating assisted solvothermal synthesis. Morphologies obtained and studied havebeen: cubes, octahedrons and rods. We tried to to give an explanation on how these synthesesallowed the formation of such morphologies. Gold has then be deposed on the surface of theseCeO2 nanoparticles, and studied by a combination of Transmission Electron Microscopystudies, and computer modelizations.

<p>This master thesis is about investigation a power efficient anti-moisture device thatcan be implemented in electronic enclosures in severe climatic environments.First, some of the existing knowledge and previous works were introduced. Then arelevant theoretical background including three main approaches in humiditymanagement are described, comparison between the enclosure heaters and localheaters, some psychrometics concepts that have been used in the project, heattransfer fundamentals, environmental test basics, some humidity and temperaturesensing techniques, computational fluid dynamics, programmable logic controlfundamentals, comparison PLCs with microcontrollers was provided.A series experiments have been performed in order to find the power efficient andmost effective anti-moisture method. Based on the analysis of the experiment data,the local heater system has been designed. CFD assisted parametric study of thelocal heater has been performed in order to find the best feasible design includingthe size and location. The local heater has been built based on the results ofparametric study. Different materials have been tested in laboratory in order tofind the proper material for final prototype of heater. The implemented localheater has been integrated with programmable logic control device. The controlalgorithm has been developed for activation/deactivation of local heater. The logiccontrolled PCB local heater has been experimentally evaluated.In the end the results achieved from environmental test have been presented andanalyzed. Some conclusions on the results and also future work have been discussed.</p>

The Stuart Oil Shale Deposit is a major oil shale resource located near Gladstone on the central Queensland coast. It contains an estimated 3.0 billion barrels of oil in place in 5.6 billion tonnes of shale. Commissioning of a plant capable of producing 4,500 barrels per day has recently commenced. The shale is preserved in Tertiary age sediments of The Narrows Beds in the southern part of The Narrows Graben. The oil shale sequence consists of repetitive cycles composed of oil shale, claystone and lesser carbonaceous oil shale in the 400 metre thick Rundle Formation. The formation is the main oil-shale bearing unit in the preserved half-graben sequence up to 1,000 metres thick. Previous studies on the lacustrine sedimentology of the Rundle Oil Shale Deposit in the northern part of The Narrows Graben have recognised eight facies that exhibit unique and recognisable cycles. The cycles and sequence for the Kerosene Creek Member of the Rundle Formation is correlatable between the Rundle and Stuart deposits. The nature of these facies and the cycles is reviewed in some detail. In conjunction with the principles of sequence stratigraphy, the ideal oil shale cycle is described as the equivalent of a parasequence within a lacustrine system. The lacustrine parasequence is bounded by lacustrine flooding surfaces. The organic material in the oil shale consists of both Type I (algal dominated) and Type III (higher plant matter dominated) kerogen. Where Type I kerogen dominate, oil yields greater than about 100 litres per tonne are common. In contrast where Type III kerogens are dominant, yields above 100 litres per tonne are rare. The variation in oil yield is described for the Stuart lacustrine system. The variation is consequent on the balance between production, preservation and degradation of the kerogen in the parasequences within systems tracts. A system for the recognition of oil shale deposition in terms of lacustrine systems tracts is established based on oil yield assay parameters and the assay oil specific gravity. The oil yield and oil specific gravity variation within the Rundle Formation is modelled by member and the nature and distribution of oil yield quality parameters in terms of the contribution of organic and inorganic source material are described. The presence of significant oil yield (greater than 50 litres per tonne) is dependent on the dominance of lacustrine transitional systems tracts and to a lesser extent, lacustrine highstand systems tracts within the parasequence sets deposited in a balanced lake system in a generally warm wet climate during the middle to late Tertiary.

The Hegselmann-Krause system (HK system for short) is one of the most popular models for the dynamics of opinion formation in multi agent systems. Agents are modeled as points in opinion space, and at every time step, each agent moves to the mass center of all the agents within unit distance. The rate of convergence of HK systems has been the subject of several recent works and the current best bounds are O(n3) in one dimension and O(n4) in higher dimension where n being the number of agents. In this work, we investigate the convergence behavior of a few natural variations of the HK system and their e act on the dynamics. In the rest variation, we only allow pairs of agents who are friends in an underlying social network to communicate with each other and we can construct conjurations. In the second variation, only one of the agents updates its position at each time step and selection of such an agent may be at random or based on some preened order; as before, these updates of agents also take social information into consideration. In the third variant, agents may not move exactly to the mass center but somewhere close to it. In the fourth variant, we allow all agents to interact with one another, but instead of assigning equal weights to all neighbors as in the HK model, we assign Gaussian weights which are inversely proportional to the distance between agents. In the fifth variant, we consider the Synchronized Bounded In hence model where the agents have in hence bounds instead of con dance bounds, which changes the way agents interact with each other. In our nil variant, we consider the dynamics of HK systems with strategic agents where we have an additional set of agents called as strategic agents whose opinions are chosen freely at each time step. One of the goals using these strategic agents is to lower the convergence time. The dynamics of all the variants are qualitatively very different from that of the classical HK system. Nevertheless, we prove convergence or show some other interesting results for all of these models. To be more specific, for the rest and third variant we show that these systems make only polynomial number of non-trivial steps, regardless of the social network in the rest vary-ant and noise patterns in the third variant. For the second variant, however, we again show polynomial number of non-trivial steps but in expectation regardless of the social network and interestingly different dynamics. For the fourth variant, we prove an upper bound for the convergence time of Gaussian weighted HK model. For the fifth variant, we consider a special case of this SBI model and prove convergence for this case. For the final variant, we improve the existing results for the optimal convergence time for dumb-bell and equidistant configurations.

The aim of this diploma thesis is to determine and compare modal properties of four swirl turbine wheels, each with a different geometry. Natural frequencies and mode shapes were obtained based on computer modelling using Ansys software and they were compared with experimental modal analysis' results. The computer modelling and the experimental modal analysis were carried out for different boundary conditions and in different environments. The beginning of the thesis is dedicated to a brief overview of literature with similar issues. Then a brief introduction of a dynamics theory is mentioned in which equations of motion for a damped and an undamped single degree of freedom system are derived. The creation of a geometry model which is obtained by a reverse engineering is shown in the second part of the thesis. The geometry model was subsequently used for the computer based modelling of the modal parameters. In the third part an experimental equipment, setting, measurement and processing of data are described. The conclusion of the thesis is dedicated to the comparison of the results obtained by the experimental modal analysis and the computing modelling is presented. Moreover, influence of boundary conditions and influence of the environment on the natural frequencies are evaluated.

Problématique : Le cancer du sein est un des types du cancer les plus diagnostiqués au Canada et il est une cause majeure de mortalité liée au cancer chez la femme. Le cancer du sein triple négatif (CSTN) a un mauvais pronostic dû à son agressivité clinique et à l’absence de réponse aux traitements habituels du cancer du sein tels que l’hormonothérapie et l’inhibition de HER2. En ce moment, les avancées pour le CSTN restent très négligeables. Il y a un besoin urgent d’identifier une nouvelle thérapie qui ciblerait les voies signalétiques pro-métastatiques du cancer du sein triple négatif et ainsi, bloquer idéalement la prolifération et la dissémination métastatique des cellules cancéreuses. Cadre conceptuel : Dernièrement le laboratoire de Sylvain Meloche à l’IRIC a montré qu’une déplétion génétique de ERK3 (Extracellular Regulated Kinase 3) inhibe la croissance des tumeurs mammaires dans un modèle de souris de CSTN et bloque la progression métastatique. Ainsi, suite à ces résultats, nous avons émis l’hypothèse que l’inhibition de ERK3 à l’aide de molécules engendrerait une diminution de la prolifération cellulaire au niveau du cancer du sein triple négatif. L’objectif principal du projet est de développer des molécules ayant des propriétés inhibitrices de ERK3 in vitro. Les deux objectifs secondaires sont d’évaluer leur potentiel d’inhibition vis-à-vis ERK3 dans des modèles in cellulo et de confirmer, parallèlement à la relation structure-activité (SAR), leur mode de liaison par des méthodes computationnelles. Méthodologie : Des composés tête de série ont été identifiés à la suite d’un criblage à haut débit d’une librairie d’inhibiteurs de kinases. Quelques composés intéressants démontrent une activité dont les IC50 (concentration inhibant 50% de l’activité de la kinase) sont inférieurs à 300 nM. Une molécule en particulier a été retenue compte tenu de son niveau d’activité et de sélectivité par rapport aux autres kinases. Une modification systématique des groupements fonctionnels lors de la synthèse d’analogues nous permet d’établir de façon claire le mode de liaison et ainsi, établir la SAR de notre composé tête de série et le site de liaison de ERK3. Les tests d’inhibition compétitifs in vitro seront effectués à l’IRIC à partir de la protéine ERK3 purifiée. Grâce à la SAR établie, on poursuit l’optimisation avec l’intégration de groupements moléculaires solubilisants qui vont permettre d’augmenter les propriétés pharmacocinétiques et ainsi, augmenter l’activité cellulaire de notre composé tête de série. En dernier lieu, à l’aide de la modélisation computationnelle, le mode de liaison de la molécule à ERK3 sera élucidé de façon à confirmer la SAR et aussi, permettre le développement de nouvelles structures (ex : bioisotères) pouvant avoir aussi une activité inhibitrice sur ERK3. Résultats : Une SAR étendue basée sur l’inhibiteur sélectionné a été obtenue. Un inhibiteur de ERK3 possédant une puissance cellulaire (IC50) de 2 μM a été synthétisé. Retombée scientifique : Les travaux effectués dans le cadre de ma maîtrise pourraient conduire au développement de nouveaux traitements pour le cancer du sein triple négatif en ciblant les voies de signalisation prométastatiques à l’aide de molécules inhibitrices. / Problem: Breast cancer is one of the most diagnosed type of cancer in Canada and it is a major cause of mortality linked to cancer for women. Triple-negative breast cancer (TNBC) is the form with the worse prognostic compared to the other forms of breast cancer due to clinical aggressiveness and the absence of response to conventional hormonal therapy and HER2 inhibition therapy. At this time, therapeutic advances for TNBC remain very negligible, which testifies to a need for a new therapy that would target the prometastatic signaling pathways of triple negative breast cancer and thus, ideally block the proliferation and the metastatic dissemination of cancer cells. Conceptual Basis: Recently, Sylvain Meloche's laboratory at IRIC showed that genetic depletion of ERK3 (Extracellular Regulated Kinase 3) inhibits the growth of mammary tumors in a TBNC mouse model and blocks metastatic progression. Thus, in view of these results, our hypothesis is that the inhibition of ERK3 using a specific inhibitor would cause a decrease in cell proliferation in triple negative breast cancer. The main objective of my project is to develop small molecules with inhibitory properties of ERK3 in vitro. The two secondary objectives are to evaluate their inhibitory potential toward ERK3 in cellulo models and to confirm, alongside the structure-activity relationship (SAR), the binding mode of inhibitors to ERK3 by computational methods. Methodology: Lead compounds have been identified following a high-throughput screening of a kinase inhibitor library. A few interesting compounds emerged with activities below 300 nM (IC50). One molecule in particular was chosen given its good selectivity as well as an acceptable inhibitory activity. Systematic modification of functional groups for analogs synthesis allows us to clearly establish the binding mode and thus, establish the SAR of our lead compound. The competitive inhibition tests in vitro have been carried out at IRIC using purified ERK3. With the established SAR, optimization is continued with the integration of solubilizing molecular groups which will increase the pharmacokinetic properties and thus increase the cellular activity of our lead compound.7 Finally, with the help of computational modeling, the binding mode of the molecule to ERK3 will be elucidated to confirm the SAR and also, allow the development of new structures (i.e. bioisosters) that can have an inhibitory activity on ERK3. Results: An extensive SAR of the inhibitor is obtained. A compound with 2 μM activity (IC50) on ERK3 in cell has been synthesized. Scientific outlook: The work done as part of my master's degree could lead to the development of a new treatment for triple-negative breast cancer by targeting prometastatic signaling pathways using small inhibitory molecules.

yes / There is an increasing need for accurate models describing the electrical behaviour of individual biological cells exposed to electromagnetic fields. In this area of solving linear problem, the most frequently used technique for computing the EM field is the Finite-Difference Time-Domain (FDTD) method. When modelling objects that are small compared with the wavelength, for example biological cells at radio frequencies, the standard Finite-Difference Time-Domain (FDTD) method requires extremely small time-step sizes, which may lead to excessive computation times. The problem can be overcome by implementing a quasi-static approximate version of FDTD, based on transferring the working frequency to a higher frequency and scaling back to the frequency of interest after the field has been computed. An approach to modeling and analysis of biological cells, incorporating the Hodgkin and Huxley membrane model, is presented here. Since the external medium of the biological cell is lossy material, a modified Berenger absorbing boundary condition is used to truncate the computation grid. Linear assemblages of cells are investigated and then Floquet periodic boundary conditions are imposed to imitate the effect of periodic replication of the assemblages. Thus, the analysis of a large structure of cells is made more computationally efficient than the modeling of the entire structure. The total fields of the simulated structures are shown to give reasonable and stable results at 900MHz, 1800MHz and 2450MHz. This method will facilitate deeper investigation of the phenomena in the interaction between EM fields and biological systems. Moreover, the nonlinear response of biological cell exposed to a 0.9GHz signal was discussed on observing the second harmonic at 1.8GHz. In this, an electrical circuit model has been proposed to calibrate the performance of nonlinear RF energy conversion inside a high quality factor resonant cavity with known nonlinear device. Meanwhile, the first and second harmonic responses of the cavity due to the loading of the cavity with the lossy material will also be demonstrated. The results from proposed mathematical model, give good indication of the input power required to detect the weakly effects of the second harmonic signal prior to perform the measurement. Hence, this proposed mathematical model will assist to determine how sensitivity of the second harmonic signal can be detected by placing the required specific input power.

Present doctoral thesis contributed to understanding of mechanistic principles of two enzymes participating in the process of carcinogenesis; DNA polymerase  (pol ) and cytochromes P450 (CYP). Pol  is part of the DNA base-excision repair mechanism (BER). The primary role of pol  in, the BER mechanism, is inserting a new nucleotide into a DNA strand according to Watson-Crick base pairing rules. Pol  plays an important role in the process of carcinogenesis, approximately 30 % of human tumors express pol  mutants. The ability of pol  to discriminate between "right" and "wrong" nucleotide during the insertion process is called fidelity. We employed computational methods to elucidate molecular basis of the fidelity of pol . First, the relative free energy calculation method LRA was employed to compare differences in free energies between the "right" and "wrong" nucleotide during its insertion into DNA. The results indicated a better stabilization of transition-state of the nucleophilic substitution catalyzed by pol  in the case of the "right" versus "wrong" nucleotide. This difference resulted in an 80-fold contribution to its fidelity. Further, computational methods FEP and LIE were used to examine how mutations effect fidelity of pol . Results were than correlated with experimental data...