A viscoelasticidade do pulmão do mamífero é determinada principalmente pelas propriedades mecânicas, estrutura e regulação do músculo liso das vias aéreas. A exposição ao ar poluído pode deteriorar essas propriedades com consequências danosas à saúde individual. O formaldeído é um importante poluente presente em ambientes internos que adentra o músculo liso formando ligações covalentes entre proteínas da matriz extracelular e da estrutura intracelular deteriorando algumas funções do músculo liso das vias aéreas, alterando propriedades mecânicas e induzindo a hiperresponsividade. O primeiro objetivo desse trabalho foi desenvolver um modelo de rede viscoelástica bidimensional baseada na tesselação de Voronoi para reproduzir algumas propriedades mecânicas do músculo liso de via aérea a nível de tecido. O segundo objetivo foi comparar os resultados obtidos com o nosso modelo com aqueles previamente observados em experimentos com tiras de tecido após a exposição ao formaldeído. Nosso modelo simula as propriedades mecânicas do músculo liso de via aérea usando um conjunto de molas e amortecedores. Esse conjunto de molas e amortecedores não somente mimetiza as propriedades viscoeláticas do músculo liso mas também o aparato contrátil das células. Nós hipotetizamos que a formação de ligações covalentes, devido à ação do formaldeído, pode ser representada no modelo por uma alteração simples na constante elástica das molas, enquanto que a ação da metacolina reduz o tamanho da mola. Nosso modelo é hábil para reproduzir uma medida de força isométrica onde o músculo liso é sujeito a um agente contrátil, com e sem exposição in vitro ao formaldeído. Assim, a nossa nova abordagem mecanicista incorpora diversas propriedades bem conhecidas do sistema contrátil das células em um tecido a nível de modelo. O modelo pode também ser usado em diferentes escalas biológicas / The viscoelastic properties of the mammalian lung is mainly determined by the mechanical properties, structure and regulation of the airways smooth muscle. The exposure to polluted air may deteriorate these properties with harmful consequences to individual health. Formaldehyde is an important indoor pollutant that permeate through the smooth muscle tissue forming covalent bonds between proteins in the extracellular matrix and intracellular protein structure deteriorating some of the airways smooth muscle functions, changing mechanical properties, and inducing hyperresponsiveness. The first objectives of this work was to develop a two-dimensional viscoelastic network model based on Voronoi tessellation to reproduce some of the mechanical properties of airway smooth muscle at the tissue level. The second objective was to compare the results obtained with our model with those previously observed in tissue strip experiments after the tissue exposure to formaldehyde. Our model simulates the mechanical properties of airway smooth muscle using a set of springs and dashpot. This set of springs and dashpot not only mimic the viscoelastic properties of the smooth muscle but also the cells contractile apparatus. We hypothesize that the formation of covalent bonds, due to the action formaldehyde, can be represented in the model by a simple change in the elastic constant of the springs, while the action of methacholine reduce the size of the spring. Our model is able to reproduce an isometric force measurement, where the smooth muscle is subjected to a titration of a contractile agent, with and without an in vitro exposure to formaldehyde. Thus, our new mechanistic approaches incorporates several well know features of the contractile system of the cells in a tissue level model. The model can also be used in different biological scales

Context. In computer graphics, realistic looking fluid is often desired. Simulating realistic fluids is a time consuming and computationally expensive task, therefore, much research has been devoted to reducing the simulation time while maintaining the realism. Two of the more recent optimization algorithms within particle based simulations are two-scale simulation and regional time stepping (RTS). Both of them are based on the predictive-corrective incompressible smoothed particle hydrodynamics (PCISPH) algorithm. Objectives. These algorithms improve on two separate aspects of PCISPH, two-scale simulation reduces the number of particles and RTS focuses computational power on regions of the fluid where it is most needed. In this paper we have developed and investigated the performance of an algorithm combining them, utilizing both optimizations. Methods. We implemented both of the base algorithms, as well as PCISPH, before combining them. Therefore we had equal conditions for all algorithms when we performed our experiments, which consisted of measuring the time it took to run each algorithm in three different scene configurations. Results. Results showed that our combined algorithm on average was faster than the other three algorithms. However, our implementation of two-scale simulation gave results inconsistent with the original paper, showing a slower time than even PCISPH. This invalidates the results for our combined algorithm since it utilizes the same implementation. Conclusions. We see that our combined algorithm has potential to speed up fluid simulations, but since the two-scale implementation was incorrect, our results are inconclusive.

Abstract Phosphatidylethanol (PEth) is an abnormal phospholipid formed only in the presence of ethanol. Ethanol causes changes in the concentration and composition of plasma lipoproteins and it also influences the enzymes and transfer proteins that modify lipoproteins in plasma. PEth might be one of these changes brought on by ethanol in the circulation. The present study was designed to investigate whether qualitative changes in high density lipoprotein (HDL) phospholipids caused by ethanol can mediate the beneficial effects of alcohol on atherosclerosis, and to investigate the transfer of PEth between lipoproteins and the effects of PEth on the charge of lipoprotein particles. PEth was shown to be transferred from low density lipoproteins (LDL) to HDL particles mainly by transfer proteins other than cholesteryl ester transfer protein (CETP). The transfer of PEth between lipoproteins enables the redistribution of PEth between lipoproteins in plasma. The results of this study provide evidence that PEth in HDL particles stimulates the vascular endothelial growth factor (VEGF) secretion from vascular wall cells. The increase in the secretion was mediated through protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) signalling pathways. PEth-containing HDL particles were able to increase the VEGF secretion in rats in vivo. Similar effects were also observed when rats were given HDL particles isolated from the plasma of alcoholics. The PEth-induced change in the electrical charge of lipoproteins may affect the binding of lipoproteins to their receptors and binding proteins. The effects of PEth on the secretion of VEGF from the endothelial cells were shown to be mediated through HDL receptor. The changes in HDL particles caused by phosphatidylethanol may modify the metabolism of lipoproteins and lipid-mediated signalling pathways regulating VEGF in vascular wall cells.

Vascular smooth muscle cells (VSMC) constitute an important component of blood vessels and are primarily responsible for vessel contraction. In vascular disorders such as hypertension and atherosclerosis as well as pregnancy and exercise, VSMC demonstrate increased capacity to proliferate and migrate, resulting in vascular remodelling. The actin cytoskeleton is an important component of vascular contractility and is also essential for proliferation and migration of VSMC. Vasoactive agonists such as Endothelin-1 (ET-1) and Noradrenaline (NA), have been shown to mediate VSMC contraction through changes in actin cytoskeleton and focal adhesion (FA) remodelling, and have also been reported to cause VSMC migration in the appropriate setting. The aim of this study was to investigate the signalling mechanisms responsible for FA dependent actin cytoskeleton remodelling of VSMC in response to ET-1 and NA, with a special focus on Hydrogen peroxide-inducible clone 5 (Hic-5). The latter is a FA protein shown to regulate actin cytoskeleton dynamics in small arteries in response to Noradrenaline (NA) and the response of VSMC to arterial injury and abdominal aortic aneurysm. We have shown that Src-dependent tyrosine phosphorylation of Hic-5 regulated its subcellular localisation in mouse embryonic fibroblasts and VSMC, but was not responsible for the effects of ET-1 and NA on actin filament remodelling or Hic-5 redistribution in VSMC. ET-1 stimulation caused an increase in Hic-5 localisation at FAs concurrent with an increase in the density of actin filaments, whereas NA stimulation caused a decrease in Hic-5 localisation at FAs in VSMC concurrent with actin filament redistribution at the cell cortex. Hic-5 was the FA protein that demonstrated the most dramatic changes in subcellular localisation in response to ET-1 and NA, when compared to paxillin (Hic-5 homologue) or vinculin (classical FA marker). NA-mediated changes in Hic-5 localisation and actin filament distribution were more pronounced compared to ET-1-mediated changes. Further investigation into the NA-induced changes suggested that actin filament disassembly preceded Hic-5 relocalisation from FAs to the cytosol. These results show that vasoactive peptides cause Hic-5 relocalisation and actin filament rearrangement in VSMCs in an agonist-dependent manner. Given that VSMC FA remodelling and actin cytoskeleton reorganisation occur during contraction and arterial remodelling, our data identify Hic-5 as a key regulator of these processes in response to NA and ET-1. Furthermore, these data have implications in agonist- specific VSM function such as migration and contraction.

Alteration in the tone of pulmonary arteries may lead to disease such as pulmonary hypertension often associated with major cardiac complications. This dysfunction is partly in the pulmonary arterial smooth muscle cells (PASMCs) where the excitation-contraction coupling is modified by ion channel behaviour to increase the contractile force. Mathematical models of systemic smooth muscle cells (SMCs) that incorporate electrophysiological and chemomechanical mechanisms to understand the underlying cellular physiology have been successfully employed. Models of pulmonary arterial smooth muscle cells (PASMCs) are only beginning to emerge. Mathematical model prototyping with available experimental data and model investigation from different parameter values is a time-consuming and complex process. This thesis is concerned with the development and validation of mathematical models of excitation-contraction coupling in three types of PASMCs of the rat species, one homogeneous type originating from the distal pulmonary arteries and two from proximal pulmonary arteries. Some key novel additions from previous vascular SMC models include the distinct modelling of Ca2+ in the subplasmalemmal cytosolic region, incorporation of subunit-specific currents from the K+ channel family and a generic G-protein receptor model able to reproduce complex Ca2+ profiles. The main pulmonary and systemic arteries statistically differ in its response to phenylephrine in a wire myograph. The ionic currents of the models were validated against experimental data largely from rat species. The models replicate the recordings of Ca2+ and the resting potential (Em) profiles arising from agonist-induced cytosolic Ca2+ ([Ca2+]i) stimulation (G-protein activation), nifedipine, ryanodine, caffeine and niflumic acid. The distal PASMC model was sensitive to an increase in [Ca2+]i from G-protein activation although were less likely to reproduce Ca2+ oscillations than proximal PASMCs. The proximal models determined the likely proximal PASMC type in literature experiments recording [Ca2+]i and Em. I have developed software that enables other users to simulate Ca2+ and Em changes in SMC studies and the ability to parse a master file describing the mathematical model into different language formats to increase productivity. These models provide a foundation for further studies to better understand PASMC function in the context of normal physiology as well as pathological conditions.

Diazoxide, a non-diuretic benzothiadiazlne antihypertensive agent, is thought to act directly upon the vascular smooth muscle of the resistance vessels to exert its therapeutic effects in hypertension. Diazoxide may exert its antihypertensive action by antagonizing calcium in vascular smooth muscle. Wohl et al. (1967 and 1968) have suggested such an interaction based on experiments conducted with isolated rabbit aortae. The present experiments were designed to investigate the possible cellular locus of the postulated interaction of diazoxide with calcium using the isolated anterior mesenteric vein of the rabbit as a model of vascular smooth muscle. This vein is spontaneously motile and possesses characteristics similar to those observed for vessels of the microcirculation. Diazoxide at 10ˉ⁴ M inhibited spontaneous motility and its associated membrane electrical activity, and caused hyperpolarization in rabbit anterior mesenteric veins examined with a sucrose gap apparatus. Diazoxide also inhibited spontaneous electrical and contractile activity in guinea-pig taenia coli and in estrogen dominated rabbit uterus. In all these tissues, calcium is believed to play an important role in spontaneous electrical membrane activity. Diazoxide failed to affect contractility, rate of spontaneous contractions, or action potential configurations in isolated rabbit heart, even though the action potential in heart tissues possesses a definite calcium current component. Diazoxide reduced contractions induced in the mesenteric vein by electrical stimulation of the smooth muscle itself or by excitation of the nerve endings within the vein. Various drugs were chosen for their ability to contract the mesenteric vein in different ways. Noradrenaline contracts vascular smooth muscle even when the tissue Is depolarized with ouabain Diazoxide failed to inhibit noradrenaline contractions in the depolarized vein, but showed the characteristics of a competitive inhibitor of noradrenaline in normally polarized veins. Diazoxide was also capable of inhibiting contractions to serotonin and procaine, agents which require membrane polarization to initiate contraction. The inhibitory effect of diazoxide was not observed to be modified in solutions containing high concentrations of calcium. Diazoxide was tested upon the contractile responses to calcium In veins depolarized in K⁺ Ringer solution. Examination of the resultant dose response curves showed that diazoxide inhibited calcium contractions ln a reversible, non surmountable manner. Hydrochlorothiazide had no effect upon calcium induced contractions. Diazoxide antagonizes drug induced contractions only if a polarized membrane is present. Calcium Induced contractions in depolarizing solutions were inhibited in an apparently Insurmountable manner, while drug responses in polarizing solutions were inhibited by diazoxide in a surmountable manner. In addition, action potentials from rabbit heart were unchanged whereas, the apparently calcium spike mediated electrical activity of certain smooth muscles is inhibited. It is concluded that diazoxide affects the membrane of vascular smooth muscle to reduce excitability of the tissue to drugs or electrical stimuli. It is possible that cell membrane bound calcium could be the locus of action of diazoxide and that this agent modifies membrane calcium to cause increased membrane stability. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Heat exchangers have a wide range of applications and engineers need accurate correlations to optimise the design of these heat exchangers. During the design process, the best compromise between high heat transfer coefficients and relatively low pressure drops is usually in the transitional flow regime. Limited research has been done on tube flow in the transitional flow regime. These studies considered either fully developed flow, or average measurements of developing flow across a tube length. No research has been done with the focus on developing flow in smooth tubes in the transitional flow regime. Therefore, the purpose of this study was to experimentally investigate the heat transfer and pressure drop characteristics of developing flow in the transitional flow regime. An experimental set-up was designed, built and validated against literature. Heat transfer and pressure drop measurements were taken at Reynolds numbers between 500 and 10 000 at three different heat fluxes (6.5, 8.0 and 9.5 kW/m2). A total of 398 mass flow rate measurements, 19 158 temperature measurements and 370 pressure drop measurements were taken. Water was used as the test fluid and the Prandtl number ranged between 3 and 7. The test section was a smooth circular tube and had an inner diameter and length of 11.52 mm and 2.03 m, respectively. An uncertainty analysis showed that the uncertainties of the Nusselt numbers and Colburn j-factors varied between 4% and 5% while the friction factor uncertainties varied between 1% and 17%. Five different flow regimes (laminar, developing laminar, transitional, low-Reynolds-number-end and turbulent) were identified in the first part of the tube during the experiments and nomenclature was developed to more clearly identify the boundaries of the different flow regimes. The developing laminar regime was unique to developing flow and decreased along the tube length. Both the start and end of transition were delayed along the tube length and the width of the transition region decreased slightly. This is in contrast with the results obtained in literature where the effect of the non-dimensional distance from the inlet on fully developed flow in the transition region was investigated. Transition was also slightly delayed with increasing heat flux, but secondary flow effects had no significant influence on the width of the transition region. The relationship between heat transfer and pressure drop was investigated and correlations were developed to predict the Nusselt number as a function of friction factor, Reynolds number and Prandtl number in the laminar, transitional, low-Reynolds-number-end and turbulent flow regimes. Overall, it can be concluded that the heat transfer characteristics of developing and fully developed flow differ significantly and more work needs to be done to fully understand the fundamentals before the heat transfer and pressure drop characteristics are fully understood. / Dissertation (MEng)--University of Pretoria, 2015. / Mechanical and Aeronautical Engineering / Unrestricted

No description available.

Il existe des nombreuses solutions lisses dans le domaine de la théorie des cordes, caractérisées par une topologie non triviale (bulles) et sans sources localisées. Dans cette thèse nous analysons quelques-unes parmi les solutions les plus importantes avec les différents objectifs pour lesquels ils sont étudiés. Des solutions lisses en onze dimensions peuvent être interprétées comme microétats BPS de trou noir dans le cadre de la Fuzzball proposal. On peut promouvoir ces microétats à être quasi-BPS en plaçant de supertubes au minimum métastable à l’intérieur de ces solutions. Nous montrons que ces minima peuvent abaisser leur énergie lorsque les bulles se déplacent dans certaines directions dans l’espace des modules, ce qui implique que ces microétats quasi-BPS sont en fait instables. L’énergie dissipée par ces solutions correspond au rayonnement Hawking et on compare le taux d’émission et la fréquence à celles du trou noir correspondant. En modifiant la géométrie asymptotique de ces microétats on pourrait construire des microétats pour des trous noirs BPS sans charge électrique en cinq dimensions. Il faut donc trouver une nouvelle solution de supergravité en cinq dimensions dont la norme du vecteur de Killing passe de positive à nulle dans certaines régions. Nous construisons des exemples explicites où la norme du vecteur de Killing supersymétrique est une fonction réelle non-analytique telle que tous ses dérivés sont nulles à un point où le vecteur de Killing devient nul. Dans la solution de Lin-Lunin-Maldacena on trouve un mécanisme pour briser la supersymétrie similaire à celui utilisé pour les microétats quasi-BPS. Nous analysons l’énergie potentielle de branes M2 polarisés en branes M5. Lorsque les charges des M2 sont parallèles à ceux de la solution, nous trouvons des configurations stables. Lorsque les charges des M2 ne sont pas parallèles, nous trouvons des états métastables qui brisent la supersymétrie et nous analysons le processus de rayonnement d’énergie. Nous analysons aussi la solution de Klebanov-Strassler et construisons sa version T- duale dans la supergravité de type IIA. Pour cela une analyse approfondie est nécessaire pour choisir l’isomérie la plus appropriée. Notre construction est la première étape d’un programme pour tester la stabilité des antibranes dans la supergravité de type IIA. / There exist many smooth solutions in String Theory characterized by a nontrivial topology threaded by fluxes and no localized sources. In this thesis we analyze some of the most important bubbled solutions along with the different purposes they are studied for. Some smooth, eleven-dimensional solutions can be interpreted as BPS black hole microstates in the context of the Fuzzball proposal. One can promote these to be microstates for near-BPS black holes by placing probe supertubes at a metastable minimum inside these solutions. We show that these minima can lower their energy when the bubbles move in certain directions in the moduli space, which implies that these near-BPS microstates are in fact unstable. The decay of these solutions corresponds to Hawking radiation and we compare the emission rate and frequency to those of the corresponding black hole. By modifying the asymptotic behavior of these microstates one could be able to construct microstates for five-dimensional BPS black holes with no electric charge. To do so one needs to find a new supergravity solution in five-dimensions whose Killing vector switches from timelike to null in some open regions. We construct explicit examples where the norm of the supersymmetric Killing vector is a real not-everywhere analytic function such that all its derivatives vanish at a point where the Killing vector becomes null. In the Lin-Lunin-Maldacena solution we find a supersymmetry-breaking mechanism similar to that used for near-BPS microstates. We analyze the potential energy of M2 probes polarized into M5 brane shells. When the charges of the probe are parallel to those of the solution we find stable configurations, while when the charges are opposite we find metastable states that break supersymmetry and analyze the decay process to supersymmetric configurations. We analyze also the Klebanov-Strassler solution and construct its T-dual version in Type IIA. This is done by just reconstructing the solution expanded on a small region of the deformed conifold, after a thorough analysis to choose the most suitable isometry. Our construction is the first step in a program to test the stability of antibranes in Type IIA backgrounds.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22641号 / 医博第4624号 / 新制||医||1044(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 湊谷 謙司, 教授 江藤 浩之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM