The vascular endothelial growth factor (VEGF) family is prominently involved in angiogenesis, the formation of new vasculature. Overexpression has been linked to pathological conditions including solid tumor growth. Responses to VEGF are mediated by Flt-1 and KDR, two cell-surface receptors selectively expressed by vascular endothelial cells. A secreted form of Flt-1 (sFlt1) retains high affinity for VEGF and can compete for VEGF binding, thereby inhibiting angiogenic responses. In this study, a computational model of this ligand-receptor binding system is used to quantitatively describe the activation of KDR signaling by VEGF and its inhibition by sFlt-1. The model consists of a system of 12 ordinary differential equations, based on mass action kinetics, which describe, based on mass-action kinetics, the formation and disappearance of receptor-ligand complexes competent to transduce a VEGF signal. Cell-based assays were used to test predictions of the in silico model by measuring dynamics of 1) KDR tyrosine hosphorylation and 2) generation of intracellular second messengers in response to VEGF stimulation in the presence and absence of sFlt-1. Results indicate that the model predicts well the maximal activation in the presence of VEGF-A or the KDR-selective agonist VEGF-E. Subsequent characteristics of binding, such as time-to-peak activations, were less realistically modeled, suggesting that the mathematical descriptions of certain receptor fates (receptor internalization, sequestration or externalization) may need refinement. Also presented are the results of KDR activation experiments in the simultaneous presence of VEGF-A, sFlt1, and the Flt1-selective agonist placental growth factor (PlGF). Here, the model predicts accurately the percentage of inhibition of maximal activation when sFlt-1 is present in the system. Finally, a revised model that includes receptor heterodimerization is presented that suggests sFlt-1 can more effectively inhibit VEGF binding and activation when acting in a dominant negative fashion. Overall, the findings support the idea that the early events in VEGF signaling can be modeled successfully. A natural extension of the model, refined based on experimental testing, will be its application to normal physiological systems. / Ph. D.

Foliage is very common feature in the habitats of echolocation bats and thus its echoes constitute the major input of bats' sensory systems. Acquiring useful information from vegetation echoes facilitates the bats significantly in the navigation and foraging behaviors. To better understand the foliage echoes, in this dissertation, a computer model was constructed to simulate foliage echoes with following simplifications: approximating leaves as circular disks, leaving out shading effects between leaves, and distributing leaves uniformly in the space. Then one tree can be described with three parameters in the model, leaf radius, orientation, and leaf density, where the first two determine the beampattern of each leaf. Compared with echoes collected from real trees, the simulation echoes are qualitatively accurate, i.e., they match in waveforms and also first-order statistics. Since the ground truth is known in the model, the three parameters were estimated with lasso model by selecting 40 features from each echo. The results have shown that estimation of one parameter with the other two known is usually successful with coefficient of determination close to one, and the classification still has reasonable accuracy when the number of known parameter is reduced to one. Besides, the three simplifications were examined with both experimental and simulation approaches. To assess the acoustic impact of leaf geometry on individual leaves, experiments were carried out by ensonifying leaves from both a single and different species. How the leaves' impulse responses change according to their equivalent radii was investigated. The simulation model of disks fits the experiments done with real leaves within one species and across species reasonably well. Shading effect is found to exist locally when two disks were 25 cm apart and were both in pulse direction. In addition, the inhomogeneous distribution of leaves was introduced by using the branching patterns of L-system. The evaluation of inhomogeneity in echoes produced with two distributions shows that there is always inhomogeneity in echoes, and L-system model does bring more inhomogeneity but not to the same extent as changes in the relative orientation between sonar beam and foliage do. / Ph. D.

In this thesis, a model of motion integration is described which is based on a recursive Bayesian estimation process. The model displays a dynamic behaviour qualitatively similar to the dynamics of the motion integration process observed experimentally in smooth eye pursuit and plaid perception. The computer simulations of the model applied to smooth pursuit eye movements confirm the psychophysical data both in humans and monkeys, and the physiological data in monkeys. The temporal dynamics of motion integration is demonstrated together with its dependence on contrast, size of the stimulus and added noise. A new theoretical approach to explaining plaid perception has been developed, based on both the application of the model and a novel geometrical analysis of the plaid’s pattern. It is shown that the results from simulating the model are consistent with the psychophysical data about the plaid motion. Furthermore, by formulating the model as an approximate version of a Kalman filter algorithm, it is shown that the model can be put into a neurally plausible, distributed recurrent form which coarsely corresponds to the recurrent circuitry of visual cortical areas V1 and MT. The model thus provides further support for the notion that the motion integration process is based on a form of Bayesian estimation, as has been suggested by many psychophysical studies, and moreover suggests that the observed dynamic properties of this process are the result of the recursive nature of the motion estimation.

The aim of this thesis is to design and implement a cognitively plausible theory of sentence processing which incorporates a mechanism for modeling a prediction and verification process in human language understanding, and to evaluate the validity of this model on specific psycholinguistic phenomena as well as on broad-coverage, naturally occurring text. Modeling prediction is a timely and relevant contribution to the field because recent experimental evidence suggests that humans predict upcoming structure or lexemes during sentence processing. However, none of the current sentence processing theories capture prediction explicitly. This thesis proposes a novel model of incremental sentence processing that offers an explicit prediction and verification mechanism. In evaluating the proposed model, this thesis also makes a methodological contribution. The design and evaluation of current sentence processing theories are usually based exclusively on experimental results from individual psycholinguistic experiments on specific linguistic structures. However, a theory of language processing in humans should not only work in an experimentally designed environment, but should also have explanatory power for naturally occurring language. This thesis first shows that the Dundee corpus, an eye-tracking corpus of newspaper text, constitutes a valuable additional resource for testing sentence processing theories. I demonstrate that a benchmark processing effect (the subject/object relative clause asymmetry) can be detected in this data set (Chapter 4). I then evaluate two existing theories of sentence processing, Surprisal and Dependency Locality Theory (DLT), on the full Dundee corpus. This constitutes the first broad-coverage comparison of sentence processing theories on naturalistic text. I find that both theories can explain some of the variance in the eye-movement data, and that they capture different aspects of sentence processing (Chapter 5). In Chapter 6, I propose a new theory of sentence processing, which explicitly models prediction and verification processes, and aims to unify the complementary aspects of Surprisal and DLT. The proposed theory implements key cognitive concepts such as incrementality, full connectedness, and memory decay. The underlying grammar formalism is a strictly incremental version of Tree-adjoining Grammar (TAG), Psycholinguistically motivated TAG (PLTAG), which is introduced in Chapter 7. I then describe how the Penn Treebank can be converted into PLTAG format and define an incremental, fully connected broad-coverage parsing algorithm with associated probability model for PLTAG. Evaluation of the PLTAG model shows that it achieves the broad coverage required for testing a psycholinguistic theory on naturalistic data. On the standardized Penn Treebank test set, it approaches the performance of incremental TAG parsers without prediction (Chapter 8). Chapter 9 evaluates the psycholinguistic aspects of the proposed theory by testing it both on a on a selection of established sentence processing phenomena and on the Dundee eye-tracking corpus. The proposed theory can account for a larger range of psycholinguistic case studies than previous theories, and is a significant positive predictor of reading times on broad-coverage text. I show that it can explain a larger proportion of the variance in reading times than either DLT integration cost or Surprisal.

The intracellular Ca2+ handling system in a cardiac myocyte is of crucial importance. It regulates the contraction and relaxation of the myocyte during the excitation-contraction (EC) coupling. A normal intracellular Ca2+ handling system keeps the contraction of the heart orderly, which represents a powerful force to pump blood to the whole body. However, disarrayed or remodelled cellular structure associated with the intracellular Ca2+ handling system at the subcellular level, such as loss of T-tubule network in diseased conditions, may promote abnormal cardiac EC coupling, leading to genesis of cardiac arrhythmias impairing cardiac mechanical functions. Up to date, it is still incompletely understood how the intracellular Ca2+ handling system is altered by changes in subcellular structures of Ca2+ handling systems. In this thesis, biophysically detailed computational models for the intracellular Ca2+ handling system of a cardiac cell were developed, providing a powerful platform to investigate the spatio-temporal complexity associated with the intracellular Ca2+ handling, and its role in generating abnormal cardiac EC coupling. First, a well-validated single cell model was used to investigate how the diastolic and systolic Ca2+ concentration responded to alterations in the model parameters related to the Ca2+ handling system, from which the mechanisms underlying the rate-dependence of EC coupling were analysed. Then, a novel single cell model, with a 2D presentation of the spatial structures of subcellular Ca2+ handling and membrane action potential, of a sheep atrial myocyte was developed for simulating the abnormal intracellular Ca2+ regulation system due to the loss of T-tubules during atrial fibrillation. Variant scenarios of T-tubule loss were considered to investigate the role of the T-tubule in affecting the intracellular Ca2+ regulation. Furthermore, membrane currents' alterations due to the electrical remodelling arising from atrial fibrillation were considered together with the loss of T-tubule. Three typical types of abnormal Ca2+ cycling phenomenon, namely intracellular Ca2+ alternans, spontaneous Ca2+ sparks and intracellular Ca2+ waves were observed in AF conditions. The relationship between T-tubule loss, AF-remodelling and the genesis of delayed afterdepolarizations (DADs) was also investigated. It was shown that the loss of T-tubule in AF condition played an important role in disturbing the Ca2+ regulation system, which increases the risk for a cell to generate impaired contraction.

Clearwells are large water reservoirs often used at the end of the water treatment process as chlorine contact chambers. Contact time required for microbe destruction is provided by residence time within the clearwell. The residence time distribution can be determined from tracer tests and is the one of the key factors in assessing the hydraulic behaviour and efficiency of these reservoirs. This work provides an evaluation of whether the two-dimensional, depth-averaged, finite element model, River2DMix can adequately simulate the flow pattern and residence time distribution in clearwells. One question in carrying out this modelling is whether or not the structural columns in the reservoir need to be included, as inclusion of the columns increases the computational effort required.<p> In this project, the residence time distribution predicted by River2DMix was compared to results of tracer tests in a scale model of the Calgary Glenmore water treatment plant northeast clearwell. Results from tracer tests in this clearwell were available. The clearwell has a serpentine baffle system and 122 square structural columns distributed throughout the flow. A comparison of the flow patterns in the hydraulic and computational models was also made. The hydraulic model tests were carried out with and without columns in the clearwell.<p> The 1:19 scale hydraulic model was developed on the basis of Froude number similarity and the maintenance of minimum Reynolds numbers in the flow through the serpentine system and the baffle wall at the entrance to the clearwell. Fluorescent tracer slug injection tests were used to measure the residence time distribution in the clearwell. Measurements of tracer concentration were taken at the clearwell outlet using a continuous flow-through fluorometer system. Flow visualization was also carried out using dye to identify and assess the dead zones in the flow. It was found that it was necessary to ensure the flow in the scale model was fully developed before starting the tracer tests, and determining the required flow development time to ensure steady state results from the tracer tests became an additional objective of the work. Tests were carried out at scale model flows of 0.85, 2.06, and 2.87 L/s to reproduce the 115, 280, and 390 ML/day flows seen in the prototype tracer tests.<p> Scale model results of the residence time distribution matched the prototype tracer test data well. However, approximately 10.5 hours was required for flow development at the lowest flow rate tested (0.85 L/s) before steady state conditions were reached and baffle factor results matched prototype values. At the intermediate flow, baffle factor results between the scale model and prototype matched well after only 1 h of flow development time, with improvements only in the Morril dispersion index towards prototype values with increased flow development time (at 5 h). Similar results were seen at the highest flow tested. For fully developed flow, there was little change in the baffle factor and dispersion index results in the scale model with varied flow rate.<p> With the addition of columns to the scale model, there was no significant change in the baffle factor compared to the case compared to without the columns, but up to a 13.9 % increase in dispersion index as compared to the tests in the scale model without columns for fully developed flow. Further, the residence time distribution results from the scale model tests without columns matched the entire residence time distribution found in the prototype tests. However, for the model with columns, the residence time distribution matched the prototype curve well at early times, but departed significantly from it at times later in the tests. It appears the major effect of the addition of columns within a model clearwell is to increase the dispersion index and increase the proportion of the clearwell which operates as a mixed reactor.<p> The results also showed there was good agreement between the physical model tests and River2DMix simulations of the scale model tests for both the flow pattern and residence time distributions. This indicates that a two-dimensional depth-averaged computer model such as River2DMix can provide representative simulation results in the case where the inlet flow is expected to be quickly mixed throughout the depth of flow in the clearwell.

Clearwells are large water reservoirs often used at the end of the water treatment process as chlorine contact chambers. Contact time required for microbe destruction is provided by residence time within the clearwell. The residence time distribution can be determined from tracer tests and is the one of the key factors in assessing the hydraulic behaviour and efficiency of these reservoirs. This work provides an evaluation of whether the two-dimensional, depth-averaged, finite element model, River2DMix can adequately simulate the flow pattern and residence time distribution in clearwells. One question in carrying out this modelling is whether or not the structural columns in the reservoir need to be included, as inclusion of the columns increases the computational effort required.<p> In this project, the residence time distribution predicted by River2DMix was compared to results of tracer tests in a scale model of the Calgary Glenmore water treatment plant northeast clearwell. Results from tracer tests in this clearwell were available. The clearwell has a serpentine baffle system and 122 square structural columns distributed throughout the flow. A comparison of the flow patterns in the hydraulic and computational models was also made. The hydraulic model tests were carried out with and without columns in the clearwell.<p> The 1:19 scale hydraulic model was developed on the basis of Froude number similarity and the maintenance of minimum Reynolds numbers in the flow through the serpentine system and the baffle wall at the entrance to the clearwell. Fluorescent tracer slug injection tests were used to measure the residence time distribution in the clearwell. Measurements of tracer concentration were taken at the clearwell outlet using a continuous flow-through fluorometer system. Flow visualization was also carried out using dye to identify and assess the dead zones in the flow. It was found that it was necessary to ensure the flow in the scale model was fully developed before starting the tracer tests, and determining the required flow development time to ensure steady state results from the tracer tests became an additional objective of the work. Tests were carried out at scale model flows of 0.85, 2.06, and 2.87 L/s to reproduce the 115, 280, and 390 ML/day flows seen in the prototype tracer tests.<p> Scale model results of the residence time distribution matched the prototype tracer test data well. However, approximately 10.5 hours was required for flow development at the lowest flow rate tested (0.85 L/s) before steady state conditions were reached and baffle factor results matched prototype values. At the intermediate flow, baffle factor results between the scale model and prototype matched well after only 1 h of flow development time, with improvements only in the Morril dispersion index towards prototype values with increased flow development time (at 5 h). Similar results were seen at the highest flow tested. For fully developed flow, there was little change in the baffle factor and dispersion index results in the scale model with varied flow rate.<p> With the addition of columns to the scale model, there was no significant change in the baffle factor compared to the case compared to without the columns, but up to a 13.9 % increase in dispersion index as compared to the tests in the scale model without columns for fully developed flow. Further, the residence time distribution results from the scale model tests without columns matched the entire residence time distribution found in the prototype tests. However, for the model with columns, the residence time distribution matched the prototype curve well at early times, but departed significantly from it at times later in the tests. It appears the major effect of the addition of columns within a model clearwell is to increase the dispersion index and increase the proportion of the clearwell which operates as a mixed reactor.<p> The results also showed there was good agreement between the physical model tests and River2DMix simulations of the scale model tests for both the flow pattern and residence time distributions. This indicates that a two-dimensional depth-averaged computer model such as River2DMix can provide representative simulation results in the case where the inlet flow is expected to be quickly mixed throughout the depth of flow in the clearwell.

<p>Impulse propagation in cardiac muscle is determined not only by the excitable properties of the myocyte membrane, but also by the gross and fine structure of cardiac muscle. Ionic diffusion pathways are defined by the muscle's interconnected myocytes and interweaving interstitial spaces. Resistive variations arising from spatial changes in tissue structure, including geometry, composition and electrical properties have a significant impact on the success or failure of impulse propagation. Although much as been learned about the impact of discrete resistive architecture of the intracellular space, the role of the interstitial space in the spread of electrical activity is less well understood or appreciated at the microscopic scale. </p><p>The interstitial space, or interstitium, occupies from 20-25% of the total heart volume. </p><p>The structural and material composition of the interstitial space is both complex and </p><p>heterogeneous, encompassing non-myocyte cell structures and a conglomeration of </p><p>extracellular matrix proteins. The spatial distribution of the interstitium can vary from confined spaces between abutting myocytes and tightly packed cardiac fibers to large gaps between cardiac bundles and sheets</p><p>This work presents a discrete multidomain formulation that describes the three-dimensional ionic diffusion pathways between connected myocytes within a variable interstitial physiology and morphology. Unlike classically used continuous and discontinuous models of impulse propagation, the intracellular and extracellular spaces are represented as spatially distinct volumes with dynamic and static boundary conditions that electrically couple neighboring spaces to form the electrically cooperative tissue model. The discrete multidomain model provides a flexible platform to simulate impulse propagation at the microscopic scale within a three-dimensional context. The three-dimensional description of the interstitial space that </p><p>encompasses a single cell improves the capability of the model to realistically investigate the impact of the discontinuous and electrotonic inhomogeneities of the myocardium's interstitium.</p><p>Under the discrete multidomain representation, a non-uniformly described interstitium </p><p>capturing the passive properties of the intravascular space or variable distribution and </p><p>composition of the extracellular space that encompasses a cardiac fiber creates an </p><p>electrotonic load perpendicular to the direction of the propagating wavefront. During </p><p>longitudinal propagation along a cardiac fiber, results demonstrate waveshape </p><p>alterations due to variations in loads experienced radially that would have been otherwise masked in traditional model descriptions. Findings present a mechanism for eliminating myocyte membrane participation in impulse propagation, as the result of decreased loading experienced radially from a non-uniformly resistive extracellular space. Ultimately, conduction velocity increases by decreasing the "effective" surface-to-volume ratio, as theoretically hypothesized to occur in the conducting Purkinje tissue.</p> / Dissertation

In the field of orthopaedics and traumatology, a whole series of problems appear related to fracture fixation by means of various types of plates. Appropriate application of the plate is the difficult task that a doctor needs to deal with in the operating room. Regarding mechanics, the number of screws and their spacing have a major impact on the healing process. If there are too many screws or lack of them, the fracture does not heal properly. This can lead to implant failure. This work deals with stress-strain analysis of screws and bone tissue with a fracture fixed by LCP. It deals with the influence of different geometrical configurations of the screws on the stress, deformation and strain of the system. For this purpose, the computational modelling was used by means of the finite element method. Two computational models have been created, on which different screw arrangement was analysed. The first computational model represents diaphysis of the femur that is at the beginning of the healing process. For the four load models and eleven geometric configurations and number of the screws, a total of 44 computations were performed. The second computational model represents the distal part of the femur. Femoral geometry model was created based on CT (computed tomography) examination, geometric model of the plate was created by 3D scanning. Deformations and stresses were compared in the three geometric configurations of the screws during the healing process.

The aim of this thesis is to assemble simplified computational 3D model for straw grate combustion, based on data provided by detailed computational 1D model. This thesis is organized as follows. Firstly, current state of CFD grate combustion modelling is described. The main body of this thesis is focused on creation simplified 3D model, which includes pressure losses calculation, aproximation of data provided by outcomes of detailed 1D model and analysis of heat transfer during combustion process. Simulation results dealing with radiation heat transfer and heat conductivity are included in conclusion.