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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
101

Vertex model approaches to epithelial tissues in developmental systems

Smith, Aaron January 2012 (has links)
The purpose of this thesis is to develop a vertex model framework that can be used to perform computational experiments related to the dynamics of epithelial tissues in developmental systems. We focus on three example systems: the Drosophila wing imaginal disc, the Drosophila epidermis and the visceral endoderm of the mouse embryo. Within these systems, key questions pertaining to size-control mechanisms and coordination of cell migration remain unanswered and are amenable to computational testing. The vertex model presented here builds upon existing frameworks in three key ways. Firstly, we include novel force terms, representing, for example, the reaction of a cell to being compressed and its shape becoming distorted during a highly dynamic process such as cell migration. Secondly, we incorporate a model of diffusing morphogenetic growth factors within the vertex framework, using an arbitrary Lagrangian-Eulerian formulation of the diffusion equation and solving with the finite-element method (FEM). Finally, we implement the vertex model on the surface of an ellipsoid, in order to simulate cell migration in the mouse embryo. Throughout this thesis, we validate our model by running simple simulations. We demonstrate convergence properties of the FEM scheme and discuss how the time taken to solve the system scales with tissue size. The model is applied to biological systems and its utility demonstrated in several contexts. We show that when growth is dependent on morphogen concentration in the Drosophila wing disc, proliferation occurs preferentially in regions of high concentration. In the Drosophila epidermis, we show that a recently proposed mechanism of compartment size-control, in which a growth-factor is released in limited amounts, is viable. Finally, we examine the phenomenon of rosettes in the mouse embryo, which occur when five or more cells meet at a common vertex. We show, by running simulations both with and without rosettes, that they are crucial facilitators of ordered migration, and are thus critical in the patterning of the early embryo.
102

Mathematical modelling of flow and transport phenomena in tissue engineering

Pearson, Natalie Clare January 2014 (has links)
Tissue engineering has great potential as a method for replacing or repairing lost or damaged tissue. However, progress in the field to date has been limited, with only a few clinical successes despite active research covering a wide range of cell types and experimental approaches. Mathematical modelling can complement experiments and help improve understanding of the inherently complex tissue engineering systems, providing an alternative perspective in a more cost- and time-efficient manner. This thesis focusses on one particular experimental setup, a hollow fibre membrane bioreactor (HFMB). We develop a suite of mathematical models which consider the fluid flow, solute transport, and cell yield and distribution within a HFMB, each relevant to a different setup which could be implemented experimentally. In each case, the governing equations are obtained by taking the appropriate limit of a generalised multiphase model, based on porous flow mixture theory. These equations are then reduced as far as possible, through exploitation of the small aspect ratio of the bioreactor and by considering suitable parameter limits in the subsequent asymptotic analysis. The reduced systems are then either solved numerically or, if possible, analytically. In this way we not only aim to illustrate typical behaviours of each system in turn, but also highlight the dependence of results on key experimentally controllable parameter values in an analytically tractable and transparent manner. Due to the flexibility of the modelling approach, the models we present can readily be adapted to specific experimental conditions given appropriate data and, once validated, be used to inform and direct future experiments.
103

Mathematical modelling of oncolytic virotherapy

Shabala, Alexander January 2013 (has links)
This thesis is concerned with mathematical modelling of oncolytic virotherapy: the use of genetically modified viruses to selectively spread, replicate and destroy cancerous cells in solid tumours. Traditional spatially-dependent modelling approaches have previously assumed that virus spread is due to viral diffusion in solid tumours, and also neglect the time delay introduced by the lytic cycle for viral replication within host cells. A deterministic, age-structured reaction-diffusion model is developed for the spatially-dependent interactions of uninfected cells, infected cells and virus particles, with the spread of virus particles facilitated by infected cell motility and delay. Evidence of travelling wave behaviour is shown, and an asymptotic approximation for the wave speed is derived as a function of key parameters. Next, the same physical assumptions as in the continuum model are used to develop an equivalent discrete, probabilistic model for that is valid in the limit of low particle concentrations. This mesoscopic, compartment-based model is then validated against known test cases, and it is shown that the localised nature of infected cell bursts leads to inconsistencies between the discrete and continuum models. The qualitative behaviour of this stochastic model is then analysed for a range of key experimentally-controllable parameters. Two-dimensional simulations of in vivo and in vitro therapies are then analysed to determine the effects of virus burst size, length of lytic cycle, infected cell motility, and initial viral distribution on the wave speed, consistency of results and overall success of therapy. Finally, the experimental difficulty of measuring the effective motility of cells is addressed by considering effective medium approximations of diffusion through heterogeneous tumours. Considering an idealised tumour consisting of periodic obstacles in free space, a two-scale homogenisation technique is used to show the effects of obstacle shape on the effective diffusivity. A novel method for calculating the effective continuum behaviour of random walks on lattices is then developed for the limiting case where microscopic interactions are discrete.
104

Computational methods for the estimation of cardiac electrophysiological conduction parameters in a patient specific setting

Wallman, Kaj Mikael Joakim January 2013 (has links)
Cardiovascular disease is the primary cause of death globally. Although this group encompasses a heterogeneous range of conditions, many of these diseases are associated with abnormalities in the cardiac electrical propagation. In these conditions, structural abnormalities in the form of scars and fibrotic tissue are known to play an important role, leading to a high individual variability in the exact disease mechanisms. Because of this, clinical interventions such as ablation therapy and CRT that work by modifying the electrical propagation should ideally be optimized on a patient specific basis. As a tool for optimizing these interventions, computational modelling and simulation of the heart have become increasingly important. However, in order to construct these models, a crucial step is the estimation of tissue conduction properties, which have a profound impact on the cardiac activation sequence predicted by simulations. Information about the conduction properties of the cardiac tissue can be gained from electrophysiological data, obtained using electroanatomical mapping systems. However, as in other clinical modalities, electrophysiological data are often sparse and noisy, and this results in high levels of uncertainty in the estimated quantities. In this dissertation, we develop a methodology based on Bayesian inference, together with a computationally efficient model of electrical propagation to achieve two main aims: 1) to quantify values and associated uncertainty for different tissue conduction properties inferred from electroanatomical data, and 2) to design strategies to optimise the location and number of measurements required to maximise information and reduce uncertainty. The methodology is validated in several studies performed using simulated data obtained from image-based ventricular models, including realistic fibre orientation and conduction heterogeneities. Subsequently, by using the developed methodology to investigate how the uncertainty decreases in response to added measurements, we derive an a priori index for placing electrophysiological measurements in order to optimise the information content of the collected data. Results show that the derived index has a clear benefit in minimising the uncertainty of inferred conduction properties compared to a random distribution of measurements, suggesting that the methodology presented in this dissertation provides an important step towards improving the quality of the spatiotemporal information obtained using electroanatomical mapping.
105

The evolution of cooperation, especially in humans

El Mouden, Claire M. January 2011 (has links)
I develop social evolution theory to study the evolution of cooperation as follows: (1) Many organisms undergo a dispersal phase prior to breeding; I demonstrate that knowing ones dispersal status aids the evolution of helping (by non-dispersers) and harming (by dispersers). (2) Policing driven by group-benefits may be selected to enforce cooperation in human and animal societies. I extend existing theory to show that policing may be harder to evolve that previously thought, but that it is maintained more readily than it evolves. (3) Archeological and anthropological evidence suggests that warfare was prevalent during our evolution. I show that, contrary to previous suggestions, between-group competition can favour any social behaviour (pro-social or anti-social) so long as it helps the group compete, and that such traits can be altruistic or mutually beneficial. (4) Reproductive leveling is analogous to policing; in the human literature there is doubt as to whether it can evolve. I extend my previous work to consider the coevolution of culturally and genetically inherited traits for reproductive leveling and selfishness. I find that cooperation can evolve between non-kin if they share the same culture. (5) Monogamy is thought to favour the evolution of cooperative breeding. I show that in the simplest case, because of the cost of competition between non-dispersing siblings, the level of promiscuity has little or no effect on the evolution of cooperation. (6) Spatial structure (limited dispersal) is thought to favour the evolution of inter-specific mutualisms as it aligns the partners’ interests. I consider the case of plant-fungi mutualisms and show that spatial structure can disfavour cooperation if it limits the potential fungal partners available to the plant.
106

Insights into the emergence of novel infectious diseases to humans

Kubiak, Ruben J. January 2012 (has links)
Novel infectious diseases in humans are of great concern to public health authorities and researchers in epidemiology. Zoonotic pathogens in particular have the potential to cause epidemics without any or little warning. In this thesis, I investigate evolutionary and environmental conditions, and the interactions between both, which facilitate the zoonotic emergence of novel pathogens. I start with a list of the mechanisms and processes which might influence a zoonotic emergence, and identify some unsolved problems. I address these with multiple, theoretical models. First, I use a village-city model with different adaptation scenarios to examine the influence of spatial heterogeneity on the emergence process. I derive general analytical results for the statistical properties of emergence events, including the probability distribution of outbreak sizes. My results suggest that, for typical connection strengths between communities, spatial heterogeneity has only a weak effect on outbreak size distributions, and on the risk of emergence per introduction. Next, I extend the research on environmental conditions by looking at pathogen specialisation in multi-host systems. I derive threshold connectivities for which generalist pathogens, which infect multiple species and might therefore be more dangerous to cross into the human species, can sustain transmission and are not dominated by specialists, which can only cause sustained transmission chains in a single host species, but are able to cause emergences with little warning. My third research chapter is interested in the effect of the loss of biodiversity. I analytically derive expected prevalences for fast growing and slow growing species. If fast growing species tend to perform better in degraded environments, my analytical results suggest that the overall prevalence level of infectious diseases will rise as environments degrade, which facilitates the chance of zoonotic jumps. In my last research chapter, I examine the actual impact of a novel, emerging infectious disease. I use data from the recent `Swine flu' epidemic in England to estimate epidemiological parameters of the infectious agent. My results suggest that the majority of infected cases showed no or only mild symptoms. This reveals that more data than just the estimated number of cases are necessary to fully evaluate the danger of a possible zoonotic, emerging infectious disease. I conclude by discussing my results and the implications which these might have.
107

Finite element simulation of a poroelastic model of the CSF system in the human brain during an infusion test

Eisenträger, Almut January 2012 (has links)
Cerebrospinal fluid (CSF) fills a system of cavities at the centre of the brain, known as ventricles, and the subarachnoid space surrounding the brain and the spinal cord. In addition, CSF is in free communication with the interstitial fluid of the brain tissue. Disturbances in CSF dynamics can lead to diseases that cause severe brain damage or even death. So-called infusion tests are frequently performed in the diagnosis of such diseases. In this type of test, changes in average CSF pressure are related to changes in CSF volume through infusion of known volumes of additional fluid. Traditionally, infusion tests are analysed with single compartment models, which treat all CSF as part of one compartment and balance fluid inflow, outflow and storage through a single ordinary differential equation. Poroelastic models of the brain, on the other hand, have been used to simulate spatial changes with disease, particularly of the ventricle size, on larger time scales of days, weeks or months. Wirth and Sobey (2008) developed a two-fluid poroelastic model of the brain in which CSF pressure pulsations are linked to arterial blood pressure pulsations. In this thesis, this model is developed further and simulation results are compared to clinical data. At first, the functional form of the compliance, which governs the storage of CSF in single compartment models, is examined by comparison of two different compliance models with clinical data. The derivations of a single-fluid and a two-fluid poroelastic model of the brain in spherical symmetry are laid out in detail and some of the parameters are related to the compliance functions considered earlier. The finite element implementation of the two-fluid model is described and finally simulation results of the average CSF pressure response and the pressure pulsations are compared to clinical data.
108

Comparing stochastic discrete and deterministic continuum models of cell migration

Yates, Christian January 2011 (has links)
Multiscale mathematical modelling is one of the major driving forces behind the systems biology revolution. The inherently interdisciplinary nature of its study and the multiple spatial and temporal scales which characterise its dynamics make cell migration an ideal candidate for a systems biology approach. Due to its ease of analysis and its compatibility with the type of data available, phenomenological continuum modelling has long been the default framework adopted by the cell migration modelling community. However, in recent years, with increased computational power, complex, discrete, cell-level models, able to capture the detailed dynamics of experimental systems, have become more prevalent. These two modelling paradigms have complementary advantages and disadvantages. The challenge now is to combine these two seemingly disparate modelling regimes in order to exploit the benefits offered by each in a comprehensive, multiscale equivalence framework for modelling cell migration. The main aim of this thesis is to begin with an on-lattice, individual-based model and derive a continuum, population-based model which is equivalent to it in certain limits. For simple models this is relatively easy to achieve: beginning with a one-dimensional, discrete model of cell migration on a regular lattice we derive a partial differential equation for the evolution of cell density on the same domain. We are also able to simply incorporate various signal sensing dynamics into our fledgling equivalence framework. However, as we begin to incorporate more complex model attributes such as cell proliferation/death, signalling dynamics and domain growth we find that deriving an equivalent continuum model requires some innovative mathematics. The same is true when considering a non-uniform domain discretisation in the one-dimensional model and when determining appropriate domain discretisations in higher dimensions. Higher-dimensional simulations of individual-based models bring with them their own computational challenges. Increased lattice sites in order to maintain spatial resolution and increased cell numbers in order to maintain consistent densities lead to dramatic reductions in simulation speeds. We consider a variety of methods to increase the efficiency of our simulations and derive novel acceleration techniques which can be applied to general reaction systems but are especially useful for our spatially extended cell migration algorithms. The incorporation of domain growth in higher dimensions is the final hurdle we clear on our way to constructing a complex discrete-continuum modelling framework capable of representing signal-mediated cell migration on growing (possibly non-standard) domains in multiple dimensions.
109

Excluded-volume effects in stochastic models of diffusion

Bruna, Maria January 2012 (has links)
Stochastic models describing how interacting individuals give rise to collective behaviour have become a widely used tool across disciplines—ranging from biology to physics to social sciences. Continuum population-level models based on partial differential equations for the population density can be a very useful tool (when, for large systems, particle-based models become computationally intractable), but the challenge is to predict the correct macroscopic description of the key attributes at the particle level (such as interactions between individuals and evolution rules). In this thesis we consider the simple class of models consisting of diffusive particles with short-range interactions. It is relevant to many applications, such as colloidal systems and granular gases, and also for more complex systems such as diffusion through ion channels, biological cell populations and animal swarms. To derive the macroscopic model of such systems, previous studies have used ad hoc closure approximations, often generating errors. Instead, we provide a new systematic method based on matched asymptotic expansions to establish the link between the individual- and the population-level models. We begin by deriving the population-level model of a system of identical Brownian hard spheres. The result is a nonlinear diffusion equation for the one-particle density function with excluded-volume effects enhancing the overall collective diffusion rate. We then expand this core problem in several directions. First, for a system with two types of particles (two species) we obtain a nonlinear cross-diffusion model. This model captures both alternative notions of diffusion, the collective diffusion and the self-diffusion, and can be used to study diffusion through obstacles. Second, we study the diffusion of finite-size particles through confined domains such as a narrow channel or a Hele–Shaw cell. In this case the macroscopic model depends on a confinement parameter and interpolates between severe confinement (e.g., a single- file diffusion in the narrow channel case) and an unconfined situation. Finally, the analysis for diffusive soft spheres, particles with soft-core repulsive potentials, yields an interaction-dependent non-linear term in the diffusion equation.
110

Exploring the fold space preferences of ancient and newborn protein superfamilies

Edwards, Hannah Elizabeth January 2014 (has links)
Protein evolution is a complex and diverse process, yielding an incredible assortment of biological functions and pathways occurring in the cells of living organisms. The way in which a protein's structure is constrained by its functional role and its notable conservation across even distant evolutionary relationships highlight structure as an important unit when considering the evolutionary dynamics of proteins. This thesis attempts to place the structural landscape of the protein universe within an evolutionary framework. We investigate potential evolutionary histories of protein superfamilies by introducing an age, which estimates when the ancestor of that superfamily first evolved. The range of ages of known protein superfamilies goes right back to those which evolved before the diversification of life into three major superkingdoms. The structures of these proteins are varied but those which have evolved more recently tend to be shorter and have a less elaborate globular packing. Protein structures sit within a complex global landscape of three-dimensional folds and we attempt to model the dynamics of this space using networks of folds. These networks consist of a structurally diverse core of folds with older ages, and neighbouring folds tend to be of similar ages. Moreover, there are a few pivotal folds which appear repeatedly as central in the landscapes, connecting together otherwise disparate portions of the space. Sequence profiles which capture patterns of conservation and variation amongst naturally occurring proteins within a superfamily can be compared to identify distant evolutionary relationships. The power of these profiles to detect such relationships is improved by seeding them with structural alignments. A landscape of evolutionary links crossing between different protein folds is presented.

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