Stochastic modelling of T cell homeostasis for two competing clonotypes via the master equation

Stochastic models for competing clonotypes of T cells by multivariate, continuous-time, discrete state, Markov processes have been proposed in the literature by Stirk, Molina-París and van den Berg (2008). A stochastic modelling framework is important because of rare events associated with small populations of some critical cell types. Usually, computational methods for these problems employ a trajectory-based approach, based on Monte Carlo simulation. This is partly because the complementary, probability density function (PDF) approaches can be expensive but here we describe some efficient PDF approaches by directly solving the governing equations, known as the Master Equation. These computations are made very efficient through an approximation of the state space by the Finite State Projection and through the use of Krylov subspace methods when evolving the matrix exponential. These computational methods allow us to explore the evolution of the PDFs associated with these stochastic models, and bimodal distributions arise in some parameter regimes. Time-dependent propensities naturally arise in immunological processes due to, for example, age-dependent effects. Incorporating time-dependent propensities into the framework of the Master Equation significantly complicates the corresponding computational methods but here we describe an efficient approach via Magnus formulas. Although this contribution focuses on the example of competing clonotypes, the general principles are relevant to multivariate Markov processes and provide fundamental techniques for computational immunology.

Parameter estimation for a phenomenological model of the cardiac action potential

The action potential (ap) of a cardiac cell is made up of a complex balance of ionic currents which flow across the cell membrane in response to electrical excitation of the cell. Biophysically detailed mathematical models of the ap have grown larger in terms of the variables and parameters required to model new findings in subcellular ionic mechanisms. The fitting of parameters to such models has seen a large degree of parameter and module re-use from earlier models. An alternative method for modelling electrically exciteable cardiac tissue is a phenomenological model, which reconstructs tissue level ap wave behaviour without subcellular details. A new parameter estimation technique to fit the morphology of the ap in a four variable phenomenological model is presented. An approximation of a nonlinear ordinary differential equation model is established that corresponds to the given phenomenological model of the cardiac ap. The parameter estimation problem is converted into a minimisation problem for the unknown parameters. A modified hybrid Nelder–Mead simplex search and particle swarm optimization is then used to solve the minimisation problem for the unknown parameters. The successful fitting of data generated from a well known biophysically detailed model is demonstrated. A successful fit to an experimental ap recording that contains both noise and experimental artefacts is also produced. The parameter estimation method’s ability to fit a complex morphology to a model with substantially more parameters than previously used is established.

Stochastic simulation for spatial modelling of dynamic process in a living cell

One of the fundamental motivations underlying computational cell biology is to gain insight into the complicated dynamical processes taking place, for example, on the plasma membrane or in the cytosol of a cell. These processes are often so complicated that purely temporal mathematical models cannot adequately capture the complex chemical kinetics and transport processes of, for example, proteins or vesicles. On the other hand, spatial models such as Monte Carlo approaches can have very large computational overheads. This chapter gives an overview of the state of the art in the development of stochastic simulation techniques for the spatial modelling of dynamic processes in a living cell.

Aircraft emission reduction through multi-disciplinary flight path optimisation

There is worldwide interest in reducing aircraft emissions. The difficulty of reducing emissions including water vapour, carbon dioxide (CO2) and oxides of nitrogen (NOx) is mainly due from the fact that a commercial aircraft is usually designed for a particular optimal cruise altitude but may be requested or required to operate and deviate at different altitude and speeds to archive a desired or commanded flight plan, resulting in increased emissions. This is a multi- disciplinary problem with multiple trade-offs such as optimising engine efficiency, minimising fuel burnt, minimise emissions while maintaining aircraft separation and air safety. This project presents the coupling of an advanced optimisation technique with mathematical models and algorithms for aircraft emission reduction through flight optimisation. Numerical results show that the method is able to capture a set of useful trade-offs between aircraft range and NOx, and mission fuel consumption and NOx. In addition, alternative cruise operating conditions including Mach and altitude that produce minimum NOx and CO2 (minimum mission fuel weight) are suggested.

Phenomenological modeling of cell-to-cell and beat-to-beat variability in isolated Guinea Pig ventricular myocytes

Experimental action potential (AP) recordings in isolated ventricular myoctes display significant temporal beat-to-beat variability in morphology and duration. Furthermore, significant cell-to-cell differences in AP also exist even for isolated cells originating from the same region of the same heart. However, current mathematical models of ventricular AP fail to replicate the temporal and cell-to-cell variability in AP observed experimentally. In this study, we propose a novel mathematical framework for the development of phenomenological AP models capable of capturing cell-to-cell and temporal variabilty in cardiac APs. A novel stochastic phenomenological model of the AP is developed, based on the deterministic Bueno-Orovio/Fentonmodel. Experimental recordings of AP are fit to the model to produce AP models of individual cells from the apex and the base of the guinea-pig ventricles. Our results show that the phenomenological model is able to capture the considerable differences in AP recorded from isolated cells originating from the location. We demonstrate the closeness of fit to the available experimental data which may be achieved using a phenomenological model, and also demonstrate the ability of the stochastic form of the model to capture the observed beat-to-beat variablity in action potential duration.

Modelling and performance evaluation of the IEEE 802.11 DCF for real-time control

Popular wireless networks, such as IEEE 802.11/15/16, are not designed for real-time applications. Thus, supporting real-time quality of service (QoS) in wireless real-time control is challenging. This paper adopts the widely used IEEE 802.11, with the focus on its distributed coordination function (DCF), for soft-real-time control systems. The concept of the critical real-time traffic condition is introduced to characterize the marginal satisfaction of real-time requirements. Then, mathematical models are developed to describe the dynamics of DCF based real-time control networks with periodic traffic, a unique feature of control systems. Performance indices such as throughput and packet delay are evaluated using the developed models, particularly under the critical real-time traffic condition. Finally, the proposed modelling is applied to traffic rate control for cross-layer networked control system design.

Adaptive cache aware multiprocessor scheduling framework

Computer resource allocation represents a significant challenge particularly for multiprocessor systems, which consist of shared computing resources to be allocated among co-runner processes and threads. While an efficient resource allocation would result in a highly efficient and stable overall multiprocessor system and individual thread performance, ineffective poor resource allocation causes significant performance bottlenecks even for the system with high computing resources. This thesis proposes a cache aware adaptive closed loop scheduling framework as an efficient resource allocation strategy for the highly dynamic resource management problem, which requires instant estimation of highly uncertain and unpredictable resource patterns. Many different approaches to this highly dynamic resource allocation problem have been developed but neither the dynamic nature nor the time-varying and uncertain characteristics of the resource allocation problem is well considered. These approaches facilitate either static and dynamic optimization methods or advanced scheduling algorithms such as the Proportional Fair (PFair) scheduling algorithm. Some of these approaches, which consider the dynamic nature of multiprocessor systems, apply only a basic closed loop system; hence, they fail to take the time-varying and uncertainty of the system into account. Therefore, further research into the multiprocessor resource allocation is required. Our closed loop cache aware adaptive scheduling framework takes the resource availability and the resource usage patterns into account by measuring time-varying factors such as cache miss counts, stalls and instruction counts. More specifically, the cache usage pattern of the thread is identified using QR recursive least square algorithm (RLS) and cache miss count time series statistics. For the identified cache resource dynamics, our closed loop cache aware adaptive scheduling framework enforces instruction fairness for the threads. Fairness in the context of our research project is defined as a resource allocation equity, which reduces corunner thread dependence in a shared resource environment. In this way, instruction count degradation due to shared cache resource conflicts is overcome. In this respect, our closed loop cache aware adaptive scheduling framework contributes to the research field in two major and three minor aspects. The two major contributions lead to the cache aware scheduling system. The first major contribution is the development of the execution fairness algorithm, which degrades the co-runner cache impact on the thread performance. The second contribution is the development of relevant mathematical models, such as thread execution pattern and cache access pattern models, which in fact formulate the execution fairness algorithm in terms of mathematical quantities. Following the development of the cache aware scheduling system, our adaptive self-tuning control framework is constructed to add an adaptive closed loop aspect to the cache aware scheduling system. This control framework in fact consists of two main components: the parameter estimator, and the controller design module. The first minor contribution is the development of the parameter estimators; the QR Recursive Least Square(RLS) algorithm is applied into our closed loop cache aware adaptive scheduling framework to estimate highly uncertain and time-varying cache resource patterns of threads. The second minor contribution is the designing of a controller design module; the algebraic controller design algorithm, Pole Placement, is utilized to design the relevant controller, which is able to provide desired timevarying control action. The adaptive self-tuning control framework and cache aware scheduling system in fact constitute our final framework, closed loop cache aware adaptive scheduling framework. The third minor contribution is to validate this cache aware adaptive closed loop scheduling framework efficiency in overwhelming the co-runner cache dependency. The timeseries statistical counters are developed for M-Sim Multi-Core Simulator; and the theoretical findings and mathematical formulations are applied as MATLAB m-file software codes. In this way, the overall framework is tested and experiment outcomes are analyzed. According to our experiment outcomes, it is concluded that our closed loop cache aware adaptive scheduling framework successfully drives co-runner cache dependent thread instruction count to co-runner independent instruction count with an error margin up to 25% in case cache is highly utilized. In addition, thread cache access pattern is also estimated with 75% accuracy.

Optimising container processes at multimodal seaport terminals : an integrated approach and application

A Multimodal Seaport Container Terminal (MSCT) is a complex system which requires careful planning and control in order to operate efficiently. It consists of a number of subsystems that require optimisation of the operations within them, as well as synchronisation of machines and containers between the various subsystems. Inefficiency in the terminal can delay ships from their scheduled timetables, as well as cause delays in delivering containers to their inland destinations, both of which can be very costly to their operators. The purpose of this PhD thesis is to use Operations Research methodologies to optimise and synchronise these subsystems as an integrated application. An initial model is developed for the overall MSCT; however, due to a large number of assumptions that had to be made, as well as other issues, it is found to be too inaccurate and infeasible for practical use. Instead, a method of developing models for each subsystem is proposed that then be integrated with each other. Mathematical models are developed for the Storage Area System (SAS) and Intra-terminal Transportation System (ITTS). The SAS deals with the movement and assignment of containers to stacks within the storage area, both when they arrive and when they are rehandled to retrieve containers below them. The ITTS deals with scheduling the movement of containers and machines between the storage areas and other sections of the terminal, such as the berth and road/rail terminals. Various constructive heuristics are explored and compared for these models to produce good initial solutions for large-sized problems, which are otherwise impractical to compute by exact methods. These initial solutions are further improved through the use of an innovative hyper-heuristic algorithm that integrates the SAS and ITTS solutions together and optimises them through meta-heuristic techniques. The method by which the two models can interact with each other as an integrated system will be discussed, as well as how this method can be extended to the other subsystems of the MSCT.

Quantitative studies of lower motor neuron degeneration in amyotrophic lateral sclerosis : Evidence for exponential decay of motor unit numbers and greatest rate of loss at the site of onset

Objective: To use our Bayesian method of motor unit number estimation (MUNE) to evaluate lower motor neuron degeneration in ALS. Methods: In subjects with ALS we performed serial MUNE studies. We examined the repeatability of the test and then determined whether the loss of MUs was fitted by an exponential or Weibull distribution. Results: The decline in motor unit (MU) numbers was well-fitted by an exponential decay curve. We calculated the half life of MUs in the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and/or extensor digitorum brevis (EDB) muscles. The mean half life of the MUs of ADM muscle was greater than those of the APB or EDB muscles. The half-life of MUs was less in the ADM muscle of subjects with upper limb than in those with lower limb onset. Conclusions: The rate of loss of lower motor neurons in ALS is exponential, the motor units of the APB decay more quickly than those of the ADM muscle and the rate of loss of motor units is greater at the site of onset of disease. Significance: This shows that the Bayesian MUNE method is useful in following the course and exploring the clinical features of ALS. 2012 International Federation of Clinical Neurophysiology.

Developing a predictive contractor satisfaction model (CoSMo) for construction projects

Over the last few decades, construction project performance has been evaluated due to the increase of delays, cost overruns and quality failures. Growing numbers of disputes, inharmonious working environments, conflict, blame cultures, and mismatches of objectives among project teams have been found to be contributory factors to poor project performance. Performance measurement (PM) approaches have been developed to overcome these issues, however, the comprehensiveness of PM as an overall approach is still criticised in terms of the iron triangle; namely time, cost, and quality. PM has primarily focused on objective measures, however, continuous improvement requires the inclusion of subjective measures, particularly contractor satisfaction (Co-S). It is challenging to deal with the two different groups of large and small-medium contractor satisfaction as to date, Co-S has not been extensively defined, primarily in developing countries such as Malaysia. Therefore, a Co-S model is developed in this research which aims to fulfil the current needs in the construction industry by integrating performance measures to address large and small-medium contractor perceptions. The positivist paradigm used in the research was adhered to by reviewing relevant literature and evaluating expert discussions on the research topic. It yielded a basis for the contractor satisfaction model (CoSMo) development which consists of three elements: contractor satisfaction (Co-S) dimensions; contributory factors and characteristics (project and participant). Using valid questionnaire results from 136 contractors in Malaysia lead to the prediction of several key factors of contractor satisfaction and to an examination of the relationships between elements. The relationships were examined through a series of sequential statistical analyses, namely correlation, one-way analysis of variance (ANOVA), t-tests and multiple regression analysis (MRA). Forward and backward MRAs were used to develop Co-S mathematical models. Sixteen Co-S models were developed for both large and small-medium contractors. These determined that the large contractor Malaysian Co-S was most affected by the conciseness of project scope and quality of the project brief. Contrastingly, Co-S for small-medium contractors was strongly affected by the efficiency of risk control in a project. The results of the research provide empirical evidence in support of the notion that appropriate communication systems in projects negatively contributes to large Co-S with respect to cost and profitability. The uniqueness of several Co-S predictors was also identified through a series of analyses on small-medium contractors. These contractors appear to be less satisfied than large contractors when participants lack effectiveness in timely authoritative decision-making and communication between project team members. Interestingly, the empirical results show that effective project health and safety measures are influencing factors in satisfying both large and small-medium contractors. The perspectives of large and small-medium contractors in respect to the performance of the entire project development were derived from the Co-S models. These were statistically validated and refined before a new Co-S model was developed. Developing such a unique model has the potential to increase project value and benefit all project participants. It is important to improve participant collaboration as it leads to better project performance. This study may encourage key project participants; such as client, consultant, subcontractor and supplier; to increase their attention to contractor needs in the development of a project. Recommendations for future research include investigating other participants‟ perspectives on CoSMo and the impact of the implementation of CoSMo in a project, since this study is focused purely on the contractor perspective.

Quantifying the roles of cell motility and cell proliferation in a circular barrier assay

Moving fronts of cells are essential features of embryonic development, wound repair and cancer metastasis. This paper describes a set of experiments to investigate the roles of random motility and proliferation in driving the spread of an initially confined cell population. The experiments include an analysis of cell spreading when proliferation was inhibited. Our data have been analysed using two mathematical models: a lattice-based discrete model and a related continuum partial differential equation model. We obtain independent estimates of the random motility parameter, D, and the intrinsic proliferation rate, λ, and we confirm that these estimates lead to accurate modelling predictions of the position of the leading edge of the moving front as well as the evolution of the cell density profiles. Previous work suggests that systems with a high λ/D ratio will be characterized by steep fronts, whereas systems with a low λ/D ratio will lead to shallow diffuse fronts and this is confirmed in the present study. Our results provide evidence that continuum models, based on the Fisher–Kolmogorov equation, are a reliable platform upon which we can interpret and predict such experimental observations.

A novel testing system for a Cycloidal drive

At present, for mechanical power transmission, Cycloidal drives are most preferred - for compact, high transmission ratio speed reduction, especially for robot joints and manipulator applications. Research on drive-train dynamics of Cycloidal drives is not well-established. This paper presents a testing rig for Cycloidal drives, which would produce data for development of mathematical models and investigation of drive-train dynamics, further aiding in optimising its design

Travelling waves for a velocity–jump model of cell migration and proliferation

Cell invasion, characterised by moving fronts of cells, is an essential aspect of development, repair and disease. Typically, mathematical models of cell invasion are based on the Fisher–Kolmogorov equation. These traditional parabolic models can not be used to represent experimental measurements of individual cell velocities within the invading population since they imply that information propagates with infinite speed. To overcome this limitation we study combined cell motility and proliferation based on a velocity–jump process where information propagates with finite speed. The model treats the total population of cells as two interacting subpopulations: a subpopulation of left–moving cells, $L(x,t)$, and a subpopulation of right–moving cells, $R(x,t)$. This leads to a system of hyperbolic partial differential equations that includes a turning rate, $\Lambda \ge 0$, describing the rate at which individuals in the population change direction of movement. We present exact travelling wave solutions of the system of partial differential equations for the special case where $\Lambda = 0$ and in the limit that $\Lambda \to \infty$. For intermediate turning rates, $0 < \Lambda < \infty$, we analyse the travelling waves using the phase plane and we demonstrate a transition from smooth monotone travelling waves to smooth nonmonotone travelling waves as $\Lambda$ decreases through a critical value $\Lambda_{crit}$. We conclude by providing a qualitative comparison between the travelling wave solutions of our model and experimental observations of cell invasion. This comparison indicates that the small $\Lambda$ limit produces results that are consistent with experimental observations.

Two novel numerical methods for solving the two-dimensional fractional Fitzhugh-Nagumo-monodomain model

Fractional mathematical models represent a new approach to modelling complex spatial problems in which there is heterogeneity at many spatial and temporal scales. In this paper, a two-dimensional fractional Fitzhugh-Nagumo-monodomain model with zero Dirichlet boundary conditions is considered. The model consists of a coupled space fractional diffusion equation (SFDE) and an ordinary differential equation. For the SFDE, we first consider the numerical solution of the Riesz fractional nonlinear reaction-diffusion model and compare it to the solution of a fractional in space nonlinear reaction-diffusion model. We present two novel numerical methods for the two-dimensional fractional Fitzhugh-Nagumo-monodomain model using the shifted Grunwald-Letnikov method and the matrix transform method, respectively. Finally, some numerical examples are given to exhibit the consistency of our computational solution methodologies. The numerical results demonstrate the effectiveness of the methods.

Cell migration and proliferation on homogeneous and non-homogeneous domains : modelling on the scale of individuals and populations

Cell migration is a behaviour critical to many key biological effects, including wound healing, cancerous cell invasion and morphogenesis, the development of an organism from an embryo. However, given that each of these situations is distinctly different and cells are extremely complicated biological objects, interest lies in more basic experiments which seek to remove conflating factors and present a less complex environment within which cell migration can be experimentally examined. These include in vitro studies like the scratch assay or circle migration assay, and ex vivo studies like the colonisation of the hindgut by neural crest cells. The reduced complexity of these experiments also makes them much more enticing as problems to mathematically model, like done here. The primary goal of the mathematical models used in this thesis is to shed light on which cellular behaviours work to generate the travelling waves of invasion observed in these experiments, and to explore how variations in these behaviours can potentially predict differences in this invasive pattern which are experimentally observed when cell types or chemical environment are changed. Relevant literature has already identified the difficulty of distinguishing between these behaviours when using traditional mathematical biology techniques operating on a macroscopic scale, and so here a sophisticated individual-cell-level model, an extension of the Cellular Potts Model (CPM), is been constructed and used to model a scratch assay experiment. This model includes a novel mechanism for dealing with cell proliferations that allowed for the differing properties of quiescent and proliferative cells to be implemented into their behaviour. This model is considered both for its predictive power and used to make comparisons with the travelling waves which result in more traditional macroscopic simulations. These comparisons demonstrate a surprising amount of agreement between the two modelling frameworks, and suggest further novel modifications to the CPM that would allow it to better model cell migration. Considerations of the model’s behaviour are used to argue that the dominant effect governing cell migration (random motility or signal-driven taxis) likely depends on the sort of invasion demonstrated by cells, as easily seen by microscopic photography. Additionally, a scratch assay simulated on a non-homogeneous domain consisting of a ’fast’ and ’slow’ region is also used to further differentiate between these different potential cell motility behaviours. A heterogeneous domain is a novel situation which has not been considered mathematically in this context, nor has it been constructed experimentally to the best of the candidate’s knowledge. Thus this problem serves as a thought experiment used to test the conclusions arising from the simulations on homogeneous domains, and to suggest what might be observed should this non-homogeneous assay situation be experimentally realised. Non-intuitive cell invasion patterns are predicted for diffusely-invading cells which respond to a cell-consumed signal or nutrient, contrasted with rather expected behaviour in the case of random-motility-driven invasion. The potential experimental observation of these behaviours is demonstrated by the individual-cell-level model used in this thesis, which does agree with the PDE model in predicting these unexpected invasion patterns. In the interest of examining such a case of a non-homogeneous domain experimentally, some brief suggestion is made as to how this could be achieved.