So called discrete models have been successfully used in engineering and computational systems biology. This thesis discusses algebraic methods for modeling and analysis of gene regulatory networks within the discrete modeling context. The first chapter gives a background for discrete models and put in context some of the main research problems that have been pursued in this field for the last fifty years. It also outlines the content of each subsequent chapter. The second chapter focuses on the problem of inferring dynamics from the structure (topology) of the network. It also discusses the characterization of the attractor structure of a network when a particular class of functions control the nodes of the network. Chapters~3 and 4 focus on the study of multi-state nested canalyzing functions as biologically inspired functions and the characterization of their dynamics. Chapter 5 focuses on stochastic methods, specifically on the development of a stochastic modeling framework for discrete models. Stochastic discrete modeling is an alternative approach from the well-known mathematical formalizations such as stochastic differential equations and Gillespie algorithm simulations. Within the discrete setting, a framework that incorporates propensity probabilities for activation and degradation is presented. This approach allows a finer analysis of discrete models and provides a natural setup for cell population simulations. Finally, Chapter 6 discusses future research directions inspired by the work presented here. / Ph. D.

In spite of remarkable progress in molecular biology, our understanding of the dynamics and functions of intra- and inter-cellular biological networks has been hampered by their complexity. Kinetics modelling, an important type of mathematical modelling, provides a rigorous and reliable way to reveal the complexity of biological networks. In this thesis, two genetic regulatory networks have been investigated via kinetic models. In the first part of the study, a model is developed to represent the transcriptional regulatory network essential for the circadian rhythms in Drosophila. The model incorporates the transcriptional feedback loops revealed so far in the network of the circadian clock (PER/TIM and VRI/PDP1 loops). Conventional Hill functions are not used to describe the regulation of genes, instead the explicit reactions of binding and unbinding processes of transcription factors to promoters are modelled. The model is described by a set of ordinary differential equations and the parameters are estimated from the in vitro experimental data of the clocks’ components. The simulation results show that the model reproduces sustained circadian oscillations in mRNA and protein concentrations that are in agreement with experimental observations. It also simulates the entrainment by light-dark cycles, the disappearance of the rhythmicity in constant light and the shape of phase response curves resembling that of experimental results. The model is robust over a wide range of parameter variations. In addition, the simulated E-box mutation, perS and perL mutants are similar to that observed in the experiments. The deficiency between the simulated mRNA levels and experimental observations in per01, tim01 and clkJrk mutants suggests some differences in the model from reality. Finally, a possible function of VRI/PDP1 loops is proposed to increase the robustness of the clock. In the second part of the study, the sources of intrinsic noise and the influence of extrinsic noise are investigated on an intracellular viral infection system. The contribution of the intrinsic noise from each reaction is measured by means of a special form of stochastic differential equation, the chemical Langevin equation. The intrinsic noise of the system is the linear sum of the noise in each of the reactions. The intrinsic noise arises mainly from the degradation of mRNA and the transcription processes. Then, the effects of extrinsic noise are studied by means of a general form of stochastic differential equation. It is found that the noise of the viral components grows logarithmically with increasing noise intensities. The system is most susceptible to noise in the virus assembly process. A high level of noise in this process can even inhibit the replication of the viruses. In summary, the success of this thesis demonstrates the usefulness of models for interpreting experimental data, developing hypotheses, as well as for understanding the design principles of genetic regulatory networks.

Self-organizing patterns arise in a variety of ways in nature, the complex patterning observed on animal coats is such an example. It is already known that the mechanisms responsible for pattern formation starts at the developmental stage of an embryo. However, the actual process determining cell fate has been, and still is, unknown. The mathematical interest for pattern formation emerged from the theories formulated by the mathematician and computer scientist Alan Turing in 1952. He attempted to explain the mechanisms behind morphogenesis and how the process of spatial cell differentiation from homogeneous cells lead to organisms with different complexities and shapes. Turing formulated a mathematical theory and proposed a reaction-diffusion system where morphogens, a postulated chemically active substance, moderated the whole mechanism. He concluded that this process was stable as long as diffusion was neglected; otherwise this would lead to a diffusion-driven instability, which is the fundamental part of pattern formation. The mathematical theory describing this process consists of solving partial differential equations and Turing considered deterministic reaction-diffusion systems.   This thesis will start with introducing the reader to the problem and then gradually build up the mathematical theory needed to get an understanding of the stochastic reaction-diffusion systems that is the focus of the thesis. This study will to a large extent simulate stochastic systems using numerical computations and in order to be computationally feasible a compartment-based model will be used. Noise is an inherent part of such systems, so the study will also discuss the effects of noise and morphogen kinetics on different geometries with boundaries of different complexities from one-dimensional cases up to three-dimensions.

In spite of remarkable progress in molecular biology, our understanding of the dynamics and functions of intra- and inter-cellular biological networks has been hampered by their complexity. Kinetics modelling, an important type of mathematical modelling, provides a rigorous and reliable way to reveal the complexity of biological networks. In this thesis, two genetic regulatory networks have been investigated via kinetic models. In the first part of the study, a model is developed to represent the transcriptional regulatory network essential for the circadian rhythms in Drosophila. The model incorporates the transcriptional feedback loops revealed so far in the network of the circadian clock (PER/TIM and VRI/PDP1 loops). Conventional Hill functions are not used to describe the regulation of genes, instead the explicit reactions of binding and unbinding processes of transcription factors to promoters are modelled. The model is described by a set of ordinary differential equations and the parameters are estimated from the in vitro experimental data of the clocks' components. The simulation results show that the model reproduces sustained circadian oscillations in mRNA and protein concentrations that are in agreement with experimental observations. It also simulates the entrainment by light-dark cycles, the disappearance of the rhythmicity in constant light and the shape of phase response curves resembling that of experimental results. The model is robust over a wide range of parameter variations. In addition, the simulated E-box mutation, perS and perL mutants are similar to that observed in the experiments. The deficiency between the simulated mRNA levels and experimental observations in per01, tim01 and clkJrk mutants suggests some differences in the model from reality. Finally, a possible function of VRI/PDP1 loops is proposed to increase the robustness of the clock. In the second part of the study, the sources of intrinsic noise and the influence of extrinsic noise are investigated on an intracellular viral infection system. The contribution of the intrinsic noise from each reaction is measured by means of a special form of stochastic differential equation, the chemical Langevin equation. The intrinsic noise of the system is the linear sum of the noise in each of the reactions. The intrinsic noise arises mainly from the degradation of mRNA and the transcription processes. Then, the effects of extrinsic noise are studied by means of a general form of stochastic differential equation. It is found that the noise of the viral components grows logarithmically with increasing noise intensities. The system is most susceptible to noise in the virus assembly process. A high level of noise in this process can even inhibit the replication of the viruses. In summary, the success of this thesis demonstrates the usefulness of models for interpreting experimental data, developing hypotheses, as well as for understanding the design principles of genetic regulatory networks.