Hopf bifurcation in a gene regulatory network model: Molecular movement causes oscillations

Gene regulatory networks, i.e. DNA segments in a cell which interact with each other indirectly through their RNA and protein products, lie at the heart of many important intracellular signal transduction processes. In this paper we analyse a mathematical model of a canonical gene regulatory network consisting of a single negative feedback loop between a protein and its mRNA (e.g. the Hes1 transcription factor system). The model consists of two partial differential equations describing the spatio-temporal interactions between the protein and its mRNA in a 1-dimensional domain. Such intracellular negative feedback systems are known to exhibit oscillatory behaviour and this is the case for our model, shown initially via computational simulations. In order to investigate this behaviour more deeply, we next solve our system using Greens functions and then undertake a linearized stability analysis of the steady states of the model. Our results show that the diffusion coefficient of the protein/mRNA acts as a bifurcation parameter and gives rise to a Hopf bifurcation. This shows that the spatial movement of the mRNA and protein molecules alone is sufficient to cause the oscillations. This has implications for transcription factors such as p53, NF-$kappa$B and heat shock proteins which are involved in regulating important cellular processes such as inflammation, meiosis, apoptosis and the heat shock response, and are linked to diseases such as arthritis and cancer

Editorial

The last year has been a very busy one for the BMB. We have published 140 articles online, which is over twice the publication rate of the previous year. This reflects the increase in the submission rates and Springer's view that papers should be published online as quickly as possible. In addition, the entire archive of the Bulletin of Mathematical Biology is now available on the Springer website for the journal, digitized back to Vol. 1, No. 1, published in 1939

Modeling the emergence of phenotypic heterogeneity in vascularized tumors

We present a mathematical study of the emergence of phenotypic heterogeneity in vascularized tumors. Our study is based on formal asymptotic analysis and numerical simulations of a system of nonlocal parabolic equations that describes the phenotypic evolution of tumor cells and their nonlinear dynamic interactions with the oxygen, which is released from the intratumoral vascular network. Numerical simulations are carried out both in the case of arbitrary distributions of intratumor blood vessels and in the case where the intratumoral vascular network is reconstructed from clinical images obtained using dynamic optical coherence tomography. The results obtained support a more in-depth theoretical understanding of the eco-evolutionary process which underpins the emergence of phenotypic heterogeneity in vascularized tumors. In particular, our results offer a theoretical basis for empirical evidence indicating that the phenotypic properties of cancer cells in vascularized tumors vary with the distance from the blood vessels, and establish a relation between the degree of tumor tissue vascularization and the level of intratumor phenotypic heterogeneity

Mathematical modelling of the loss of tissue compression responsiveness and its role in solid tumour development

This paper presents a mathematical model of normal and abnormal tissue growth. The modelling focuses on the potential role that stress responsiveness may play in causing proliferative disorders which are at the basis of the development of avascular tumours. In particular, we study how an incorrect sensing of its compression state by a cell population can represent a clonal advantage and can generate hyperplasia and tumour growth with well known characteristics such as compression of the tissue, structural changes in the extracellular matrix, change in the percentage of cell type (normal or abnormal), extracellular matrix and extracellular liquid. A spatially independent description of the phenomenon is given initially by a system of nonlinear ordinary dierential equations which is explicitly solved in some cases of biological interest showing a rst phase in which some abnormal cells simply replace the normal ones, a second phase in which the hyper-proliferation of the abnormal cells causes a progressive compression within the tissue itself, and a third phase in which the tissue reaches a compressed state, which presses on the surrounding environment. A travelling wave analysis is also performed which gives an estimate of the velocity of the growing mass

Modeling virus pandemics in a globally connected world a challenge towards a mathematics for living systems

This editorial paper presents the papers published in a special issue devoted to the modeling and simulation of mutating virus pandemics in a globally connected world. The presentation is proposed in three parts. First, motivations and objectives are presented according to the idea that mathematical models should go beyond deterministic population dynamics by considering the multiscale, heterogeneous features of the complex system under consideration. Subsequently, the contents of the papers in this issue are presented referring to the aforementioned complexity features. Finally, a critical analysis of the overall contents of the issue is proposed, with the aim of providing a forward look to research perspectives.PostprintPeer reviewe

Evolutionary Dynamics in Vascularised Tumours under Chemotherapy: Mathematical Modelling, Asymptotic Analysis and Numerical Simulations

We consider a mathematical model for the evolutionary dynamics of tumour cells in vascularised tumours under chemotherapy. The model comprises a system of coupled partial integro-differential equations for the phenotypic distribution of tumour cells, the concentration of oxygen and the concentration of a chemotherapeutic agent. In order to disentangle the impact of different evolutionary parameters on the emergence of intra-tumour phenotypic heterogeneity and the development of resistance to chemotherapy, we construct explicit solutions to the equation for the phenotypic distribution of tumour cells and provide a detailed quantitative characterisation of the long-time asymptotic behaviour of such solutions. Analytical results are integrated with numerical simulations of a calibrated version of the model based on biologically consistent parameter values. The results obtained provide a theoretical explanation for the observation that the phenotypic properties of tumour cells in vascularised tumours vary with the distance from the blood vessels. Moreover, we demonstrate that lower oxygen levels may correlate with higher levels of phenotypic variability, which suggests that the presence of hypoxic regions supports intra-tumour phenotypic heterogeneity. Finally, the results of our analysis put on a rigorous mathematical basis the idea, previously suggested by formal asymptotic results and numerical simulations, that hypoxia favours the selection for chemoresistant phenotypic variants prior to treatment. Consequently, this facilitates the development of resistance following chemotherapy

Periodic solutions of a delayed predator-prey model with stage structure for predator

A periodic time-dependent Lotka-Volterra-type predator-prey model with stage structure for the predator and time delays due to negative feedback and gestation is investigated. Sufficient conditions are derived, respectively, for the existence and global stability of positive periodic solutions to the proposed model

Bridging the gap between individual-based and continuum models of growing cell populations

Continuum models for the spatial dynamics of growing cell populations have been widely used to investigate the mechanisms underpinning tissue development and tumour invasion. These models consist of nonlinear partial differential equations that describe the evolution of cellular densities in response to pressure gradients generated by population growth. Little prior work has explored the relation between such continuum models and related single-cell-based models. We present here a simple stochastic individual-based model for the spatial dynamics of multicellular systems whereby cells undergo pressure-driven movement and pressure-dependent proliferation. We show that nonlinear partial differential equations commonly used to model the spatial dynamics of growing cell populations can be formally derived from the branching random walk that underlies our discrete model. Moreover, we carry out a systematic comparison between the individual-based model and its continuum counterparts, both in the case of one single cell population and in the case of multiple cell populations with different biophysical properties. The outcomes of our comparative study demonstrate that the results of computational simulations of the individual-based model faithfully mirror the qualitative and quantitative properties of the solutions to the corresponding nonlinear partial differential equations. Ultimately, these results illustrate how the simple rules governing the dynamics of single cells in our individual-based model can lead to the emergence of complex spatial patterns of population growth observed in continuum models

A hybrid discrete-continuum approach to model Turing pattern formation

Since its introduction in 1952, with a further refinement in 1972 by Gierer and Meinhardt, Turing's (pre-)pattern theory (the chemical basis of morphogenesis) has been widely applied to a number of areas in developmental biology, where evolving cell and tissue structures are naturally observed. The related pattern formation models normally comprise a system of reaction-diffusion equations for interacting chemical species (morphogens), whose heterogeneous distribution in some spatial domain acts as a template for cells to form some kind of pattern or structure through, for example, differentiation or proliferation induced by the chemical pre-pattern. Here we develop a hybrid discrete-continuum modelling framework for the formation of cellular patterns via the Turing mechanism. In this framework, a stochastic individual-based model of cell movement and proliferation is combined with a reaction-diffusion system for the concentrations of some morphogens. As an illustrative example, we focus on a model in which the dynamics of the morphogens are governed by an activator-inhibitor system that gives rise to Turing pre-patterns. The cells then interact with the morphogens in their local area through either of two forms of chemically-dependent cell action: Chemotaxis and chemically-controlled proliferation. We begin by considering such a hybrid model posed on static spatial domains, and then turn to the case of growing domains. In both cases, we formally derive the corresponding deterministic continuum limit and show that that there is an excellent quantitative match between the spatial patterns produced by the stochastic individual-based model and its deterministic continuum counterpart, when sufficiently large numbers of cells are considered. This paper is intended to present a proof of concept for the ideas underlying the modelling framework, with the aim to then apply the related methods to the study of specific patterning and morphogenetic processes in the future