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We present a detailed study of a scalar differential equation with threshold state-dependent delayed feedback. This equation arises as a simplification of a gene regulatory model. There are two monotone nonlinearities in the model: one describes the dependence of delay on state, and the other is the feedback nonlinearity. Both increasing and decreasing nonlinearities are considered. Our analysis is exhaustive both analytically and numerically as we examine the bifurcations of the system for various combinations of increasing and decreasing nonlinearities. We identify rich bifurcation patterns including Bautin, Bogdanov–Takens, cusp, fold, homoclinic, and Hopf bifurcations whose existence depend on the derivative signs of nonlinearities. Our analysis confirms many of these patterns in the limit where the nonlinearities are switch-like and change their value abruptly at a threshold. Perhaps one of the most surprising findings is the existence of a Hopf bifurcation to a periodic solution when the nonlinearity is monotone increasing and the time delay is a decreasing function of the state variable. 

Abstract Mathematical modeling of the emergent dynamics of gene regulatory networks (GRN) faces a double challenge of (a) dependence of model dynamics on parameters, and (b) lack of reliable experimentally determined parameters. In this paper we compare two complementary approaches for describing GRN dynamics across unknown parameters: (1) parameter sampling and resulting ensemble statistics used by RACIPE (RAndom CIrcuit PErturbation), and (2) use of rigorous analysis of combinatorial approximation of the ODE models by DSGRN (Dynamic Signatures Generated by Regulatory Networks). We find a very good agreement between RACIPE simulation and DSGRN predictions for four different 2- and 3-node networks typically observed in cellular decision making. This observation is remarkable since the DSGRN approach assumes that the Hill coefficients of the models are very high while RACIPE assumes the values in the range 1-6. Thus DSGRN parameter domains, explicitly defined by inequalities between systems parameters, are highly predictive of ODE model dynamics within a biologically reasonable range of parameters. 

In this paper, we study equilibria of differential equation models for networks. When interactions between nodes are taken to be piecewise constant, an efficient combinatorial analysis can be used to characterize the equilibria. When the piecewise constant functions are replaced with piecewise linear functions, the equilibria are preserved as long as the piecewise linear functions are sufficiently steep. Therefore the combinatorial analysis can be leveraged to understand a broader class of interactions. To better understand how broad this class is, we explicitly characterize how steep the piecewise linear functions must be for the correspondence between equilibria to hold. To do so, we analyze the steady state and Hopf bifurcations which cause a change in the number or stability of equilibria as slopes are decreased. Additionally, we show how to choose a subset of parameters so that the correspondence between equilibria holds for the smallest possible slopes when the remaining parameters are fixed. 

Over the last twenty years advances in systems biology have changed our views on microbial communities and promise to revolutionize treatment of human diseases. In almost all scientific breakthroughs since time of Newton, mathematical modeling has played a prominent role. Regulatory networks emerged as preferred descriptors of how abundances of molecular species depend on each other. However, the central question on how cellular phenotypes emerge from dynamics of these network remains elusive. The principal reason is that differential equation models in the field of biology (while so successful in areas of physics and physical chemistry), do not arise from first principles, and these models suffer from lack of proper parameterization. In response to these challenges, discrete time models based on Boolean networks have been developed. In this review, we discuss an emerging modeling paradigm that combines ideas from differential equations and Boolean models, and has been developed independently within dynamical systems and computer science communities. The result is an approach that can associate a range of potential dynamical behaviors to a network, arrange the descriptors of the dynamics in a searchable database, and allows for multi-parameter exploration of the dynamics akin to bifurcation theory. Since this approach is computationally accessible for moderately sized networks, it allows, perhaps for the first time, to rationally compare different network topologies based on their dynamics.