Philipp Getto’s research while affiliated with Technische Universität Dresden and other places

We analyze a system of differential equations with state-dependent delay (SD-DDE) from cell biology, in which the delay is implicitly defined as the time when the solution of an ODE, parametrized by the SD-DDE state, meets a threshold. We show that the system is well-posed and that the solutions define a continuous semiflow on a state space of Lipschitz functions. Moreover we establish for an associated system a convex and compact set that is invariant under the time-t-map for a finite time. It is known that, due to the state dependence of the delay, necessary and sufficient conditions for well-posedness can be related to functionals being almost locally Lipschitz, which roughly means locally Lipschitz on the restriction of the domain to Lipschitz functions, and our methodology involves such conditions. To achieve transparency and wider applicability, we elaborate a general class of two component functional differential equation systems, that contains the SD-DDE from cell biology and formulate our results also for this class.

In this paper we study, at different levels of generality, certain systems of delay differential equations (DDE). One focus and motivation is a system with state-dependent delay (SD-DDE) that has been formulated to describe the maturation of stem cells. We refer to this system as the cell SD-DDE. In the cell SD-DDE, the delay is implicitly defined by a threshold condition. The latter is specified by the time at which the (also implicitly defined) solution of an external nonlinear ordinary differential equation (ODE), which is parametrised by a component of the SD-DDE, meets a given threshold value. We focus on the dynamical properties global asymptotic stability (GAS) of the zero equilibrium, persistence and dissipativity/ultimate boundedness.

We consider a mathematical model describing the maturation process of stem cells up to fully mature cells. The model is formulated as a differential equation with state-dependent delay, where maturity is described as a continuous variable. The maturation rate of cells may be regulated by the amount of mature cells and, moreover, it may depend on cell maturity: we investigate how the stability of equilibria is affected by the choice of the maturation rate. We show that the principle of linearised stability holds for this model, and develop some analytical methods for the investigation of characteristic equations for fixed delays. For a general maturation rate we resort to numerical methods and we extend the pseudospectral discretisation technique to approximate the state-dependent delay equation with a system of ordinary differential equations. This is the first application of the technique to nonlinear state-dependent delay equations, and currently the only method available for studying the stability of equilibria by means of established software packages for bifurcation analysis. The numerical method is validated on some cases when the maturation rate is independent of maturity and the model can be reformulated as a fixed-delay equation via a suitable time transformation. We exploit the analytical and numerical methods to investigate the stability boundary in parameter planes. Our study shows some drastic qualitative changes in the stability boundary under assumptions on the model parameters, which may have important biological implications.

We establish variants of existing results on existence, uniqueness and continuous dependence for a class of delay differential equations (DDE). We apply these to continue the analysis of a differential equation from cell biology with state-dependent delay, implicitly defined as the time when the solution of a nonlinear ODE, that depends on the state of the DDE, reaches a threshold. For this application, previous results are restricted to initial histories belonging to the so-called solution manifold. We here generalize the results to a set of nonnegative Lipschitz initial histories which is much larger than the solution manifold and moreover convex. Additionally, we show that the solutions define a semiflow that is continuous in the state-component in the $C([-h,0],\R^2)$ topology, which is a variant of established differentiability of the semiflow in $C^1([-h,0],\R^2)$. For an associated system we show invariance of convex and compact sets under the semiflow for finite time.

With the aim of applying numerical methods, we develop a formalism for physiologically structured population models in a new generality that includes consumer–resource, cannibalism and trophic models. The dynamics at the population level are formulated as a system of Volterra functional equations coupled to ODE. For this general class, we develop numerical methods to continue equilibria with respect to a parameter, detect transcritical and saddle-node bifurcations and compute curves in parameter planes along which these bifurcations occur. The methods combine curve continuation, ODE solvers and test functions. Finally, we apply the methods to the above models using existing data for Daphnia magna consuming Algae and for Perca fluviatilis feeding on Daphnia magna. In particular, we validate the methods by deriving expressions for equilibria and bifurcations with respect to which we compute errors, and by comparing the obtained curves with curves that were computed earlier with other methods. We also present new curves to show how the methods can easily be applied to derive new biological insight. Schemes of algorithms are included.

In this paper we characterize the stability boundary in the (Formula presented.) -plane, for fixed (Formula presented.) with (Formula presented.) , for the characteristic equation from the title. Subsequently we describe a nonlinear cell population model involving quiescence and show that this characteristic equation governs the (in)stability of the nontrivial steady state. By relating the parameters of the cell model to the (Formula presented.) , we are able to derive some biological conclusions.

Mathematical modeling is a powerful technique to address key questions and paradigms in a variety of complex biological systems and can provide quantitative insights into cell kinetics, fate determination and development of cell populations. The chapter is devoted to a review of modeling of the dynamics of stem cell-initiated systems using mathematical methods of ordinary differential equations. Some basic concepts and tools for cell population dynamics are summarized and presented as a gentle introduction to non-mathematicians. The models take into account different plausible mechanisms regulating homeostasis. Two mathematical frameworks are proposed reflecting, respectively, a discrete (punctuated by division events) and a continuous character of transitions between differentiation stages. Advantages and constraints of the mathematical approaches are presented on examples of models of blood systems and compared to patients data on healthy hematopoiesis.

This work deals with physiologically structured populations of the Daphnia type. Their biological modeling poses several computational challenges. In such models, indeed, the evolution of a size structured consumer described by a Volterra functional equation (VFE) is coupled to the evolution of an unstructured resource described by a delay differential equation (DDE), resulting in dynamics over an infinite dimensional state space. As additional complexities, the right-hand sides are both of integral type (continuous age distribution) and given implicitly through external ordinary differential equations (ODEs). Moreover, discontinuities in the vital rates occur at a maturation age, also given implicitly through one of the above ODEs. With the aim at studying the local asymptotic stability of equilibria and relevant bifurcations, we revisit a pseudospectral approach recently proposed to compute the eigenvalues of the infinitesimal generator of linearized systems of coupled VFEs/DDEs. First, we modify it in view of extension to nonlinear problems for future developments. Then, we consider a suitable implementation to tackle all the computational difficulties mentioned above: a piecewise approach to handle discontinuities, numerical quadrature of integrals, and numerical solution of ODEs. Moreover, we rigorously prove the spectral accuracy of the method in approximating the eigenvalues and how this outstanding feature is influenced by the other unavoidable error sources. Implementation details and experimental computations on existing available data conclude the work.

We analyze a differential equation with a state-dependent delay that is implicitly defined via the solution of an ODE. The equation describes an established though little analyzed cell population model. Based on theoretical results of Hartung, Krisztin, Walther and Wu we elaborate conditions for the model ingredients, in particular vital rates, that guarantee the existence of a local semiflow. Here proofs are based on implicit function arguments. To show global existence, we adapt a theorem from a classical book on functional differential equations by Hale and Lunel, which gives conditions under which - if there is no global existence - closed and bounded sets are left for good, to the $C^1$-topology, which is the natural setting when dealing with state-dependent delays. The proof is based on an older result for semiflows on metric spaces.

We propose a model to analyze the dynamics of interacting proliferating and quiescent cell populations. The model includes age dependence of cell division, transitions between the two subpopulations, and regulation of the recruitment of quiescent cells. We formulate the model as a pair of renewal equations and apply a rather recent general result to prove that (in) stability of equilibria can be analyzed by locating roots of characteristic equations. We are led to a parameter plane analysis of a characteristic equation, which has not been analyzed in this way so far. We conclude with how quiescence of cells as well as two submodels for cell division may influence the possibility of destabilization via oscillations.