Comparison of Perron and Floquet eigenvalues in age structured cell division cycle models

We study the growth rate of a cell population that follows an age-structured PDE with time-periodic coefficients. Our motivation comes from the comparison between experimental tumor growth curves in mice endowed with intact or disrupted circadian clocks, known to exert their influence on the cell division cycle. We compare the growth rate of the model controlled by a time-periodic control on its coefficients with the growth rate of stationary models of the same nature, but with averaged coefficients. We firstly derive a delay differential equation which allows us to prove several inequalities and equalities on the growth rates. We also discuss about the necessity to take into account the structure of the cell division cycle for chronotherapy modeling. Numerical simulations illustrate the results.Comment: 26 page

Circadian rhythm and cell population growth

Molecular circadian clocks, that are found in all nucleated cells of mammals, are known to dictate rhythms of approximately 24 hours (circa diem) to many physiological processes. This includes metabolism (e.g., temperature, hormonal blood levels) and cell proliferation. It has been observed in tumor-bearing laboratory rodents that a severe disruption of these physiological rhythms results in accelerated tumor growth. The question of accurately representing the control exerted by circadian clocks on healthy and tumour tissue proliferation to explain this phenomenon has given rise to mathematical developments, which we review. The main goal of these previous works was to examine the influence of a periodic control on the cell division cycle in physiologically structured cell populations, comparing the effects of periodic control with no control, and of different periodic controls between them. We state here a general convexity result that may give a theoretical justification to the concept of cancer chronotherapeutics. Our result also leads us to hypothesize that the above mentioned effect of disruption of circadian rhythms on tumor growth enhancement is indirect, that, is this enhancement is likely to result from the weakening of healthy tissue that are at work fighting tumor growth

An inequality for the Perron and Floquet eigenvalues of monotone differential systems and age structured equations

For monotone linear differential systems with periodic coefficients, the (first) Floquet eigenvalue measures the growth rate of the system. We define an appropriate arithmetico-geometric time average of the coefficients for which we can prove that the Perron eigenvalue is smaller than the Floquet eigenvalue. We apply this method to Partial Differential Equations, and we use it for an age-structured systems of equations for the cell cycle. This opposition between Floquet and Perron eigenvalues models the loss of circadian rhythms by cancer cells.Comment: 7 pages, in English, with an abridged French versio

Isomorphisms of types in the presence of higher-order references

We investigate the problem of type isomorphisms in a programming language with higher-order references. We first recall the game-theoretic model of higher-order references by Abramsky, Honda and McCusker. Solving an open problem by Laurent, we show that two finitely branching arenas are isomorphic if and only if they are geometrically the same, up to renaming of moves (Laurent's forest isomorphism). We deduce from this an equational theory characterizing isomorphisms of types in a finitary language with higher order references. We show however that Laurent's conjecture does not hold on infinitely branching arenas, yielding a non-trivial type isomorphism in the extension of this language with natural numbers.Comment: Twenty-Sixth Annual IEEE Symposium on Logic In Computer Science (LICS 2011), Toronto : Canada (2011

Perspective on "New and Less New Opportunities For Mathematical Biology as Applied To Biological and Clinical Medicine"

International audienceAnother conception that makes applications of mathematics quite different from applications of mathematics to sole biology resides in the interventionist nature of medicine ..

Undecidability of Equality in the Free Locally Cartesian Closed Category (Extended version)

We show that a version of Martin-L\"of type theory with an extensional identity type former I, a unit type N1 , Sigma-types, Pi-types, and a base type is a free category with families (supporting these type formers) both in a 1- and a 2-categorical sense. It follows that the underlying category of contexts is a free locally cartesian closed category in a 2-categorical sense because of a previously proved biequivalence. We show that equality in this category is undecidable by reducing it to the undecidability of convertibility in combinatory logic. Essentially the same construction also shows a slightly strengthened form of the result that equality in extensional Martin-L\"of type theory with one universe is undecidable

Thin Games with Symmetry and Concurrent Hyland-Ong Games

We build a cartesian closed category, called Cho, based on event structures. It allows an interpretation of higher-order stateful concurrent programs that is refined and precise: on the one hand it is conservative with respect to standard Hyland-Ong games when interpreting purely functional programs as innocent strategies, while on the other hand it is much more expressive. The interpretation of programs constructs compositionally a representation of their execution that exhibits causal dependencies and remembers the points of non-deterministic branching.The construction is in two stages. First, we build a compact closed category Tcg. It is a variant of Rideau and Winskel's category CG, with the difference that games and strategies in Tcg are equipped with symmetry to express that certain events are essentially the same. This is analogous to the underlying category of AJM games enriching simple games with an equivalence relations on plays. Building on this category, we construct the cartesian closed category Cho as having as objects the standard arenas of Hyland-Ong games, with strategies, represented by certain events structures, playing on games with symmetry obtained as expanded forms of these arenas.To illustrate and give an operational light on these constructions, we interpret (a close variant of) Idealized Parallel Algol in Cho

Phenotype divergence and cooperation in isogenic multicellularity and in cancer

We discuss the mathematical modelling of two of the main mechanisms which pushed forward the emergence of multicellularity: phenotype divergence in cell differentiation, and between-cell cooperation. In line with the atavistic theory of cancer, this disease being specific of multicellular animals, we set special emphasis on how both mechanisms appear to be reversed, however not totally impaired, rather hijacked, in tumour cell populations. Two settings are considered: the completely innovating, tinkering, situation of the emergence of multicellularity in the evolution of species, which we assume to be constrained by external pressure on the cell populations, and the completely planned-in the body plan-situation of the physiological construction of a developing multicellular animal from the zygote, or of bet hedging in tumours, assumed to be of clonal formation, although the body plan is largely-but not completely-lost in its constituting cells. We show how cancer impacts these two settings and we sketch mathematical models for them. We present here our contribution to the question at stake with a background from biology, from mathematics, and from philosophy of science