This work investigates the emergence of oscillations in one of the simplest cellular signaling networks exhibiting oscillations, namely, the dual-site phosphorylation and dephosphorylation network (futile cycle), in which the mechanism for phosphorylation is processive while the one for dephosphorylation is distributive (or vice-versa). The fact that this network yields oscillations was shown recently by Suwanmajo and Krishnan. Our results, which significantly extend their analyses, are as follows. First, in the three-dimensional space of total amounts, the border between systems with a stable versus unstable steady state is a surface defined by the vanishing of a single Hurwitz determinant. Second, this surface consists generically of simple Hopf bifurcations. Next, simulations suggest that when the steady state is unstable, oscillations are the norm. Finally, the emergence of oscillations via a Hopf bifurcation is enabled by the catalytic and association constants of the distributive part of the mechanism: if these rate constants satisfy two inequalities, then the system generically admits a Hopf bifurcation. Our proofs are enabled by the Routh-Hurwitz criterion, a Hopf-bifurcation criterion due to Yang, and a monomial parametrization of steady states.
Finally, we revisit Suwanmajo and Krishnan's claim mentioned earlier that the mixed-mechanism network is among the simplest enzymatic mechanisms with oscillations. In support of this claim, Tung proved that the simpler system obtained from the mixed-mechanism network by taking its (two-dimensional) Michaelis-Menten approximation, is not oscillatory @cite_25 . Moreover, Rao showed that this approximation is globally convergent to a unique steady state @cite_30 . The validity of the Michaelis-Menten approximation for phosphorylation systems has been called into question @cite_24 , and what we know about the mixed-mechanism system concurs: this system is oscillatory, but its Michaelis-Menten approximation is not.
@cite_30 @cite_25 @cite_24
2773192016 2141663593 2722982242 2801873640
Oscillations play a major role in a number of biological systems, from predator-prey models of ecology to circadian clocks. In this paper we focus on the question of whether oscillations exist within dual-site phosphorylation systems. Previously, Wang and Sontag showed, using monotone systems theory, that the Michaelis-Menten (MM) approximation of the distributive and sequential dual-site phosphorylation system lacks oscillations. However, biological systems are generally not purely distributive; there is generally some processive behavior as well. Accordingly, this paper focuses on the MM approximation of a general sequential dual-site phosphorylation system that contains both processive and distributive components, termed the composite system. Expanding on the methods of Bozeman and Morales, we preclude oscillations in the MM approximation of the composite system. This implies the lack of oscillations in the MM approximations of the processive and distributive systems, shown previously, as well as in the MM approximation of the partially processive and partially distributive mixed-mechanism system. We consider the problem of makespan minimization on m unrelated machines in the context of algorithmic mechanism design, where the machines are the strategic players. This is a multidimensional scheduling domain, and the only known positive results for makespan minimization in such a domain are O(m)-approximation truthful mechanisms [22, 20]. We study a well-motivated special case of this problem, where the processing time of a job on each machine may either be "low" or "high", and the low and high values are public and job-dependent. This preserves the multidimensionality of the domain, and generalizes the restricted-machines (i.e., pj,∞ ) setting in scheduling. We give a general technique to convert any c-approximation algorithm to a 3c-approximation truthful-in-expectation mechanism. This is one of the few known results that shows how to export approximation algorithms for a multidimensional problem into truthful mechanisms in a black-box fashion. When the low and high values are the same for all jobs, we devise a deterministic 2-approximation truthful mechanism. These are the first truthful mechanisms with non-trivial performance guarantees for a multidimensional scheduling domain. Our constructions are novel in two respects. First, we do not utilize or rely on explicit price definitions to prove truthfulness; instead we design algorithms that satisfy cycle monotonicity. Cycle monotonicity [23] is a necessary and sufficient condition for truthfulness, is a generalization of value monotonicity for multidimensional domains. However, whereas value monotonicity has been used extensively and successfully to design truthful mechanisms in single-dimensional domains, ours is the first work that leverages cycle monotonicity in the multidimensional setting. Second, our randomized mechanisms are obtained by first constructing a fractional truthful mechanism for a fractional relaxation of the problem, and then converting it into a truthful-in-expectation mechanism. This builds upon a technique of [16], and shows the usefulness of fractional mechanisms in truthful mechanism design. Prompted by the recent growing evidence of oscillatory behavior involving MAPK cascades we present a systematic approach of analyzing models and elucidating the nature of biochemical oscillations based on reaction network theory. In particular, we formulate a minimal biochemically consistent mass action subnetwork of the Huang-Ferrell model of the MAPK signalling that provides an oscillatory response when a parameter controlling the activation of the top-tier kinase is varied. Such dynamics are either intertwined with or separated from the earlier found bistable hysteretic behavior in this model. Using the theory of stability of stoichiometric networks, we reduce the original MAPK model, convert kinetic to convex parameters and examine those properties of the minimal subnetwork that underlie the oscillatory dynamics. We also use the methods of classification of chemical oscillatory networks to explain the rhythmic behavior in physicochemical terms, i.e., we identify of the role of individual biochemical species in positive and negative feedback loops and describe their coordinated action leading to oscillations. Our approach provides an insight into dynamics without the necessity of knowing rate coefficients and thus is useful prior the statistical evaluation of parameters. Abstract In this paper, we consider a mixed mechanism of a n-site phosphorylation system in which the mechanism of phosphorylation is distributive and that of dephosphorylation is processive. It is assumed that the concentrations of the substrates are much higher than those of the enzymes and their intermediate complexes. This assumption enables us to reduce the system using the steady-state approach to a Michaelis–Menten approximation of the system. It is proved that the resulting system of nonlinear ordinary differential equations admits a unique positive equilibrium in every positive stoichiometric compatibility class using the theory of quadratic equations. We then consider two special cases. In the first case, we assume that the Michaelis constants associated with the different substrates in the phosphorylation reactions are equal and construct a Lyapunov function to prove asymptotic stability of the system. In the second case, we assume that there are just two sites of phosphorylation and dephoshorylation and prove that the resulting system is asymptotically stable using Poincar e ´ Bendixson theorem.