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.
As mentioned earlier, there has been much interest in the dynamics of phosphorylation systems @cite_28 . The mixed-mechanism network fits into the related literature as follows. The mixed network is a dual-site network situated between two extremes: the fully processive dual-site network -- in which the phosphorylation and dephosphorylation mechanisms are both processive -- and the fully distributive dual-site network. One might therefore expect the dynamics of the mixed-mechanism network to straddle those of the two networks. This is indeed the case. As summarized in Table , and reviewed in @cite_28 , fully processive networks are globally convergent to a unique steady state @cite_26 @cite_12 @cite_9 , while mixed-mechanism networks admit oscillations but not bistability @cite_3 , and fully distributive networks admit bistability @cite_16 (and the question of oscillations is open @cite_28 ).
@cite_26 @cite_28 @cite_9 @cite_3 @cite_16 @cite_12
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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. Multisite phosphorylation plays an important role in intracellular signaling. There has been much recent work aimed at understanding the dynamics of such systems when the phosphorylation dephosphorylation mechanism is distributive, that is, when the binding of a substrate and an enzyme molecule results in the addition or removal of a single phosphate group and repeated binding therefore is required for multisite phosphorylation. In particular, such systems admit bistability. Here, we analyze a different class of multisite systems, in which the binding of a substrate and an enzyme molecule results in the addition or removal of phosphate groups at all phosphorylation sites, that is, we consider systems in which the mechanism is processive, rather than distributive. We show that in contrast to distributive systems, processive systems modeled with mass-action kinetics do not admit bistability and, moreover, exhibit rigid dynamics: each invariant set contains a unique equilibrium, which is a global attractor. Additionally, we obtain a monomial parametrization of the steady states. Our proofs rely on a technique of Johnston for using “translated” networks to study systems with “toric steady states,” recently given sign conditions for the injectivity of polynomial maps, and a result from monotone systems theory due to Angeli and Sontag. Multi-site phosphorylation is ubiquitous in cell biology and has been widely studied experimentally and theoretically. The underlying chemical modification mechanisms are typically assumed to be distributive or processive. In this paper, we study the behaviour of mixed mechanisms that can arise either because phosphorylation and dephosphorylation involve different mechanisms or because phosphorylation and or dephosphorylation can occur through a combination of mechanisms. We examine a hierarchy of models to assess chemical information processing through different mixed mechanisms, using simulations, bifurcation analysis and analytical work. We demonstrate how mixed mechanisms can show important and unintuitive differences from pure distributive and processive mechanisms, in some cases resulting in monostable behaviour with simple dose–response behaviour, while in other cases generating new behaviour-like oscillations. Our results also suggest patterns of information processing that are relevant as the number of modification sites increases. Overall, our work creates a framework to examine information processing arising from complexities of multi-site modification mechanisms and their impact on signal transduction. 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. Abstract Phosphorylation, the enzyme-mediated addition of a phosphate group to a molecule, is a ubiquitous chemical mechanism in biology. Multisite phosphorylation, the addition of phosphate groups to multiple sites of a single molecule, may be distributive or processive. Distributive systems, which require an enzyme and substrate to bind several times in order to add multiple phosphate groups, can be bistable. Processive systems, in contrast, require only one binding to add all phosphate groups, and were recently shown to be globally stable. However, this global convergence result was proven only for a specific mechanism of processive phosphorylation dephosphorylation (namely, all catalytic reactions are reversible). Accordingly, we generalize this result to allow for processive phosphorylation networks in which each reaction may be irreversible, and also to account for possible product inhibition. We accomplish this by first defining an all-encompassing processive network that encapsulates all of these schemes, and then appealing to recent results of Marcondes de that assert global convergence by way of monotone systems theory and network graph reductions (corresponding to removing intermediate complexes). Our results form a case study into the question of when global convergence is preserved when reactions and or intermediate complexes are added to or removed from a network. Dual phosphorylation of proteins is a principal component of intracellular signalling. Bistability is considered an important property of such systems and its origin is not yet completely understood. Theoretical studies have established parameter values for multistationarity and bistability for many types of proteins. However, up to now no formal criterion linking multistationarity and bistability to the parameter values characterizing dual phosphorylation has been established. Deciding whether an unclassified protein has the capacity for bistability, therefore requires careful numerical studies. Here, we present two general algebraic conditions in the form of inequalities. The first employs the catalytic constants, and if satisfied guarantees multistationarity (and hence the potential for bistability). The second involves the catalytic and Michaelis constants, and if satisfied guarantees uniqueness of steady states (and hence absence of bistability). Our method also allows for the direct computation of the total concentration values such that multistationarity occurs. Applying our results yields insights into the emergence of bistability in the ERK–MEK–MKP system that previously required a delicate numerical effort. Our algebraic conditions present a practical way to determine the capacity for bistability and hence will be a useful tool for examining the origin of bistability in many models containing dual phosphorylation. We give a detailed description of the geometry of single droplet patterns in a non- local isoperimetric problem. In particular we focus on the sharp interface limit of the Ohta- Kawasaki free energy for diblock copolymers, regarded as a paradigm for those energies modeling physical systems characterized by a competition between short and a long-range interactions. Exploiting fine properties of the regularity theory for minimal surfaces, we extend previous partial results in different directions and give robust tools for the geometric analysis of more complex patterns. where u is the order parameter of a two-phases system confined in ⊂ R n , and and m are two nonnegative numerical parameters. The two terms in the energy mimic attractive short-range and repulsive long-range energies between the phases. More precisely the first term is local, it favors minimal interface area and drives the system toward a partition into few pure phases while the second term, involving a Coulomb-like kernel G, is non-local and favor a fine mixing of the phases. A detailed description of the energy is given in § 1. The competition between these two terms is expected to induce the formation of highly regular mesoscopic patterns, whose geometry strongly depends on the choice of the parameters and m (e.g. spherical spots, cylinders, gyroids and lamellae). 0.1. The Ohta-Kawasaki functional for diblock copolymers. The model we consider arises as a simplification of a Ginzburg-Landau functional proposed by Ohta and Kawasaki in their pioneering paper (41) as a possible description of a diblock copolymers' (DBC) system. Even though it is questionable whether such an energy actually describes DBCs (see Choksi and Ren (15), Muratov (39) and Niethammer and Oshita (40)), nevertheless it is a first, and mathematically non-trivial, attempt to capture some of the main features of these systems. For such a reason it deserved over the last twenty years great attention from both the mathematical and the physical 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. We propose an abstraction method for medium-scale biomolecular networks, based on hybrid dynamical systems with continuous multi-affine dynamics. This abstraction method follows naturally from the notion of approximating nonlinear rate laws with continuous piecewise linear functions and can be easily automated. An efficient reachability algorithm is possible for the resulting class of hybrid systems. An efficient reachability algorithm is possible for the resulting class of hybrid systems. An approximation for an ordinary differential equation model of the lac operon is constructed, and it is shown that the abstraction passes the same experimental tests as were used to validate the original model. The well studied biological system exhibits bistability and switching behaviour, arising from positive feedback in the expression mechanism of the lac operon. The switching property of the lac system is an example of the major qualitative features that are the building blocks of higher level, more coarse-grained descriptions. The present approach is useful in helping to correctly identify such properties and in connecting them to the underlying molecular dynamical details. Reachability analysis together with the knowledge of the steady-state structure are used to identify ranges of parameter values for which the system maintains the bistable switching property. Quantitative analysis of biochemical networks often requires consideration of both spatial and stochastic aspects of chemical processes. Despite significant progress in the field, it is still computationally prohibitive to simulate systems involving many reactants or complex geometries using a microscopic framework that includes the finest length and time scales of diffusion-limited molecular interactions. For this reason, spatially or temporally discretized simulations schemes are commonly used when modeling intracellular reaction networks. The challenge in defining such coarse-grained models is to calculate the correct probabilities of reaction given the microscopic parameters and the uncertainty in the molecular positions introduced by the spatial or temporal discretization. In this paper we have solved this problem for the spatially discretized Reaction-Diffusion Master Equation; this enables a seamless and physically consistent transition from the microscopic to the macroscopic frameworks of reaction-diffusion kinetics. We exemplify the use of the methods by showing that a phosphorylation-dephosphorylation motif, commonly observed in eukaryotic signaling pathways, is predicted to display fluctuations that depend on the geometry of the system. Many biochemical and industrial applications involve complicated networks of simultaneously occurring chemical reactions. Under the assumption of mass action kinetics, the dynamics of these chemical reaction networks are governed by systems of polynomial ordinary differential equations. The steady states of these mass action systems have been analyzed via a variety of techniques, including stoichiometric network analysis, deficiency theory, and algebraic techniques (e.g., Grobner bases). In this paper, we present a novel method for characterizing the steady states of mass action systems. Our method explicitly links a network’s capacity to permit a particular class of steady states, called toric steady states, to topological properties of a generalized network called a translated chemical reaction network. These networks share their reaction vectors with their source network but are permitted to have different complex stoichiometries and different network topologies. We apply the results to examples drawn from the biochemical literature. This is the second in a series of papers in which we derive a @math -expansion for the two-dimensional non-local Ginzburg-Landau energy with Coulomb repulsion known as the Ohta-Kawasaki model in connection with diblock copolymer systems. In this model, two phases appear, which interact via a nonlocal Coulomb type energy. Here we focus on the sharp interface version of this energy in the regime where one of the phases has very small volume fraction, thus creating small "droplets" of the minority phase in a "sea" of the majority phase. In our previous paper, we computed the @math -limit of the leading order energy, which yields the averaged behavior for almost minimizers, namely that the density of droplets should be uniform. Here we go to the next order and derive a next order @math -limit energy, which is exactly the Coulombian renormalized energy obtained by Sandier and Serfaty as a limiting interaction energy for vortices in the magnetic Ginzburg-Landau model. The derivation is based on the abstract scheme of Sandier-Serfaty that serves to obtain lower bounds for 2-scale energies and express them through some probabilities on patterns via the multiparameter ergodic theorem. Without thus appealing to the Euler-Lagrange equation, we establish for all configurations which have "almost minimal energy" the asymptotic roundness and radius of the droplets, and the fact that they asymptotically shrink to points whose arrangement minimizes the renormalized energy in some averaged sense. Via a kind of @math -equivalence, the obtained results also yield an expansion of the minimal energy for the original Ohta-Kawasaki energy. This leads to expecting to see triangular lattices of droplets as energy minimizers. 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. .We consider a class of stochastic processing networks. Assume that the networks satisfy a complete resource pooling condition. We prove that each maximum pressure policy asymptotically minimizes the workload process in a stochastic processing network in heavy traffic. We also show that, under each quadratic holding cost structure, there is a maximum pressure policy that asymptotically minimizes the holding cost. A key to the optimality proofs is to prove a state space collapse result and a heavy traffic limit theorem for the network processes under a maximum pressure policy. We extend a framework of Bramson [Queueing Systems Theory Appl. 30 (1998) 89–148] and Williams [Queueing Systems Theory Appl. 30 (1998b) 5–25] from the multiclass queueing network setting to the stochastic processing network setting to prove the state space collapse result and the heavy traffic limit theorem. The extension can be adapted to other studies of stochastic processing networks. 1. Introduction. This paper is a continuation of Dai and Lin (2005), in which maximum pressure policies are shown to be throughput optimal for a class of stochastic processing networks. Throughput optimality is an important, first-order objective for many networks, but it ignores some key secondary performance measures like queueing delays experienced by jobs in these networks. In this paper we show that maximum pressure policies enjoy additional optimality properties; they are asymptotically optimal in minimizing a certain workload or holding cost of a stochastic processing network. Stochastic processing networks have been introduced in a series of three papers by Harrison (2000, 2002, 2003). In Dai and Lin (2005) and this paper we consider a special class of Harrison’s model. This class of stochastic processing networks is much more general than multiclass queueing networks that have been a subject of intensive study in the last 20 years; see, for example, Harrison (1988), Williams Recent years have witnessed an increasing interest in neuron–glia communication. This interest stems from the realization that glia participate in cognitive functions and information processing and are involved in many brain disorders and neurodegenerative diseases. An important process in neuron–glia communications is astrocyte encoding of synaptic information transfer—the modulation of intracellular calcium (Ca2 + ) dynamics in astrocytes in response to synaptic activity. Here, we derive and investigate a concise mathematical model for glutamate-induced astrocytic intracellular Ca2 + dynamics that captures the essential biochemical features of the regulatory pathway of inositol 1,4,5-trisphosphate (IP3). Starting from the well-known two-variable (intracellular Ca2 + and inactive IP3 receptors) Li–Rinzel model for calcium-induced calcium release, we incorporate the regulation of IP3 production and phosphorylation. Doing so, we extend it to a three-variable model (which we refer to as the ChI model) that could account for Ca2 + oscillations with endogenous IP3 metabolism. This ChI model is then further extended into the G-ChI model to include regulation of IP3 production by external glutamate signals. Compared with previous similar models, our three-variable models include a more realistic description of IP3 production and degradation pathways, lumping together their essential nonlinearities within a concise formulation. Using bifurcation analysis and time simulations, we demonstrate the existence of new putative dynamical features. The cross-couplings between IP3 and Ca2 + pathways endow the system with self-consistent oscillatory properties and favor mixed frequency–amplitude encoding modes over pure amplitude–modulation ones. These and additional results of our model are in general agreement with available experimental data and may have important implications for the role of astrocytes in the synaptic transfer of information. The temporal and stationary behavior of protein modification cascades has been extensively studied, yet little is known about the spatial aspects of signal propagation. We have previously shown that the spatial separation of opposing enzymes, such as a kinase and a phosphatase, creates signaling activity gradients. Here we show under what conditions signals stall in the space or robustly propagate through spatially distributed signaling cascades. Robust signal propagation results in activity gradients with long plateaus, which abruptly decay at successive spatial locations. We derive an approximate analytical solution that relates the maximal amplitude and propagation length of each activation profile with the cascade level, protein diffusivity, and the ratio of the opposing enzyme activities. The control of the spatial signal propagation appears to be very different from the control of transient temporal responses for spatially homogenous cascades. For spatially distributed cascades where activating and deactivating enzymes operate far from saturation, the ratio of the opposing enzyme activities is shown to be a key parameter controlling signal propagation. The signaling gradients characteristic for robust signal propagation exemplify a pattern formation mechanism that generates precise spatial guidance for multiple cellular processes and conveys information about the cell size to the nucleus. Based on the empirical analysis of the dependency network in 18 Java projects, we develop a novel model of network growth which considersboth: an attachment mechanism and the addition of new nodes with a heterogeneous distribution of their initial degree, k0. Empirically we find that the cumulative degree distributions of initial degrees and of the final network, follow power-law behaviors: P(k0) ∝ k01−α, and P(k) ∝ k1−γ, respectively. For the total number of links as a function of the network size, we find empirically K(N) ∝ Nβ, where β is (at the beginning of thenetwork evolution) between 1.25 and 2, while converging to ∼ 1 for large N. This indicates a transition from a growth regime with increasing network density towards a sustainable regime, which revents a collapse because of ever increasing dependencies. Our theoretical framework is able to predict relations between the exponents α, β, γ, which also link issues of software engineering and developer activity. These relations are verified by means of computer simulations and empirical investigations. They indicate that the growth of real Open Source Software networks occurs on the edge between two regimes, which are either dominated by the initial degree distribution of added nodes, or by the preferential attachment mechanism. Hence, the heterogeneous degree distribution of newly added nodes, found empirically, is essential to describe the laws of sustainable growth in networks. In this paper, a decentralized and self-organizing mechanism for small cell networks (such as micro-, femto- and picocells) is proposed. In particular, an application to the case in which small cell networks aim to mitigate the interference caused to the macrocell network, while maximizing their own spectral efficiencies, is presented. The proposed mechanism is based on new notions of reinforcement learning (RL) through which small cells jointly estimate their time-average performance and optimize their probability distributions with which they judiciously choose their transmit configurations. Here, a minimum signal to interference plus noise ratio (SINR) is guaranteed at the macrocell user equipment (UE), while the small cells maximize their individual performances. The proposed RL procedure is fully distributed as every small cell base station requires only an observation of its instantaneous performance which can be obtained from its UE. Furthermore, it is shown that the proposed mechanism always converges to an epsilon Nash equilibrium when all small cells share the same interest. In addition, this mechanism is shown to possess better convergence properties and incur less overhead than existing techniques such as best response dynamics, fictitious play or classical RL. Finally, numerical results are given to validate the theoretical findings, highlighting the inherent tradeoffs facing small cells, namely exploration exploitation, myopic foresighted behavior and complete incomplete information. The brain must both react quickly to new inputs as well as store a memory of past activity. This requires biology that operates over a vast range of time scales. Fast time scales are determined by the kinetics of synaptic conductances and ionic channels; however, the mechanics of slow time scales are more complicated. In this opinion article we review two distinct network-based mechanisms that impart slow time scales in recurrently coupled neuronal networks. The first is in strongly coupled networks where the time scale of the internally generated fluctuations diverges at the transition between stable and chaotic firing rate activity. The second is in networks with finitely many members where noise-induced transitions between metastable states appear as a slow time scale in the ongoing network firing activity. We discuss these mechanisms with an emphasis on their similarities and differences. We prove that for finite range discrete spin systems on the two dimensional latticeZ2, the (weak) mixing condition which follows, for instance, from the Dobrushin-Shlosman uniqueness condition for the Gibbs state implies a stronger mixing property of the Gibbs state, similar to the Dobrushin-Shlosman complete analyticity condition, but restricted to all squares in the lattice, or, more generally, to all sets multiple of a large enough square. The key observation leading to the proof is that a change in the boundary conditions cannot propagate either in the bulk, because of the weak mixing condition, or along the boundary because it is one dimensional. As a consequence we obtain for ferromagnetic Ising-type systems proofs that several nice properties hold arbitrarily close to the critical temperature; these properties include the existence of a convergent cluster expansion and uniform boundedness of the logarithmic Sobolev constant and rapid convergence to equilibrium of the associated Glauber dynamics on nice subsets ofZ2, including the full lattice.