Deriving Behavior of Boolean Bioregulatory Networks from Subnetwork Dynamics

In the well-known discrete modeling framework developed by R. Thomas, the structure of a biological regulatory network is captured in an interaction graph, which, together with a set of Boolean parameters, gives rise to a state transition graph describing all possible dynamical behaviors. For complex networks the analysis of the dynamics becomes more and more difficult, and efficient methods to carry out the analysis are needed. In this paper, we focus on identifying subnetworks of the system that govern the behavior of the system as a whole. We present methods to derive trajectories and attractors of the network from the dynamics suitable subnetworks display in isolation. In addition, we use these ideas to link the existence of certain structural motifs, namely circuits, in the interaction graph to the character and number of attractors in the state transition graph, generalizing and refining results presented in [10]. Lastly, we show for a specific class of networks that all possible asymptotic behaviors of networks in that class can be derived from the dynamics of easily identifiable subnetworks.      

Visualization of network structure by the application of hypernodes

In the literature several authors describe methods to construct simplified models of networks. These methods are motivated by the need to gain insight into the main properties of medium sized or large networks. The present paper contributes to this research by setting focus on weighted networks, the geographical component of networks and introducing a class of functions to model how the weights propagate from one level of abstraction to the next. Hierarchies of network models can be constructed from reordering of the adjacency matrix of the network; this is how “hypernodes” are derived in the present paper. The hypernode algorithm is explored and it is shown how it can be formulated to handle weighted networks. Weighted networks enable handling the uncertainty or the strength of the components which make up the network. The hypernode algorithm can be run in an iterative manner so that a hierarchy of simplified models of the network can be derived. Some case studies demonstrate the hypernode algorithm. In the first case the algorithm is compared with a similar implementation described in the literature. In the second case an airline dataset is analysed. This study shows that when networks are embedded in the geographical space hypernodes may relate to clusters in the spatial domain. The selection of the visual variables to illustrate the strength of the edges and nodes in a weighted network is discussed.     

复杂疾病的分子网络模型研究

复杂疾病是危害人类健康的主要杀手.不同于单基因缺陷性遗传病,复杂疾病的发生发展与多个基因之间、基因与环境之间的相互作用有关,致病机理复杂,其早期诊断及治疗困难是21世纪生物医学研究的重大挑战之一.随着生物知识的不断积累和多层次"组学"数据的井喷式涌现,复杂疾病研究迎来了新的"组学革命",研究模式从以往的只关注某个分子扩展到对分子之间相互形成的生物分子网络的系统分析.作为系统生物学核心概念,生物分子网络系统整合大量生物知识和高通量生物数据,是研究复杂疾病的强有力工具.本文以分子网络为主线,以数学建模为工具来研究复杂疾病,针对复杂疾病关系和复杂疾病的发生发展机制等复杂疾病研究的关键热点问题,分析和集成高通量多层次组学数据,构建并求解生物分子网络的数学模型,在若干复杂疾病相关系统生物学问题中取得有生物学意义的结果.本文提出若干生物网络建模、分析及应用的方法并提供若干应用软件,为从系统层面理解复杂疾病提供重要参考;同时,网络模型在若干实例中的应用得到若干有生物学意义的结论,为揭示复杂疾病机理、推动疾病治疗与预防起到了一定的作用.     

Deadlock properties of queueing networks with finite capacities and multiple routing chains

Blocking in queueing network models with finite capacities can lead to deadlock situations. In this paper, deadlock properties are investigated in queueing networks with multiple routing chains. The necessary and sufficient conditions for deadlockfree queueing networks with blocking are provided. An optimization algorithm is presented for finding deadlock-free capacity assignments with the least total capacity. The optimization algorithm maps the queueing network into a directed graph and obtains the deadlock freedom conditions from a specified subset of cycles in the directed graph. In certain network topologies, the number of deadlock freedom conditions can be large, thus, making any optimization computationally expensive. For a special class of topologies, so-calledtandem networks, it is shown that a minimal capacity assignment can be directly obtained without running an optimization algorithm. Here, the solution to the minimal capacity assignment takes advantage of the regular topology of tandem networks.This work was supported by the National Science Foundation under Grant No. CCR-90-11981.     

A scale-free graph model based on bipartite graphs

Most biological networks have some common properties, on which models have to fit. The main one is that those networks are scale-free, that is that the distribution of the vertex degrees follows a power-law. Among the existing models, the ones which fit those characteristics best are based on a time evolution which makes impossible the analytic calculation of the number of motifs in the network. Focusing on applications, this calculation is very important to decompose networks in a modular manner, as proposed by Milo et al.. On the contrary, models whose construction does not depend on time, miss one or several properties of real networks or are not computationally tractable. In this paper, we propose a new random graph model that satisfies the global features of biological networks and the non-time-dependency condition. It is based on a bipartite graph structure, which has a biological interpretation in metabolic networks.     

Broad-scale small-world network topology induces optimal synchronization of flexible oscillators

The discovery of small-world and scale-free properties of many man-made and natural complex networks has attracted increasing attention. Of particular interest is how the structural properties of a network facilitate and constrain its dynamical behavior. In this paper we study the synchronization of weakly coupled limit-cycle oscillators in dependence on the network topology as well as the dynamical features of individual oscillators. We show that flexible oscillators, characterized by near zero values of divergence, express maximal correlation in broad-scale small-world networks, whereas the non-flexible (rigid) oscillators are best correlated in more heterogeneous scale-free networks. We found that the synchronization behavior is governed by the interplay between the networks global efficiency and the mutual frequency adaptation. The latter differs for flexible and rigid oscillators. The results are discussed in terms of evolutionary advantages of broad-scale small-world networks in biological systems.     

A Mathematical Model for Optimal Functional Disruption of Biochemical Networks

Biochemical networks are a particular kind of biological networks which describe the cell metabolism and regulate various biological functions, from biochemical pathways to cell growth. The relationship between structure, function and regulation in complex cellular networks is still a largely open question. This complexity calls for proper mathematical models and methods relating network structure and functional properties. In this paper we focus on the problem of drug targets’ identification by detecting network alteration strategies which lead to a cell functionality loss. We propose a mathematical model, based on a bi-level programming formulation, to obtain the minimum cost disruption policy through the identification of specific gene deletions. These deletions represent drug target identification of new drug treatments for hindering bacterial infections.     

Bursting synchronization in networks with long-range coupling mediated by a diffusing chemical substance

Many networks of physical and biological interest are characterized by a long-range coupling mediated by a chemical which diffuses through a medium in which oscillators are embedded. We considered a one-dimensional model for this effect for which the diffusion is fast enough so as to be implemented through a coupling whose intensity decays exponentially with the lattice distance. In particular, we analyzed the bursting synchronization of neurons described by two timescales (spiking and bursting activity), and coupled through such a long-range interaction network. One of the advantages of the model is that one can pass from a local (Laplacian) type of coupling to a global (all-to-all) one by varying a single parameter in the interaction term. We characterized bursting synchronization using an order parameter which undergoes a transition as the coupling parameters are changed through a critical value. We also investigated the role of an external time-periodic signal on the bursting synchronization properties of the network. We show potential applications in the control of pathological rhythms in biological neural networks.     

Frequency transitions in synchronized neural networks

Temporal organization of events can emerge in complex systems, like neural networks. Here, random graph and cellular automaton are used to represent coupled neural structures, in order to investigate the occurrence of synchronization. The connectivity pattern of this toy model of neural system is of Newman–Watts type, formed from a regular lattice with additional random connections. Two networks with this coupling topology are connected by extra random links and an impulse stimulus is either constantly or periodically applied to a unique neuron. Numerical simulations reveal that this model can exhibit a variety of dynamic behaviors. Usually, the whole system achieves synchronization; however, the oscillation frequencies of the stimulus and of each network can be different. The dynamics is evaluated in function of the network size, the amount of the randomly added edges and the number of time steps in which a neuron can remain firing. The biological relevance of these results is discussed.     

复杂网络连接的Chen系统的同步化

利用Chen系统的有界性和挤压性质,提出了一种新的研究网络同步化的方法．选取以N个Chen系统作为结点的4种复杂网络(环形网络、星形双向耦合网络、小世界网络、全局耦合网络)作为研究对象,理论推导得出网络中Chen系统同步需满足的参数条件．通过比较证明了小世界网络具有易于同步和结构简单的优点,数值仿真结果与理论分析相一致．     

Mean-field modeling approach for understanding epidemic dynamics in interconnected networks

Modern systems (e.g., social, communicant, biological networks) are increasingly interconnected each other formed as ‘networks of networks’. Such complex systems usually possess inconsistent topologies and permit agents distributed in different subnetworks to interact directly/indirectly. Corresponding dynamics phenomena, such as the transmission of information, power, computer virus and disease, would exhibit complicated and heterogeneous tempo-spatial patterns. In this paper, we focus on the scenario of epidemic spreading in interconnected networks. We intend to provide a typical mean-field modeling framework to describe the time-evolution dynamics, and offer some mathematical skills to study the spreading threshold and the global stability of the model. Integrating the research with numerical analysis, we are able to quantify the effects of networks structure and epidemiology parameters on the transmission dynamics. Interestingly, we find that the diffusion transition in the whole network is governed by a unique threshold, which mainly depends on the most heterogenous connection patterns of network substructures. Further, the dynamics is highly sensitive to the critical values of cross infectivity with switchable phases.     

Dynamic network reliability modeling under nonhomogeneous Poisson processes

In this paper, we consider a two-state (up and down) network consisting of n links. We study the D-spectrum based dynamic reliability of the network under the assumption that the links are subject to failure according to a nonhomogeneous Poisson process. Several mixture representations are provided for the reliability function of residual lifetime of used networks, under different conditions on the status of the network or its links. These representations enable us to explore the residual reliability of operating networks in terms of the reliability functions of residual lifetimes of upper record values. The distribution function of inactivity time of a network is examined under the condition that the network has failed by inspection time t. Stochastic ordering properties of the residual lifetimes of networks under conditional D-spectra are investigated. Several examples and graphs are also provided to illustrate the established results.     

几何随机图大连通分支覆盖面积及其在传感器网络中的应用

随机网络中的大连通分支能体现一个网络的连通情况,是几何随机图研究的-个热点,具有重要的理论意义和应用价值.本文利用渗流理论,研究了几何随机图大连通分支覆盖面积所具有的性质,并将理论结果应用到大型无线传感器网络中,研究了无线传感器网络覆盖的性质.研究结果表明,对于节点服从泊松分布的大型无线传感器网络,其大连通分支覆盖区域大小与总区域大小的比值趋于-个常数,且并估计出了2维空间中没有被大连通分支所覆盖的连通区域(本文称为空洞)的大小.这些结果为衡量无线传感器网络性能提供了理论基础,对实际布网和网络优化等具有一定的指导意义.     

Gene Regulation Network Inference With Joint Sparse Gaussian Graphical Models

Revealing biological networks is one key objective in systems biology. With microarrays, researchers now routinely measure expression profiles at the genome level under various conditions, and such data may be used to statistically infer gene regulation networks. Gaussian graphical models (GGMs) have proven useful for this purpose by modeling the Markovian dependence among genes. However, a single GGM may not be adequate to describe the potentially differing networks across various conditions, and hence it is more natural to infer multiple GGMs from such data. In this article we propose a class of nonconvex penalty functions aiming at the estimation of multiple GGMs with a flexible joint sparsity constraint. We illustrate the property of our proposed nonconvex penalty functions by simulation study. We then apply the method to a gene expression dataset from the GenCord Project, and show that our method can identify prominent pathways across different conditions. Supplementary materials for this article are available online.     

Dynamical community structure of populations evolving on genotype networks

Neutral evolutionary dynamics of replicators occurs on large and heterogeneous networks of genotypes. These networks, formed by all genotypes that yield the same phenotype, have a complex architecture that conditions the molecular composition of populations and their movements on genome spaces. Here we consider as an example the case of populations evolving on RNA secondary structure neutral networks and study the community structure of the network revealed through dynamical properties of the population at equilibrium and during adaptive transients. We unveil a rich hierarchical community structure that, eventually, can be traced back to the non-trivial relationship between RNA secondary structure and sequence composition. We demonstrate that usual measures of modularity that only take into account the static, topological structure of networks, cannot identify the community structure disclosed by population dynamics.     

General results on preferential attachment and clustering coefficient

This is a review paper that covers some recent results on the behavior of the clustering coefficient in preferential attachment networks and scale-free networks in general. The paper focuses on general approaches to network science. In other words, instead of discussing different fully specified random graph models, we describe some generic results which hold for classes of models. Namely, we first discuss a generalized class of preferential attachment models which includes many classical models. It turns out that some properties can be analyzed for the whole class without specifying the model. Such properties are the degree distribution and the global and average local clustering coefficients. Finally, we discuss some surprising results on the behavior of the global clustering coefficient in scale-free networks. Here we do not assume any underlying model.     

Stability analysis of quaternion‐valued Cohen‐Grossberg neural networks

In this paper, by starting from basic quaternion algebra properties and algorithms, a quaternion‐valued Cohen‐Grossberg neural network was derived, subsequently, several new sufficient conditions are derived to ensure existence and global asymptotic stability (GAS) and global exponential stability (GES) of the equilibrium point (EP) for quaternion‐valued Cohen‐Grossberg neural networks. The obtained criteria can be checked easily in practice and have a distinguished feature from previous studies. Finally, we have numerical evidences that the mathematical system and the conclusions presented are validated.     

Partial regularity of weak solutions to a PDE system with cubic nonlinearity

In this paper we investigate regularity properties of weak solutions to a PDE system that arises in the study of biological transport networks. The system consists of a possibly singular elliptic equation for the scalar pressure of the underlying biological network coupled to a diffusion equation for the conductance vector of the network. There are several different types of nonlinearities in the system. Of particular mathematical interest is a term that is a polynomial function of solutions and their partial derivatives and this polynomial function has degree three. That is, the system contains a cubic nonlinearity. Only weak solutions to the system have been shown to exist. The regularity theory for the system remains fundamentally incomplete. In particular, it is not known whether or not weak solutions develop singularities. In this paper we obtain a partial regularity theorem, which gives an estimate for the parabolic Hausdorff dimension of the set of possible singular points.