A system-wide network reconstruction of gene regulation and metabolism in Escherichia coli.

Genome-scale metabolic models have become a fundamental tool for examining metabolic principles. However, metabolism is not solely characterized by the underlying biochemical reactions and catalyzing enzymes, but also affected by regulatory events. Since the pioneering work of Covert and co-workers as well as Shlomi and co-workers it is debated, how regulation and metabolism synergistically characterize a coherent cellular state. The first approaches started from metabolic models, which were extended by the regulation of the encoding genes of the catalyzing enzymes. By now, bioinformatics databases in principle allow addressing the challenge of integrating regulation and metabolism on a system-wide level. Collecting information from several databases we provide a network representation of the integrated gene regulatory and metabolic system for Escherichia coli, including major cellular processes, from metabolic processes via protein modification to a variety of regulatory events. Besides transcriptional regulation, we also take into account regulation of translation, enzyme activities and reactions. Our network model provides novel topological characterizations of system components based on their positions in the network. We show that network characteristics suggest a representation of the integrated system as three network domains (regulatory, metabolic and interface networks) instead of two. This new three-domain representation reveals the structural centrality of components with known high functional relevance. This integrated network can serve as a platform for understanding coherent cellular states as active subnetworks and to elucidate crossover effects between metabolism and gene regulation.

Ensembles, dynamics, and cell types: Revisiting the statistical mechanics perspective on cellular regulation.

Genetic regulatory networks control ontogeny. For fifty years Boolean networks have served as models of such systems, ranging from ensembles of random Boolean networks as models for generic properties of gene regulation to working dynamical models of a growing number of sub-networks of real cells. At the same time, their statistical mechanics has been thoroughly studied. Here we recapitulate their original motivation in the context of current theoretical and empirical research. We discuss ensembles of random Boolean networks whose dynamical attractors model cell types. A sub-ensemble is the critical ensemble. There is now strong evidence that genetic regulatory networks are dynamically critical, and that evolution is exploring the critical sub-ensemble. The generic properties of this sub-ensemble predict essential features of cell differentiation. In particular, the number of attractors in such networks scales as the DNA content raised to the 0.63 power. Data on the number of cell types as a function of the DNA content per cell shows a scaling relationship of 0.88. Thus, the theory correctly predicts a power law relationship between the number of cell types and the DNA contents per cell, and a comparable slope. We discuss these new scaling values and show prospects for new research lines for Boolean networks as a base model for systems biology.

Evolution of robust network topologies: emergence of central backbones.

We model the robustness against random failure or an intentional attack of networks with an arbitrary large-scale structure. We construct a block-based model which incorporates--in a general fashion--both connectivity and interdependence links, as well as arbitrary degree distributions and block correlations. By optimizing the percolation properties of this general class of networks, we identify a simple core-periphery structure as the topology most robust against random failure. In such networks, a distinct and small "core" of nodes with higher degree is responsible for most of the connectivity, functioning as a central "backbone" of the system. This centralized topology remains the optimal structure when other constraints are imposed, such as a given fraction of interdependence links and fixed degree distributions. This distinguishes simple centralized topologies as the most likely to emerge, when robustness against failure is the dominant evolutionary force.

No need for conspiracy: self-organized cartel formation in a modified trust game.

We investigate the dynamics of a trust game on a mixed population, where individuals with the role of buyers are forced to play against a predetermined number of sellers whom they choose dynamically. Agents with the role of sellers are also allowed to adapt the level of value for money of their products, based on payoff. The dynamics undergoes a transition at a specific value of the strategy update rate, above which an emergent cartel organization is observed, where sellers have similar values of below-optimal value for money. This cartel organization is not due to an explicit collusion among agents; instead, it arises spontaneously from the maximization of the individual payoffs. This dynamics is marked by large fluctuations and a high degree of unpredictability for most of the parameter space and serves as a plausible qualitative explanation for observed elevated levels and fluctuations of certain commodity prices.

Epidemics with asymptomatic transmission: Subcritical phase from recursive contact tracing.

The challenges presented by the COVID-19 epidemic have created a renewed interest in the development of new methods to combat infectious diseases, and it has shown the importance of preparedness for possible future diseases. A prominent property of the SARS-CoV-2 transmission is the significant fraction of asymptomatic transmission. This may influence the effectiveness of the standard contact tracing procedure for quarantining potentially infected individuals. However, the effects of asymptomatic transmission on the epidemic threshold of epidemic spreading on networks have rarely been studied explicitly. Here we study the critical percolation transition for an arbitrary disease with a nonzero asymptomatic rate in a simple epidemic network model in the presence of a recursive contact tracing algorithm for instant quarantining. We find that, above a certain fraction of asymptomatic transmission, standard contact tracing loses its ability to suppress spreading below the epidemic threshold. However, we also find that recursive contact tracing opens a possibility to contain epidemics with a large fraction of asymptomatic or presymptomatic transmission. In particular, we calculate the required fraction of network nodes participating in the contact tracing for networks with arbitrary degree distributions and for varying recursion depths and discuss the influence of recursion depth and asymptomatic rate on the epidemic percolation phase transition. We anticipate recursive contact tracing to provide a basis for digital, app-based contact tracing tools that extend the efficiency of contact tracing to diseases with a large fraction of asymptomatic transmission.

Self-organized criticality in neural networks from activity-based rewiring.

Neural systems process information in a dynamical regime between silence and chaotic dynamics. This has lead to the criticality hypothesis, which suggests that neural systems reach such a state by self-organizing toward the critical point of a dynamical phase transition. Here, we study a minimal neural network model that exhibits self-organized criticality in the presence of stochastic noise using a rewiring rule which only utilizes local information. For network evolution, incoming links are added to a node or deleted, depending on the node's average activity. Based on this rewiring-rule only, the network evolves toward a critical state, showing typical power-law-distributed avalanche statistics. The observed exponents are in accord with criticality as predicted by dynamical scaling theory, as well as with the observed exponents of neural avalanches. The critical state of the model is reached autonomously without the need for parameter tuning, is independent of initial conditions, is robust under stochastic noise, and independent of details of the implementation as different variants of the model indicate. We argue that this supports the hypothesis that real neural systems may utilize such a mechanism to self-organize toward criticality, especially during early developmental stages.

Reliability of regulatory networks and its evolution.

The problem of reliability of the dynamics in biological regulatory networks is studied in the framework of a generalized Boolean network model with continuous timing and noise. Using well-known artificial genetic networks such as the repressilator, we discuss concepts of reliability of rhythmic attractors. In a simple evolution process we investigate how overall network structure affects the reliability of the dynamics. In the course of the evolution, networks are selected for reliable dynamics. We find that most networks can be easily evolved towards reliable functioning while preserving the original function.

Morphogenesis by coupled regulatory networks: reliable control of positional information and proportion regulation.

Based on a non-equilibrium mechanism for spatial pattern formation we study how position information can be controlled by locally coupled discrete dynamical networks, similar to gene regulation networks of cells in a developing multicellular organism. As an example we study the developmental problems of domain formation and proportion regulation in the presence of noise, as well as in the presence of cell flow. We find that networks that solve this task exhibit a hierarchical structure of information processing and are of similar complexity as developmental circuits of living cells. Proportion regulation is scalable with system size and leads to sharp, precisely localized boundaries of gene expression domains, even for large numbers of cells. A detailed analysis of noise-induced dynamics, using a mean-field approximation, shows that noise in gene expression states stabilizes (rather than disrupts) the spatial pattern in the presence of cell movements, both for stationary as well as growing systems. Finally, we discuss how this mechanism could be realized in the highly dynamic environment of growing tissues in multicellular organisms.

Critical excitation-inhibition balance in dense neural networks.

The "edge of chaos" phase transition in artificial neural networks is of renewed interest in light of recent evidence for criticality in brain dynamics. Statistical mechanics traditionally studied this transition with connectivity k as the control parameter and an exactly balanced excitation-inhibition ratio. While critical connectivity has been found to be low in these model systems, typically around k=2, which is unrealistic for natural neural systems, a recent study utilizing the excitation-inhibition ratio as the control parameter found a new, nearly degree independent, critical point when connectivity is large. However, the new phase transition is accompanied by an unnaturally high level of activity in the network. Here we study random neural networks with the additional properties of (i) a high clustering coefficient and (ii) neurons that are solely either excitatory or inhibitory, a prominent property of natural neurons. As a result, we observe an additional critical point for networks with large connectivity, regardless of degree distribution, which exhibits low activity levels that compare well with neuronal brain networks.

Imitating the winner leads to discrimination in spatial prisoner's dilemma model.

The occurrence of discrimination is an important problem in the social and economical sciences. Much of the discrimination observed in empirical studies can be explained by the theory of in-group favouritism, which states that people tend to act more positively towards peers whose appearances are more similar to their own. Some studies, however, find hierarchical structures in inter-group relations, where members of low-status groups also favour the high-status group members. These observations cannot be understood in the light of in-group favouritism. Here we present an agent based model in which evolutionary dynamics can result in a hierarchical discrimination between two groups characterized by a meaningless, but observable binary label. We find that discriminating strategies end up dominating the system when the selection pressure is high, i.e. when agents have a much higher probability of imitating their neighbour with the highest payoff. These findings suggest that the puzzling persistence of hierarchical discrimination may result from the evolutionary dynamics of the social system itself, namely the social imitation dynamics. It also predicts that discrimination will occur more often in highly competitive societies.

Discrimination emerging through spontaneous symmetry breaking in a spatial prisoner's dilemma model with multiple labels.

Social discrimination seems to be a persistent phenomenon in many cultures. It is important to understand the mechanisms that lead people to judge others by the group to which they belong rather than individual qualities. It was recently shown that evolutionary (imitation) dynamics can lead to a hierarchical discrimination between agents marked with observable, but otherwise meaningless, labels. These findings suggest that it can give useful insight to describe the phenomenon of social discrimination in terms of spontaneous symmetry breaking. The investigations so far have, however, only considered binary labels. In this contribution we extend the investigations to models with up to seven different labels. We find the features known from the binary label model remain remarkably robust when the number of labels is increased. We also discover a new feature, namely that it is more likely for neighbors to have strategies which are similar, in the sense that they agree on how to act toward a subset of the labels.

Repulsion in controversial debate drives public opinion into fifty-fifty stalemate.

Opinion formation is a process with strong implications for public policy. In controversial debates with large consequences, the public opinion is often trapped in a fifty-fifty stalemate, jeopardizing broadly accepted political decisions. Emergent effects from millions of private discussions make it hard to understand or influence this kind of opinion dynamics. Here we demonstrate that repulsion from opinions favors fifty-fifty stalemates. We study a voter model where agents can have two opinions or an undecided state in between, and where we allow for repulsion of opinions and for doubt: in pairwise discussions, undecided agents can be not only convinced, but also repelled from the opinion expressed by another agent, and decided agents may return to the undecided state. As a result, we observe that, if an agent is repelled instead of being convinced in at least one out of four interactions, as in controversial debates, the frequencies of both opinions equalize. This voter model attractor reproduces the phenomenology of repeated Brexit poll data well and provides a mechanism solely based on local interactions between agents that may explain stalemate polarization in controversial opinion formation.

The transition from differential equations to Boolean networks: a case study in simplifying a regulatory network model.

Methods for modeling cellular regulatory networks as diverse as differential equations and Boolean networks co-exist, however, without much closer correspondence to each other. With the example system of the fission yeast cell cycle control network, we here discuss these two approaches with respect to each other. We find that a Boolean network model can be formulated as a specific coarse-grained limit of the more detailed differential equations model for this system. This demonstrates the mathematical foundation on which Boolean networks can be applied to biological regulatory networks in a controlled way.

Boolean network models of cellular regulation: prospects and limitations.

Computer models are valuable tools towards an understanding of the cell's biochemical regulatory machinery. Possible levels of description of such models range from modelling the underlying biochemical details to top-down approaches, using tools from the theory of complex networks. The latter, coarse-grained approach is taken where regulatory circuits are classified in graph-theoretical terms, with the elements of the regulatory networks being reduced to simply nodes and links, in order to obtain architectural information about the network. Further, considering dynamics on networks at such an abstract level seems rather unlikely to match dynamical regulatory activity of biological cells. Therefore, it came as a surprise when recently examples of discrete dynamical network models based on very simplistic dynamical elements emerged which in fact do match sequences of regulatory patterns of their biological counterparts. Here I will review such discrete dynamical network models, or Boolean networks, of biological regulatory networks. Further, we will take a look at such models extended with stochastic noise, which allow studying the role of network topology in providing robustness against noise. In the end, we will discuss the interesting question of why at all such simple models can describe aspects of biology despite their simplicity. Finally, prospects of Boolean models in exploratory dynamical models for biological circuits and their mutants will be discussed.

Reliability of genetic networks is evolvable.

Control of the living cell functions with remarkable reliability despite the stochastic nature of the underlying molecular networks--a property presumably optimized by biological evolution. We ask here to what extent the ability of a stochastic dynamical network to produce reliable dynamics is an evolvable trait. Using an evolutionary algorithm based on a deterministic selection criterion for the reliability of dynamical attractors, we evolve networks of noisy discrete threshold nodes. We find that, starting from any random network, reliability of the attractor landscape can often be achieved with only a few small changes to the network structure. Further, the evolvability of networks toward reliable dynamics while retaining their function is investigated and a high success rate is found.

Partitioning and modularity of graphs with arbitrary degree distribution.

We solve the graph bipartitioning problem in dense graphs with arbitrary degree distribution using the replica method. We find the cut size to scale universally with . In contrast, earlier results studying the problem in graphs with a Poissonian degree distribution had found a scaling with square root [Fu and Anderson, J. Phys. A 19, 1605 (1986)]. Our results also generalize to the problem of q partitioning. They can be used to find the expected modularity Q [Newman and Girvan, Phys. Rev. E 69, 026113 (2004)] of random graphs and allow for the assessment of the statistical significance of the output of community detection algorithms.

The interdependent network of gene regulation and metabolism is robust where it needs to be.

Despite being highly interdependent, the major biochemical networks of the living cell-the networks of interacting genes and of metabolic reactions, respectively-have been approached mostly as separate systems so far. Recently, a framework for interdependent networks has emerged in the context of statistical physics. In a first quantitative application of this framework to systems biology, here we study the interdependent network of gene regulation and metabolism for the model organism Escherichia coli in terms of a biologically motivated percolation model. Particularly, we approach the system's conflicting tasks of reacting rapidly to (internal and external) perturbations, while being robust to minor environmental fluctuations. Considering its response to perturbations that are localized with respect to functional criteria, we find the interdependent system to be sensitive to gene regulatory and protein-level perturbations, yet robust against metabolic changes. We expect this approach to be applicable to a range of other interdependent networks.Although networks of interacting genes and metabolic reactions are interdependent, they have largely been treated as separate systems. Here the authors apply a statistical framework for interdependent networks to E. coli, and show that it is sensitive to gene and protein perturbations but robust against metabolic changes.

Statistical mechanics of community detection.

Starting from a general ansatz, we show how community detection can be interpreted as finding the ground state of an infinite range spin glass. Our approach applies to weighted and directed networks alike. It contains the ad hoc introduced quality function from [J. Reichardt and S. Bornholdt, Phys. Rev. Lett. 93, 218701 (2004)] and the modularity Q as defined by Newman and Girvan [Phys. Rev. E 69, 026113 (2004)] as special cases. The community structure of the network is interpreted as the spin configuration that minimizes the energy of the spin glass with the spin states being the community indices. We elucidate the properties of the ground state configuration to give a concise definition of communities as cohesive subgroups in networks that is adaptive to the specific class of network under study. Further, we show how hierarchies and overlap in the community structure can be detected. Computationally efficient local update rules for optimization procedures to find the ground state are given. We show how the ansatz may be used to discover the community around a given node without detecting all communities in the full network and we give benchmarks for the performance of this extension. Finally, we give expectation values for the modularity of random graphs, which can be used in the assessment of statistical significance of community structure.

Stable and unstable attractors in Boolean networks.

Boolean networks at the critical point have been a matter of debate for many years as, e.g., the scaling of numbers of attractors with system size. Recently it was found that this number scales superpolynomially with system size, contrary to a common earlier expectation of sublinear scaling. We point out here that these results are obtained using deterministic parallel update, where a large fraction of attractors are an artifact of the updating scheme. This limits the significance of these results for biological systems where noise is omnipresent. Here we take a fresh look at attractors in Boolean networks with the original motivation of simplified models for biological systems in mind. We test the stability of attractors with respect to infinitesimal deviations from synchronous update and find that most attractors are artifacts arising from synchronous clocking. The remaining fraction of attractors are stable against fluctuating delays. The average number of these stable attractors grows sublinearly with system size in the numerically tractable range.

Econophysics of adaptive power markets: When a market does not dampen fluctuations but amplifies them.

The average economic agent is often used to model the dynamics of simple markets, based on the assumption that the dynamics of a system of many agents can be averaged over in time and space. A popular idea that is based on this seemingly intuitive notion is to dampen electric power fluctuations from fluctuating sources (as, e.g., wind or solar) via a market mechanism, namely by variable power prices that adapt demand to supply. The standard model of an average economic agent predicts that fluctuations are reduced by such an adaptive pricing mechanism. However, the underlying assumption that the actions of all agents average out on the time axis is not always true in a market of many agents. We numerically study an econophysics agent model of an adaptive power market that does not assume averaging a priori. We find that when agents are exposed to source noise via correlated price fluctuations (as adaptive pricing schemes suggest), the market may amplify those fluctuations. In particular, small price changes may translate to large load fluctuations through catastrophic consumer synchronization. As a result, an adaptive power market may cause the opposite effect than intended: Power demand fluctuations are not dampened but amplified instead.