Degree distributions under general node removal: Power-law or Poisson?

Perturbations made to networked systems may result in partial structural loss, such as a blackout in a power-grid system. Investigating the resulting disturbance in network properties is quintessential to understand real networks in action. The removal of nodes is a representative disturbance, but previous studies are seemingly contrasting about its effect on arguably the most fundamental network statistic, the degree distribution. The key question is about the functional form of the degree distributions that can be altered during node removal or sampling. The functional form is decisive in the remaining subnetwork's static and dynamical properties. In this work, we clarify the situation by utilizing the relative entropies with respect to the reference distributions in the Poisson and power-law form, to quantify the distance between the subnetwork's degree distribution and either of the reference distributions. Introducing general sequential node removal processes with continuously different levels of hub protection to encompass a series of scenarios including uniform random removal and preferred or protective (i.e., biased random) removal of the hub, we classify the altered degree distributions starting from various power-law forms by comparing two relative entropy values. From the extensive investigation in various scenarios based on direct node-removal simulations and by solving the rate equation of degree distributions, we discover in the parameter space two distinct regimes, one where the degree distribution is closer to the power-law reference distribution and the other closer to the Poisson distribution.

Exploring the human diseasome: the human disease network.

Advances in genome-scale molecular biology and molecular genetics have greatly elevated our knowledge on the basic components of human biology and diseases. At the same time, the importance of cellular networks between those biological components is increasingly appreciated. Built upon these recent technological and conceptual advances, a new discipline called the network medicine, an approach to understand human diseases from a network point-of-view, is about to emerge. In this review article, we will survey some recent endeavours along this direction, centred on the concept and applications of the human diseasome and the human disease network. Questions, and partial answers thereof, such as how the connectivity between molecular parts translates into the relationships between the related disorders on a global scale and how central the disease-causing genetic components are in the cellular network, will be discussed. The use of the diseasome in combination with various interactome networks and other disease-related factors is also reviewed.

Impact of the topology of global macroeconomic network on the spreading of economic crises.

Throughout economic history, the global economy has experienced recurring crises. The persistent recurrence of such economic crises calls for an understanding of their generic features rather than treating them as singular events. The global economic system is a highly complex system and can best be viewed in terms of a network of interacting macroeconomic agents. In this regard, from the perspective of collective network dynamics, here we explore how the topology of the global macroeconomic network affects the patterns of spreading of economic crises. Using a simple toy model of crisis spreading, we demonstrate that an individual country's role in crisis spreading is not only dependent on its gross macroeconomic capacities, but also on its local and global connectivity profile in the context of the world economic network. We find that on one hand clustering of weak links at the regional scale can significantly aggravate the spread of crises, but on the other hand the current network structure at the global scale harbors higher tolerance of extreme crises compared to more "globalized" random networks. These results suggest that there can be a potential hidden cost in the ongoing globalization movement towards establishing less-constrained, trans-regional economic links between countries, by increasing vulnerability of the global economic system to extreme crises.

An empirical framework for binary interactome mapping.

Several attempts have been made to systematically map protein-protein interaction, or 'interactome', networks. However, it remains difficult to assess the quality and coverage of existing data sets. Here we describe a framework that uses an empirically-based approach to rigorously dissect quality parameters of currently available human interactome maps. Our results indicate that high-throughput yeast two-hybrid (HT-Y2H) interactions for human proteins are more precise than literature-curated interactions supported by a single publication, suggesting that HT-Y2H is suitable to map a significant portion of the human interactome. We estimate that the human interactome contains approximately 130,000 binary interactions, most of which remain to be mapped. Similar to estimates of DNA sequence data quality and genome size early in the Human Genome Project, estimates of protein interaction data quality and interactome size are crucial to establish the magnitude of the task of comprehensive human interactome mapping and to elucidate a path toward this goal.

Sustained oscillations in extended genetic oscillatory systems.

Various dynamic cellular behaviors have been successfully modeled in terms of elementary circuitries showing particular characteristics such as negative feedback loops for sustained oscillations. Given, however, the increasing evidences indicating that cellular components do not function in isolation but form a complex interwoven network, it is still unclear to what extent the conclusions drawn from the elementary circuit analogy hold for systems that are highly interacting with surrounding environments. In this article, we consider a specific example of genetic oscillator systems, the so-called repressilator, as a starting point toward a systematic investigation into the dynamic consequences of the extension through interlocking of elementary biological circuits. From in silico analyses with both continuous and Boolean dynamics approaches to the four-node extension of the repressilator, we found that 1), the capability of sustained oscillation depends on the topology of extended systems; and 2), the stability of oscillation under the extension also depends on the coupling topology. We then deduce two empirical rules favoring the sustained oscillations, termed the coherent coupling and the homogeneous regulation. These simple rules will help us prioritize candidate patterns of network wiring, guiding both the experimental investigations for further physiological verification and the synthetic designs for bioengineering.

Drug-target network.

The global set of relationships between protein targets of all drugs and all disease-gene products in the human protein-protein interaction or 'interactome' network remains uncharacterized. We built a bipartite graph composed of US Food and Drug Administration-approved drugs and proteins linked by drug-target binary associations. The resulting network connects most drugs into a highly interlinked giant component, with strong local clustering of drugs of similar types according to Anatomical Therapeutic Chemical classification. Topological analyses of this network quantitatively showed an overabundance of 'follow-on' drugs, that is, drugs that target already targeted proteins. By including drugs currently under investigation, we identified a trend toward more functionally diverse targets improving polypharmacology. To analyze the relationships between drug targets and disease-gene products, we measured the shortest distance between both sets of proteins in current models of the human interactome network. Significant differences in distance were found between etiological and palliative drugs. A recent trend toward more rational drug design was observed.

The human disease network.

A network of disorders and disease genes linked by known disorder-gene associations offers a platform to explore in a single graph-theoretic framework all known phenotype and disease gene associations, indicating the common genetic origin of many diseases. Genes associated with similar disorders show both higher likelihood of physical interactions between their products and higher expression profiling similarity for their transcripts, supporting the existence of distinct disease-specific functional modules. We find that essential human genes are likely to encode hub proteins and are expressed widely in most tissues. This suggests that disease genes also would play a central role in the human interactome. In contrast, we find that the vast majority of disease genes are nonessential and show no tendency to encode hub proteins, and their expression pattern indicates that they are localized in the functional periphery of the network. A selection-based model explains the observed difference between essential and disease genes and also suggests that diseases caused by somatic mutations should not be peripheral, a prediction we confirm for cancer genes.

Modeling bursts and heavy tails in human dynamics.

The dynamics of many social, technological and economic phenomena are driven by individual human actions, turning the quantitative understanding of human behavior into a central question of modern science. Current models of human dynamics, used from risk assessment to communications, assume that human actions are randomly distributed in time and thus well approximated by Poisson processes. Here we provide direct evidence that for five human activity patterns, such as email and letter based communications, web browsing, library visits and stock trading, the timing of individual human actions follow non-Poisson statistics, characterized by bursts of rapidly occurring events separated by long periods of inactivity. We show that the bursty nature of human behavior is a consequence of a decision based queuing process: when individuals execute tasks based on some perceived priority, the timing of the tasks will be heavy tailed, most tasks being rapidly executed, while a few experiencing very long waiting times. In contrast, priority blind execution is well approximated by uniform interevent statistics. We discuss two queuing models that capture human activity. The first model assumes that there are no limitations on the number of tasks an individual can handle at any time, predicting that the waiting time of the individual tasks follow a heavy tailed distribution P(tau(w)) approximately tau(w)(-alpha) with alpha=3/2. The second model imposes limitations on the queue length, resulting in a heavy tailed waiting time distribution characterized by alpha=1. We provide empirical evidence supporting the relevance of these two models to human activity patterns, showing that while emails, web browsing and library visitation display alpha=1, the surface mail based communication belongs to the alpha=3/2 universality class. Finally, we discuss possible extension of the proposed queuing models and outline some future challenges in exploring the statistical mechanics of human dynamics.

Lethality and synthetic lethality in the genome-wide metabolic network of Escherichia coli.

Recent genomic analyses on the cellular metabolic network show that reaction flux across enzymes are diverse and exhibit power-law behavior in its distribution. While intuition might suggest that the reactions with larger fluxes are more likely to be lethal under the blockade of its catalysing gene products or gene knockouts, we find, by in silico flux analysis, that the lethality rarely has correlations with the flux level owing to the widespread backup pathways innate in the genome-wide metabolism of Escherichia coli. Lethal reactions, of which the deletion generates cascading failure of following reactions up to the biomass reaction, are identified in terms of the Boolean network scheme as well as the flux balance analysis. The avalanche size of a reaction, defined as the number of subsequently blocked reactions after its removal, turns out to be a useful measure of lethality. As a means to elucidate phenotypic robustness to a single deletion, we investigate synthetic lethality in reaction level, where simultaneous deletion of a pair of nonlethal reactions leads to the failure of the biomass reaction. Synthetic lethals identified via flux balance and Boolean scheme are consistently shown to act in parallel pathways, working in such a way that the backup machinery is compromised.

Classification of scale-free networks.

While the emergence of a power-law degree distribution in complex networks is intriguing, the degree exponent is not universal. Here we show that the between ness centrality displays a power-law distribution with an exponent eta, which is robust, and use it to classify the scale-free networks. We have observed two universality classes with eta approximately equal 2.2(1) and 2.0, respectively. Real-world networks for the former are the protein-interaction networks, the metabolic networks for eukaryotes and bacteria, and the coauthorship network, and those for the latter one are the Internet, the World Wide Web, and the metabolic networks for Archaea. Distinct features of the mass-distance relation, generic topology of geodesics, and resilience under attack of the two classes are identified. Various model networks also belong to either of the two classes, while their degree exponents are tunable.