The fundamental advantages of temporal networks.

Most networked systems of scientific interest are characterized by temporal links, meaning the network's structure changes over time. Link temporality has been shown to hinder many dynamical processes, from information spreading to accessibility, by disrupting network paths. Considering the ubiquity of temporal networks in nature, we ask: Are there any advantages of the networks' temporality? We use an analytical framework to show that temporal networks can, compared to their static counterparts, reach controllability faster, demand orders of magnitude less control energy, and have control trajectories, that are considerably more compact than those characterizing static networks. Thus, temporality ensures a degree of flexibility that would be unattainable in static networks, enhancing our ability to control them.

Small but slow world: how network topology and burstiness slow down spreading.

While communication networks show the small-world property of short paths, the spreading dynamics in them turns out slow. Here, the time evolution of information propagation is followed through communication networks by using empirical data on contact sequences and the susceptible-infected model. Introducing null models where event sequences are appropriately shuffled, we are able to distinguish between the contributions of different impeding effects. The slowing down of spreading is found to be caused mainly by weight-topology correlations and the bursty activity patterns of individuals.

Blueprint for antimicrobial hit discovery targeting metabolic networks.

Advances in genome analysis, network biology, and computational chemistry have the potential to revolutionize drug discovery by combining system-level identification of drug targets with the atomistic modeling of small molecules capable of modulating their activity. To demonstrate the effectiveness of such a discovery pipeline, we deduced common antibiotic targets in Escherichia coli and Staphylococcus aureus by identifying shared tissue-specific or uniformly essential metabolic reactions in their metabolic networks. We then predicted through virtual screening dozens of potential inhibitors for several enzymes of these reactions and showed experimentally that a subset of these inhibited both enzyme activities in vitro and bacterial cell viability. This blueprint is applicable for any sequenced organism with high-quality metabolic reconstruction and suggests a general strategy for strain-specific antiinfective therapy.

Cancer metastasis networks and the prediction of progression patterns.

BACKGROUND: Metastasis patterns in cancer vary both spatially and temporally. Network modelling may allow the incorporation of the temporal dimension in the analysis of these patterns. METHODS: We used Medicare claims of 2,265,167 elderly patients aged > or = 65 years to study the large-scale clinical pattern of metastases. We introduce the concept of a cancer metastasis network, in which nodes represent the primary cancer site and the sites of subsequent metastases, connected by links that measure the strength of co-occurrence. RESULTS: These cancer metastasis networks capture both temporal and subtle relational information, the dynamics of which differ between cancer types. Using these networks as entities on which the metastatic disease of individual patients may evolve, we show that they may be used, for certain cancer types, to make retrograde predictions of a primary cancer type given a sequence of metastases, as well as anterograde predictions of future sites of metastasis. CONCLUSION: Improvements over traditional techniques show that such a network-based modelling approach may be suitable for studying metastasis patterns.

The implications of human metabolic network topology for disease comorbidity.

Most diseases are the consequence of the breakdown of cellular processes, but the relationships among genetic/epigenetic defects, the molecular interaction networks underlying them, and the disease phenotypes remain poorly understood. To gain insights into such relationships, here we constructed a bipartite human disease association network in which nodes are diseases and two diseases are linked if mutated enzymes associated with them catalyze adjacent metabolic reactions. We find that connected disease pairs display higher correlated reaction flux rate, corresponding enzyme-encoding gene coexpression, and higher comorbidity than those that have no metabolic link between them. Furthermore, the more connected a disease is to other diseases, the higher is its prevalence and associated mortality rate. The network topology-based approach also helps to uncover potential mechanisms that contribute to their shared pathophysiology. Thus, the structure and modeled function of the human metabolic network can provide insights into disease comorbidity, with potentially important consequences for disease diagnosis and prevention.

Intracellular crowding defines the mode and sequence of substrate uptake by Escherichia coli and constrains its metabolic activity.

The influence of the high intracellular concentration of macromolecules on cell physiology is increasingly appreciated, but its impact on system-level cellular functions remains poorly quantified. To assess its potential effect, here we develop a flux balance model of Escherichia coli cell metabolism that takes into account a systems-level constraint for the concentration of enzymes catalyzing the various metabolic reactions in the crowded cytoplasm. We demonstrate that the model's predictions for the relative maximum growth rate of wild-type and mutant E. coli cells in single substrate-limited media, and the sequence and mode of substrate uptake and utilization from a complex medium are in good agreement with subsequent experimental observations. These results suggest that molecular crowding represents a bound on the achievable functional states of a metabolic network, and they indicate that models incorporating this constraint can systematically identify alterations in cellular metabolism activated in response to environmental change.

The product space conditions the development of nations.

Economies grow by upgrading the products they produce and export. The technology, capital, institutions, and skills needed to make newer products are more easily adapted from some products than from others. Here, we study this network of relatedness between products, or "product space," finding that more-sophisticated products are located in a densely connected core whereas less-sophisticated products occupy a less-connected periphery. Empirically, countries move through the product space by developing goods close to those they currently produce. Most countries can reach the core only by traversing empirically infrequent distances, which may help explain why poor countries have trouble developing more competitive exports and fail to converge to the income levels of rich countries.

Structure and tie strengths in mobile communication networks.

Electronic databases, from phone to e-mails logs, currently provide detailed records of human communication patterns, offering novel avenues to map and explore the structure of social and communication networks. Here we examine the communication patterns of millions of mobile phone users, allowing us to simultaneously study the local and the global structure of a society-wide communication network. We observe a coupling between interaction strengths and the network's local structure, with the counterintuitive consequence that social networks are robust to the removal of the strong ties but fall apart after a phase transition if the weak ties are removed. We show that this coupling significantly slows the diffusion process, resulting in dynamic trapping of information in communities and find that, when it comes to information diffusion, weak and strong ties are both simultaneously ineffective.

Dynamics of information access on the web.

While current studies on complex networks focus on systems that change relatively slowly in time, the structure of the most visited regions of the web is altered at the time scale from hours to days. Here we investigate the dynamics of visitation of a major news portal, representing the prototype for such a rapidly evolving network. The nodes of the network can be classified into stable nodes, which form the time-independent skeleton of the portal, and news documents. The visitations of the two node classes are markedly different, the skeleton acquiring visits at a constant rate, while a news document's visitation peaks after a few hours. We find that the visitation pattern of a news document decays as a power law, in contrast with the exponential prediction provided by simple models of site visitation. This is rooted in the inhomogeneous nature of the browsing pattern characterizing individual users: the time interval between consecutive visits by the same user to the site follows a power-law distribution, in contrast to the exponential expected for Poisson processes. We show that the exponent characterizing the individual user's browsing patterns determines the power-law decay in a document's visitation. Finally, our results document the fleeting quality of news and events: while fifteen minutes of fame is still an exaggeration in the online media, we find that access to most news items significantly decays after 36 hours of posting.

Topological units of environmental signal processing in the transcriptional regulatory network of Escherichia coli.

Recent evidence indicates that potential interactions within metabolic, protein-protein interaction, and transcriptional regulatory networks are used differentially according to the environmental conditions in which a cell exists. However, the topological units underlying such differential utilization are not understood. Here we use the transcriptional regulatory network of Escherichia coli to identify such units, called origons, representing regulatory subnetworks that originate at a distinct class of sensor transcription factors. Using microarray data, we find that specific environmental signals affect mRNA expression levels significantly only within the origons responsible for their detection and processing. We also show that small regulatory interaction patterns, called subgraphs and motifs, occupy distinct positions in and between origons, offering insights into their dynamical role in information processing. The identified features are likely to represent a general framework for environmental signal processing in prokaryotes.

The topological relationship between the large-scale attributes and local interaction patterns of complex networks.

Recent evidence indicates that the abundance of recurring elementary interaction patterns in complex networks, often called subgraphs or motifs, carry significant information about their function and overall organization. Yet, the underlying reasons for the variable quantity of different subgraph types, their propensity to form clusters, and their relationship with the networks' global organization remain poorly understood. Here we show that a network's large-scale topological organization and its local subgraph structure mutually define and predict each other, as confirmed by direct measurements in five well studied cellular networks. We also demonstrate the inherent existence of two distinct classes of subgraphs, and show that, in contrast to the low-density type II subgraphs, the highly abundant type I subgraphs cannot exist in isolation but must naturally aggregate into subgraph clusters. The identified topological framework may have important implications for our understanding of the origin and function of subgraphs in all complex networks.

Separating internal and external dynamics of complex systems.

The observable behavior of a complex system reflects the mechanisms governing the internal interactions between the system's components and the effect of external perturbations. Here we show that by capturing the simultaneous activity of several of the system's components we can separate the internal dynamics from the external fluctuations. The method allows us to systematically determine the origin of fluctuations in various real systems, finding that while the Internet and the computer chip have robust internal dynamics, highway and Web traffic are driven by external demand. As multichannel measurements are becoming the norm in most fields, the method could help uncover the collective dynamics of a wide array of complex systems.

Global organization of metabolic fluxes in the bacterium Escherichia coli.

Cellular metabolism, the integrated interconversion of thousands of metabolic substrates through enzyme-catalysed biochemical reactions, is the most investigated complex intracellular web of molecular interactions. Although the topological organization of individual reactions into metabolic networks is well understood, the principles that govern their global functional use under different growth conditions raise many unanswered questions. By implementing a flux balance analysis of the metabolism of Escherichia coli strain MG1655, here we show that network use is highly uneven. Whereas most metabolic reactions have low fluxes, the overall activity of the metabolism is dominated by several reactions with very high fluxes. E. coli responds to changes in growth conditions by reorganizing the rates of selected fluxes predominantly within this high-flux backbone. This behaviour probably represents a universal feature of metabolic activity in all cells, with potential implications for metabolic engineering.

Fluctuations in network dynamics.

Most complex networks serve as conduits for various dynamical processes, ranging from mass transfer by chemical reactions in the cell to packet transfer on the Internet. We collected data on the time dependent activity of five natural and technological networks, finding that for each the coupling of the flux fluctuations with the total flux on individual nodes obeys a unique scaling law. We show that the observed scaling can explain the competition between the system's internal collective dynamics and changes in the external environment, allowing us to predict the relevant scaling exponents.

Experimental determination and system level analysis of essential genes in Escherichia coli MG1655.

Defining the gene products that play an essential role in an organism's functional repertoire is vital to understanding the system level organization of living cells. We used a genetic footprinting technique for a genome-wide assessment of genes required for robust aerobic growth of Escherichia coli in rich media. We identified 620 genes as essential and 3,126 genes as dispensable for growth under these conditions. Functional context analysis of these data allows individual functional assignments to be refined. Evolutionary context analysis demonstrates a significant tendency of essential E. coli genes to be preserved throughout the bacterial kingdom. Projection of these data over metabolic subsystems reveals topologic modules with essential and evolutionarily preserved enzymes with reduced capacity for error tolerance.

Evolutionary conservation of motif constituents in the yeast protein interaction network.

Understanding why some cellular components are conserved across species but others evolve rapidly is a key question of modern biology. Here we show that in Saccharomyces cerevisiae, proteins organized in cohesive patterns of interactions are conserved to a substantially higher degree than those that do not participate in such motifs. We find that the conservation of proteins in distinct topological motifs correlates with the interconnectedness and function of that motif and also depends on the structure of the overall interactome topology. These findings indicate that motifs may represent evolutionary conserved topological units of cellular networks molded in accordance with the specific biological function in which they participate.

Emerging behavior in electronic bidding.

We characterize the statistical properties of a large number of agents on two major online auction sites. The measurements indicate that the total number of bids placed in a single category and the number of distinct auctions frequented by a given agent follow power-law distributions, implying that a few agents are responsible for a significant fraction of the total bidding activity on the online market. We find that these agents exert an unproportional influence on the final price of the auctioned items. This domination of online auctions by an unusually active minority may be a generic feature of all online mercantile processes.

Percolation in directed scale-free networks.

Many complex networks in nature have directed links, a property that affects the network's navigability and large-scale topology. Here we study the percolation properties of such directed scale-free networks with correlated in and out degree distributions. We derive a phase diagram that indicates the existence of three regimes, determined by the values of the degree exponents. In the first regime we regain the known directed percolation mean field exponents. In contrast, the second and third regimes are characterized by anomalous exponents, which we calculate analytically. In the third regime the network is resilient to random dilution, i.e., the percolation threshold is p(c)-->1.

Hierarchical organization of modularity in metabolic networks.

Spatially or chemically isolated functional modules composed of several cellular components and carrying discrete functions are considered fundamental building blocks of cellular organization, but their presence in highly integrated biochemical networks lacks quantitative support. Here, we show that the metabolic networks of 43 distinct organisms are organized into many small, highly connected topologic modules that combine in a hierarchical manner into larger, less cohesive units, with their number and degree of clustering following a power law. Within Escherichia coli, the uncovered hierarchical modularity closely overlaps with known metabolic functions. The identified network architecture may be generic to system-level cellular organization.

Monte Carlo simulation of sinusoidally modulated superlattice growth.

The fabrication of ZnSe/ZnTe superlattices grown by the process of rotating the substrate in the presence of an inhomogeneous flux distribution instead of the successively closing and opening of source shutters is studied via Monte Carlo simulations. It is found that the concentration of each compound is sinusoidally modulated along the growth direction, caused by the uneven arrival of Se and Te atoms at a given point of the sample, and by the variation of the Te/Se ratio at that point due to the rotation of the substrate. In this way we obtain a ZnSe(1-x)Tex alloy in which the composition x varies sinusoidally along the growth direction. The period of the modulation is directly controlled by the rate of the substrate rotation. The amplitude of the compositional modulation is monotonic for small angular velocities of the substrate rotation, but is itself modulated for large angular velocities. The average amplitude of the modulation pattern decreases as the angular velocity of substrate rotation increases and the measurement position approaches the center of rotation. The simulation results are in good agreement with previously published experimental measurements on superlattices fabricated in this manner.