Heterogeneous Popularity of Metabolic Reactions from Evolution.

The composition of cellular metabolism is different across species. Empirical data reveal that bacterial species contain similar numbers of metabolic reactions but that the cross-species popularity of reactions is so heterogenous that some reactions are found in all the species while others are in just few species, characterized by a power-law distribution with the exponent one. Introducing an evolutionary model concretizing the stochastic recruitment of chemical reactions into the metabolism of different species at different times and their inheritance to descendants, we demonstrate that the exponential growth of the number of species containing a reaction and the saturated recruitment rate of brand-new reactions lead to the empirically identified power-law popularity distribution. Furthermore, the structural characteristics of metabolic networks and the species' phylogeny in our simulations agree well with empirical observations.

Contagion dynamics on hypergraphs with nested hyperedges.

In complex social systems encoded as hypergraphs, higher-order (i.e., group) interactions taking place among more than two individuals are represented by hyperedges. One of the higher-order correlation structures native to hypergraphs is the nestedness: Some hyperedges can be entirely contained (that is, nested) within another larger hyperedge, which itself can also be nested further in a hierarchical manner. Yet the effect of such hierarchical structure of hyperedges on the dynamics has remained unexplored. In this context, here we propose a random nested-hypergraph model with a tunable level of nestedness and investigate the effects of nestedness on a higher-order susceptible-infected-susceptible process. By developing an analytic framework called the facet approximation, we obtain the steady-state fraction of infected nodes on the random nested-hypergraph model more accurately than existing methods. Our results show that the hyperedge-nestedness affects the phase diagram significantly. Monte Carlo simulations support the analytical results.

Scaling in local to global condensation of wealth on sparse networks.

The prevalence of wealth inequality propels us to characterize its origin and progression via empirical and theoretical studies. The yard-sale (YS) model, in which a portion of the smaller wealth is transferred between two individuals, culminates in the concentration of almost all wealth to a single individual, while distributing the rest of the wealth with a power law of exponent one. By incorporating redistribution to the model, in which the transferred wealth is proportional to the sender's wealth, we show that such extreme inequality is suppressed if the frequency ratio of redistribution to the YS-type exchange exceeds the inverse of the population size. Studying our model on a sparsely-connected population, we find that the wealth inequality ceases to grow for a period, when local rich nodes can no longer acquire wealth from their broke nearest neighbors. Subsequently, inequality resumes growth due to the redistribution effect by allowing locally amassed wealth to move and coalesce. Analyzing the Langevin equations and the coalescing random walk on complex networks, we elucidate the scaling behaviors of wealth inequality in those multiple phases. These findings reveal the influence of network structure on wealth distribution, offering a novel perspective on wealth inequality.

Stability and selective extinction in complex mutualistic networks.

We study species abundance in the empirical plant-pollinator mutualistic networks exhibiting broad degree distributions, with uniform intragroup competition assumed, by the Lotka-Volterra equation. The stability of a fixed point is found to be identified by the signs of its nonzero components and those of its neighboring fixed points. Taking the annealed approximation, we derive the nonzero components to be formulated in terms of degrees and the rescaled interaction strengths, which lead us to find different stable fixed points depending on parameters, and we obtain the phase diagram. The selective extinction phase finds small-degree species extinct and effective interaction reduced, maintaining stability and hindering the onset of instability. The nonzero minimum species abundances from different empirical networks show data collapse when rescaled as predicted theoretically.

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.

From coarse to fine: the absolute Escherichia coli proteome under diverse growth conditions.

Accurate measurements of cellular protein concentrations are invaluable to quantitative studies of gene expression and physiology in living cells. Here, we developed a versatile mass spectrometric workflow based on data-independent acquisition proteomics (DIA/SWATH) together with a novel protein inference algorithm (xTop). We used this workflow to accurately quantify absolute protein abundances in Escherichia coli for > 2,000 proteins over > 60 growth conditions, including nutrient limitations, non-metabolic stresses, and non-planktonic states. The resulting high-quality dataset of protein mass fractions allowed us to characterize proteome responses from a coarse (groups of related proteins) to a fine (individual) protein level. Hereby, a plethora of novel biological findings could be elucidated, including the generic upregulation of low-abundant proteins under various metabolic limitations, the non-specificity of catabolic enzymes upregulated under carbon limitation, the lack of large-scale proteome reallocation under stress compared to nutrient limitations, as well as surprising strain-dependent effects important for biofilm formation. These results present valuable resources for the systems biology community and can be used for future multi-omics studies of gene regulation and metabolic control in E. coli.

Skewness of local logarithmic exports.

The distributions of trade values and relationships among countries and product categories reflect how countries select their trade partners and design export portfolios. Here we consider the exporter-importer network and the exporter-product network with links weighted by the logarithm of the corresponding export values each year from 1962 to 2018, and study how the weights of the outgoing links from each country are distributed. Such local logarithmic export distributions by destinations and products are found to follow approximately the Gaussian distribution across exporters and time, implying random assignment of export values on a logarithmic scale. However, a nonzero skewness is identified, changing from positive to negative as exporters have more partner importers and more product categories in their portfolios. Seeking the origin, we analyze how local exports depend on the out-degree of the exporter and the in-degrees of destinations or products and formulate their quantitative and measurable relation incorporating randomness, which uncovers the fundamental nature of the export strategies of individual countries.

Optimizing hospital distribution across districts to reduce tuberculosis fatalities.

The spatial distributions of diverse facilities are often understood in terms of the optimization of the commute distance or the economic profit. Incorporating more general objective functions into such optimization framework may be useful, helping the policy decisions to meet various social and economic demands. As an example, we consider how hospitals should be distributed to minimize the total fatalities of tuberculosis (TB). The empirical data of Korea shows that the fatality rate of TB in a district decreases with the areal density of hospitals, implying their correlation and the possibility of reducing the nationwide fatalities by adjusting the hospital distribution across districts. Approximating the fatality rate by the probability of a patient not to visit a hospital in her/his residential district for the duration period of TB and evaluating the latter probability in the random-walk framework, we obtain the fatality rate as an exponential function of the hospital density with a characteristic constant related to each district's effective lattice constant estimable empirically. This leads us to the optimal hospital distribution which finds the hospital density in a district to be a logarithmic function of the rescaled patient density. The total fatalities is reduced by 13% with this optimum. The current hospital density deviates from the optimized one in different manners from district to district, which is analyzed in the proposed model framework. The assumptions and limitations of our study are also discussed.

Giant component in a configuration-model power-law graph with a variable number of links.

We generalize an algorithm used widely in the configuration model such that power-law degree sequences with the degree exponent λ and the number of links per node K controllable independently may be generated. It yields the degree distribution in a different form from that of the static model or under random removal of links while sharing the same λ and K. With this generalized power-law degree distribution, the critical point K_{c} for the appearance of the giant component remains zero not only for λ≤3 but also for 3<λ<λ_{l}≃3.81. This is contrasted with K_{c}=0 only for λ≤3 in the static model and under random link removal. The critical exponents and the cluster-size distribution for λ<λ_{l} are also different from known results. By analyzing the moments and the generating function of the degree distribution and comparison with those of other models, we show that the asymptotic behavior and the degree exponent may not be the only properties of the degree distribution relevant to the critical phenomena but that its whole functional form can be relevant. These results can be useful in designing and assessing the structure and robustness of networked systems.

Engel's law in the commodity composition of exports.

Different shares of distinct commodity sectors in production, trade, and consumption illustrate how resources and capital are allocated and invested. Economic progress has been claimed to change the share distribution in a universal manner as exemplified by the Engel's law for the household expenditure and the shift from primary to manufacturing and service sector in the three sector model. Searching for large-scale quantitative evidence of such correlation, we analyze the gross-domestic product (GDP) and international trade data based on the standard international trade classification (SITC) in the period 1962 to 2000. Three categories, among ten in the SITC, are found to have their export shares significantly correlated with the GDP over countries and time; The machinery category has positive and food and crude materials have negative correlations. The export shares of commodity categories of a country are related to its GDP by a power-law with the exponents characterizing the GDP-elasticity of their export shares. The distance between two countries in terms of their export portfolios is measured to identify several clusters of countries sharing similar portfolios in 1962 and 2000. We show that the countries whose GDP is increased significantly in the period are likely to transit to the clusters displaying large share of the machinery category.

Understanding the temporal pattern of spreading in heterogeneous networks: Theory of the mean infection time.

For a reliable prediction of an epidemic or information spreading pattern in complex systems, well-defined measures are essential. In the susceptible-infected model on heterogeneous networks, the cluster of infected nodes in the intermediate-time regime exhibits too large fluctuation in size to use its mean size as a representative value. The cluster size follows quite a broad distribution, which is shown to be derived from the variation of the cluster size with the time when a hub node was first infected. On the contrary, the distribution of the time taken to infect a given number of nodes is well concentrated at its mean, suggesting the mean infection time is a better measure. We show that the mean infection time can be evaluated by using the scaling behaviors of the boundary area of the infected cluster and use it to find a nonexponential but algebraic spreading phase in the intermediate stage on strongly heterogeneous networks. Such slow spreading originates in only small-degree nodes left susceptible, while most hub nodes are already infected in the early exponential-spreading stage. Our results offer a way to detour around large statistical fluctuations and quantify reliably the temporal pattern of spread under structural heterogeneity.

Evolution of regulatory networks towards adaptability and stability in a changing environment.

Diverse biological networks exhibit universal features distinguished from those of random networks, calling much attention to their origins and implications. Here we propose a minimal evolution model of Boolean regulatory networks, which evolve by selectively rewiring links towards enhancing adaptability to a changing environment and stability against dynamical perturbations. We find that sparse and heterogeneous connectivity patterns emerge, which show qualitative agreement with real transcriptional regulatory networks and metabolic networks. The characteristic scaling behavior of stability reflects the balance between robustness and flexibility. The scaling of fluctuation in the perturbation spread shows a dynamic crossover, which is analyzed by investigating separately the stochasticity of internal dynamics and the network structure differences depending on the evolution pathways. Our study delineates how the ambivalent pressure of evolution shapes biological networks, which can be helpful for studying general complex systems interacting with environments.

Lattice model for spontaneous imbibition in porous media: the role of effective tension and universality class.

Recently, anomalous scaling properties of front broadening during spontaneous imbibition of water in Vycor glass, a nanoporous medium, were reported: the mean height and the width of the propagating front increase with time t both proportional to t(1/2). Here, we propose a simple lattice imbibition model and elucidate quantitatively how the correlation range of the hydrostatic pressure and the disorder strength of the pore radii affect the scaling properties of the imbibition front. We introduce an effective tension of liquid across neighboring pores, which depends on the aspect ratio of each pore, and show that it leads to a dynamical crossover: both the mean height and the roughness grow faster in the presence of tension in the intermediate-time regime but eventually saturate in the long-time regime. The universality class of the long-time behavior is discussed by examining the associated scaling exponents and their relation to directed percolation.

Metabolic network analysis-based identification of antimicrobial drug targets in category A bioterrorism agents.

The 2001 anthrax mail attacks in the United States demonstrated the potential threat of bioterrorism, hence driving the need to develop sophisticated treatment and diagnostic protocols to counter biological warfare. Here, by performing flux balance analyses on the fully-annotated metabolic networks of multiple, whole genome-sequenced bacterial strains, we have identified a large number of metabolic enzymes as potential drug targets for each of the three Category A-designated bioterrorism agents including Bacillus anthracis, Francisella tularensis and Yersinia pestis. Nine metabolic enzymes- belonging to the coenzyme A, folate, phosphatidyl-ethanolamine and nucleic acid pathways common to all strains across the three distinct genera were identified as targets. Antimicrobial agents against some of these enzymes are available. Thus, a combination of cross species-specific antibiotics and common antimicrobials against shared targets may represent a useful combinatorial therapeutic approach against all Category A bioterrorism agents.

Impact of compatibility on the organization of mutualistic networks.

Distinct relationships such as activation, inhibition, cooperation, and competition are not established independently but in a correlated manner in complex systems. Thus the patterns of one type of interaction may reflect the impacts of other classes of interactions, but its quantitative understanding remains to be done. Referring to the plant-pollinator mutualistic networks, here we propose and investigate the structural features of a model bipartite network, in which the mutualistic relationship between two different types of nodes is established under the influence of the compatibility among the nodes of the same type. Interestingly, we find that the degree distributions obtained for extremely broad compatibility distributions are similar to those for a constant compatibility, both of which deviate from those for the Gaussian compatibility distributions. We present the analytic arguments to explain this finding. Also the dependence of the topological similarity of two nodes on their compatibility is illustrated. We discuss the application of our findings to complex systems.

Viral perturbations of host networks reflect disease etiology.

Many human diseases, arising from mutations of disease susceptibility genes (genetic diseases), are also associated with viral infections (virally implicated diseases), either in a directly causal manner or by indirect associations. Here we examine whether viral perturbations of host interactome may underlie such virally implicated disease relationships. Using as models two different human viruses, Epstein-Barr virus (EBV) and human papillomavirus (HPV), we find that host targets of viral proteins reside in network proximity to products of disease susceptibility genes. Expression changes in virally implicated disease tissues and comorbidity patterns cluster significantly in the network vicinity of viral targets. The topological proximity found between cellular targets of viral proteins and disease genes was exploited to uncover a novel pathway linking HPV to Fanconi anemia.

Interspecific competition underlying mutualistic networks.

Multiple classes of interactions may exist affecting one another in a given system. For the mutualistic networks of plants and pollinating animals, it has been known that the degree distribution is broad but often deviates from power-law form more significantly for plants than animals. To illuminate the origin of such asymmetry, we study a model network in which links are assigned under generalized preferential-selection rules between two groups of nodes and find the sensitive dependence of the resulting connectivity pattern on the model parameters. The nonlinearity of preferential selection can come from interspecific interactions among animals and among plants. The model-based analysis of real-world mutualistic networks suggests that a new animal determines its partners not only by their abundance but also under the competition with existing animal species, which leads to the stretched-exponential degree distributions of plants.

A mapping of drug space from the viewpoint of small molecule metabolism.

Small molecule drugs target many core metabolic enzymes in humans and pathogens, often mimicking endogenous ligands. The effects may be therapeutic or toxic, but are frequently unexpected. A large-scale mapping of the intersection between drugs and metabolism is needed to better guide drug discovery. To map the intersection between drugs and metabolism, we have grouped drugs and metabolites by their associated targets and enzymes using ligand-based set signatures created to quantify their degree of similarity in chemical space. The results reveal the chemical space that has been explored for metabolic targets, where successful drugs have been found, and what novel territory remains. To aid other researchers in their drug discovery efforts, we have created an online resource of interactive maps linking drugs to metabolism. These maps predict the "effect space" comprising likely target enzymes for each of the 246 MDDR drug classes in humans. The online resource also provides species-specific interactive drug-metabolism maps for each of the 385 model organisms and pathogens in the BioCyc database collection. Chemical similarity links between drugs and metabolites predict potential toxicity, suggest routes of metabolism, and reveal drug polypharmacology. The metabolic maps enable interactive navigation of the vast biological data on potential metabolic drug targets and the drug chemistry currently available to prosecute those targets. Thus, this work provides a large-scale approach to ligand-based prediction of drug action in small molecule metabolism.

The impact of cellular networks on disease comorbidity.

The impact of disease-causing defects is often not limited to the products of a mutated gene but, thanks to interactions between the molecular components, may also affect other cellular functions, resulting in potential comorbidity effects. By combining information on cellular interactions, disease-gene associations, and population-level disease patterns extracted from Medicare data, we find statistically significant correlations between the underlying structure of cellular networks and disease comorbidity patterns in the human population. Our results indicate that such a combination of population-level data and cellular network information could help build novel hypotheses about disease mechanisms.

Comparative genome-scale metabolic reconstruction and flux balance analysis of multiple Staphylococcus aureus genomes identify novel antimicrobial drug targets.

Mortality due to multidrug-resistant Staphylococcus aureus infection is predicted to surpass that of human immunodeficiency virus/AIDS in the United States. Despite the various treatment options for S. aureus infections, it remains a major hospital- and community-acquired opportunistic pathogen. With the emergence of multidrug-resistant S. aureus strains, there is an urgent need for the discovery of new antimicrobial drug targets in the organism. To this end, we reconstructed the metabolic networks of multidrug-resistant S. aureus strains using genome annotation, functional-pathway analysis, and comparative genomic approaches, followed by flux balance analysis-based in silico single and double gene deletion experiments. We identified 70 single enzymes and 54 pairs of enzymes whose corresponding metabolic reactions are predicted to be unconditionally essential for growth. Of these, 44 single enzymes and 10 enzyme pairs proved to be common to all 13 S. aureus strains, including many that had not been previously identified as being essential for growth by gene deletion experiments in S. aureus. We thus conclude that metabolic reconstruction and in silico analyses of multiple strains of the same bacterial species provide a novel approach for potential antibiotic target identification.