A hierarchy index for networks in the brain reveals a complex entangled organizational structure.

Networks involved in information processing often have their nodes arranged hierarchically, with the majority of connections occurring in adjacent levels. However, despite being an intuitively appealing concept, the hierarchical organization of large networks, such as those in the brain, is difficult to identify, especially in absence of additional information beyond that provided by the connectome. In this paper, we propose a framework to uncover the hierarchical structure of a given network, that identifies the nodes occupying each level as well as the sequential order of the levels. It involves optimizing a metric that we use to quantify the extent of hierarchy present in a network. Applying this measure to various brain networks, ranging from the nervous system of the nematode Caenorhabditis elegans to the human connectome, we unexpectedly find that they exhibit a common network architectural motif intertwining hierarchy and modularity. This suggests that brain networks may have evolved to simultaneously exploit the functional advantages of these two types of organizations, viz., relatively independent modules performing distributed processing in parallel and a hierarchical structure that allows sequential pooling of these multiple processing streams. An intriguing possibility is that this property we report may be common to information processing networks in general.

Modelling the first wave of COVID-19 in India.

Estimating the burden of COVID-19 in India is difficult because the extent to which cases and deaths have been undercounted is hard to assess. Here, we use a 9-component, age-stratified, contact-structured epidemiological compartmental model, which we call the INDSCI-SIM model, to analyse the first wave of COVID-19 spread in India. We use INDSCI-SIM, together with Bayesian methods, to obtain optimal fits to daily reported cases and deaths across the span of the first wave of the Indian pandemic, over the period Jan 30, 2020 to Feb 15, 2021. We account for lock-downs and other non-pharmaceutical interventions (NPIs), an overall increase in testing as a function of time, the under-counting of cases and deaths, and a range of age-specific infection-fatality ratios. We first use our model to describe data from all individual districts of the state of Karnataka, benchmarking our calculations using data from serological surveys. We then extend this approach to aggregated data for Karnataka state. We model the progress of the pandemic across the cities of Delhi, Mumbai, Pune, Bengaluru and Chennai, and then for India as a whole. We estimate that deaths were undercounted by a factor between 2 and 5 across the span of the first wave, converging on 2.2 as a representative multiplier that accounts for the urban-rural gradient. We also estimate an overall under-counting of cases by a factor of between 20 and 25 towards the end of the first wave. Our estimates of the infection fatality ratio (IFR) are in the range 0.05-0.15, broadly consistent with previous estimates but substantially lower than values that have been estimated for other LMIC countries. We find that approximately 35% of India had been infected overall by the end of the first wave, results broadly consistent with those from serosurveys. These results contribute to the understanding of the long-term trajectory of COVID-19 in India.

Morphogen-regulated contact-mediated signaling between cells can drive the transitions underlying body segmentation in vertebrates.

We propose a unified mechanism that reproduces the sequence of dynamical transitions observed during somitogenesis, the process of body segmentation during embryonic development, that is invariant across all vertebrate species. This is achieved by combining inter-cellular interactions mediated via receptor-ligand coupling with global spatial heterogeneity introduced through a morphogen gradient known to occur along the anteroposterior axis. Our model reproduces synchronized oscillations in the gene expression in cells at the anterior of the presomitic mesoderm as it grows by adding new cells at its posterior, followed by travelling waves and subsequent arrest of activity, with the eventual appearance of somite-like patterns. This framework integrates a boundary-organized pattern formation mechanism, which uses positional information provided by a morphogen gradient, with the coupling-mediated self-organized emergence of collective dynamics, to explain the processes that lead to segmentation.

Developmental trajectory of Caenorhabditis elegans nervous system governs its structural organization.

A central problem of neuroscience involves uncovering the principles governing the organization of nervous systems which ensure robustness in brain development. The nematode Caenorhabditis elegans provides us with a model organism for studying this question. In this paper, we focus on the invariant connection structure and spatial arrangement of the neurons comprising the somatic neuronal network of this organism to understand the key developmental constraints underlying its design. We observe that neurons with certain shared characteristics-such as, neural process lengths, birth time cohort, lineage and bilateral symmetry-exhibit a preference for connecting to each other. Recognizing the existence of such homophily and their relative degree of importance in determining connection probability within neurons (for example, in synapses, symmetric pairing is the most dominant factor followed by birth time cohort, process length and lineage) helps in connecting specific neuronal attributes to the topological organization of the network. Further, the functional identities of neurons appear to dictate the temporal hierarchy of their appearance during the course of development. Providing crucial insights into principles that may be common across many organisms, our study shows how the trajectory in the developmental landscape constrains the structural organization of a nervous system.

Epidemic prevalence information on social networks can mediate emergent collective outcomes in voluntary vaccine schemes.

The effectiveness of a mass vaccination program can engender its own undoing if individuals choose to not get vaccinated believing that they are already protected by herd immunity. This would appear to be the optimal decision for an individual, based on a strategic appraisal of her costs and benefits, even though she would be vulnerable during subsequent outbreaks if the majority of the population argues in this manner. We investigate how voluntary vaccination can nevertheless emerge in a social network of rational agents, who make informed decisions whether to be vaccinated, integrated with a model of epidemic dynamics. The information available to each agent includes the prevalence of the disease in their local network neighborhood and/or globally in the population, as well as the fraction of their neighbors that are protected against the disease. Crucially, the payoffs governing the decision of agents vary with disease prevalence, resulting in the vaccine uptake behavior changing in response to contagion spreading. The collective behavior of the agents responding to local prevalence can lead to a significant reduction in the final epidemic size, particularly for less contagious diseases having low basic reproduction number [Formula: see text]. Near the epidemic threshold ([Formula: see text]) the use of local prevalence information can result in divergent responses in the final vaccine coverage. Our results suggest that heterogeneity in the risk perception resulting from the spatio-temporal evolution of an epidemic differentially affects agents' payoffs, which is a critical determinant of the success of voluntary vaccination schemes.

Precision of morphogen-driven tissue patterning during development is enhanced through contact-mediated cellular interactions.

Cells in developing embryos reliably differentiate to attain location-specific fates, despite fluctuations in morphogen concentrations that provide positional information and in molecular processes that interpret it. We show that local contact-mediated cell-cell interactions utilize inherent asymmetry in the response of patterning genes to the global morphogen signal yielding a bimodal response. This results in robust developmental outcomes with a consistent identity for the dominant gene at each cell, substantially reducing the uncertainty in the location of boundaries between distinct fates.

Self-organized transition to coherent activity in disordered media.

Synchronized oscillations are of critical functional importance in many biological systems. We show that such oscillations can arise without centralized coordination in a disordered system of electrically coupled excitable and passive cells. Increasing the coupling strength results in waves that lead to coherent periodic activity, exhibiting cluster, local and global synchronization under different conditions. Our results may explain the self-organized transition in a pregnant uterus from transient, localized activity initially to system-wide coherent excitations just before delivery.

Modular organization of gene-tumor association network allows identification of key molecular players in cancer.

The role played by the topological structure of biological networks in their dynamics and function is receiving increasing attention over the last decade as large-throughput experiments have provided large volumes of highly resolved data on the interactions between the components of such networks. This has provided new perspectives on systems diseases: for example, there has been a gradual shift in cancer research away from the study of individual molecules and of single gene mutations to the emerging consensus that it is a complex disease involving large-scale disruptions in the intracellular signaling network. One of the drawbacks of a systems- or network-based approach is the large number of cellular agents whose interactions need to be investigated. We tried to solve this problem by taking a mesoscopic view of the cancer diseases-genes network, whose modular organization we studied after projecting it onto two networks, one comprising only disease types and the other consisting of only genes related to one or more categories of cancer. Using community partitioning, we identified several modules in these networks. Projecting cancer gene clusters onto an abstract 'modular space' allows us to infer the relations between different tumor types. By classifying the functional role of particular genes in terms of their inter- and intra-modular connectivity, we identified a number of genes that play the key role of 'connector hubs' in the network. Using data from the human protein- protein interaction network we showed that genes that are 'connector hubs' or 'global hubs' are, in fact, much more likely to be related to cancer than other genes. More important from a therapeutic point of view, we showed that the connector hubs in the cancer gene network are involved in a significantly larger number of human signaling pathways associated with cancer than other types of cancer genes. Furthermore, the types of cancer linked to connector hub genes have significantly reduced survival rates compared with other types of cancer, thereby enhancing their importance in the search for potential therapeutic targets.

Contact-mediated signaling enables disorder-driven transitions in cellular assemblies.

We show that, when cells communicate by contact-mediated interactions, heterogeneity in cell shapes and sizes leads to qualitatively distinct collective behavior in the tissue. For intercellular coupling that implements lateral inhibition, such disorder-driven transitions can substantially alter the asymptotic pattern of differentiated cells by modulating their fate choice through changes in the neighborhood geometry. In addition, when contact-induced signals influence inherent cellular oscillations, disorder leads to the emergence of functionally relevant partially-ordered dynamical states.

Mesoscopic architecture enhances communication across the macaque connectome revealing structure-function correspondence in the brain.

Analyzing the brain in terms of organizational structures at intermediate scales provides an approach to unravel the complexity arising from interactions between its large number of components. Focusing on a wiring diagram that spans the cortex, basal ganglia, and thalamus of the macaque brain, we identify robust modules in the network that provide a mesoscopic-level description of its topological architecture. Surprisingly, we find that the modular architecture facilitates rapid communication across the network, instead of localizing activity as is typically expected in networks having community organization. By considering processes of diffusive spreading and coordination, we demonstrate that the specific pattern of inter- and intramodular connectivity in the network allows propagation to be even faster than equivalent randomized networks with or without modular structure. This pattern of connectivity is seen at different scales and is conserved across principal cortical divisions, as well as subcortical structures. Furthermore, we find that the physical proximity between areas is insufficient to explain the modular organization, as similar mesoscopic structures can be obtained even after factoring out the effect of distance constraints on the connectivity. By supplementing the topological information about the macaque connectome with physical locations, volumes, and functions of the constituent areas and analyzing this augmented dataset, we reveal a counterintuitive role played by the modular architecture of the brain in promoting global coordination of its activity. It suggests a possible explanation for the ubiquity of modularity in brain networks.

Contact-mediated cellular communication supplements positional information to regulate spatial patterning during development.

Development in multicellular organisms is marked by a high degree of spatial organization of the cells attaining distinct fates in the embryo. Recent experiments showing that suppression of intercellular interactions can alter the spatial patterns arising during development suggest that cell fates cannot be determined by the exclusive regulation of differential gene expression by morphogen gradients (the conventional view encapsulated in the French flag model). Using a mathematical model that describes the receptor-ligand interaction between cells in close physical proximity, we show that such intercellular signaling can regulate the process of selective gene expression within each cell, allowing information from the cellular neighborhood to influence the process by which the thresholds of morphogen concentration that dictate cell fates adaptively emerge. This results in local modulations of the positional cues provided by the global field set up by the morphogen, allowing interaction-mediated self-organized pattern formation to complement boundary-organized mechanisms in the context of development.

Disorder in cellular packing can alter proliferation dynamics to regulate growth.

The mechanisms by which an organ regulates its growth are not yet fully understood, especially when the cells are closely packed as in epithelial tissues. We explain growth arrest as a collective dynamical transition in coupled oscillators on disordered lattices. As the cellular morphologies become homogeneous over the course of development, the signals induced by cell-cell contact increase beyond a critical value that triggers coordinated cessation of the cell-cycle oscillators driving cell division. Thus, control of cell proliferation is causally related to the geometry of cellular packing.

Phase of Ising spins on modular networks analogous to social polarization.

Coordination processes in complex systems can be related to the problem of collective ordering in networks, many of which have modular organization. Investigating the order-disorder transition for Ising spins on modular random networks, corresponding to consensus formation in society, we observe two distinct phases: (i) ordering within each module at a critical temperature followed by (ii) global ordering at a lower temperature. This indicates polarization of society into groups having contrary opinions can persist indefinitely even when mutual interactions between agents favor consensus.

Emergence of frustration signals systemic risk.

We show that the emergence of systemic risk in complex systems can be understood from the evolution of functional networks representing interactions inferred from fluctuation correlations between macroscopic observables. Specifically, we analyze the long-term collective dynamics in the New York Stock Exchange, the largest financial market in the world, for almost a century and show that periods marked by systemic crisis are associated with emergence of frustration. This is indicated by the loss of structural balance in the networks of interaction between stocks. Moreover, the mesoscopic organization of the networks during these periods exhibits prominent core-periphery organization. This suggests an increased degree of coherence in the collective dynamics of the system, which is reinforced by our observation of the transition to delocalization in the dominant eigenmodes when the systemic risk builds up. While frustration has been associated with phase transitions in physical systems such as spin glasses, its role as a signal for systemic risk buildup leading to severe crisis as shown here provides a novel perspective into the dynamical processes leading to catastrophic failures in complex systems.

Lateral inhibition provides a unifying framework for spatiotemporal pattern formation in media comprising relaxation oscillators.

Differential excitatory and inhibitory interactions, specifically lateral inhibition, between the constituent elements of complex systems underlie a wide range of spatiotemporal patterns in nature. Here, we show that when systems of relaxation oscillators, whose dynamics involve widely separate timescales, are coupled primarily through diffusion of the inactivation component, they exhibit strikingly similar patterns regardless of specific details of the model kinetics and spatial topology. This universality stems from the fact that all observed patterns can be viewed as either specific manifestations of, or arising through interactions between, two fundamental classes of collective dynamics, viz., a state comprising clusters of synchronized oscillators, and a time-invariant spatially inhomogeneous state resulting from oscillator death. Our work provides an unifying framework for understanding the emergent global behavior of various chemical, biological, and ecological systems spanning several time and length scales.

Understanding the mind of a worm: hierarchical network structure underlying nervous system function in C. elegans.

The nervous system of the nematode C. elegans provides a unique opportunity to understand how behavior ('mind') emerges from activity in the nervous system ('brain') of an organism. The hermaphrodite worm has only 302 neurons, all of whose connections (synaptic and gap junctional) are known. Recently, many of the functional circuits that make up its behavioral repertoire have begun to be identified. In this paper, we investigate the hierarchical structure of the nervous system through k-core decomposition and find it to be intimately related to the set of all known functional circuits. Our analysis also suggests a vital role for the lateral ganglion in processing information, providing an essential connection between the sensory and motor components of the C. elegans nervous system.

Emergent memory in cell signaling: Persistent adaptive dynamics in cascades can arise from the diversity of relaxation time-scales.

The mitogen-activated protein kinase (MAPK) signaling cascade, an evolutionarily conserved motif present in all eukaryotic cells, is involved in coordinating crucial cellular functions. While the asymptotic dynamical behavior of the pathway stimulated by a time-invariant signal is relatively well-understood, we show using a computational model that it exhibits a rich repertoire of transient adaptive responses to changes in stimuli. When the signal is switched on, the response is characterized by long-lived modulations in frequency as well as amplitude. On withdrawing the stimulus, the activity decays over long timescales, exhibiting reverberations characterized by repeated spiking in the activated MAPK concentration. The long-term persistence of such post-stimulus activity suggests that the cascade retains memory of the signal for a significant duration following its removal. The molecular mechanism underlying the reverberatory activity is related to the existence of distinct relaxation rates for the different cascade components. This results in the imbalance of fluxes between different layers of the cascade, with the reuse of activated kinases as enzymes when they are released from sequestration in complexes. The persistent adaptive response, indicative of a cellular "short-term" memory, suggests that this ubiquitous signaling pathway plays an even more central role in information processing by eukaryotic cells.

When big data fails: Adaptive agents using coarse-grained information have competitive advantage.

The recent trend for acquiring big data assumes that possessing quantitatively more and qualitatively finer data necessarily provides an advantage that may be critical in competitive situations. Using a model complex adaptive system where agents compete for a limited resource using information coarse grained to different levels, we show that agents having access to more and better data perform worse than others in certain situations. The relation between information asymmetry and individual payoffs is seen to be complex, depending on the composition of the population of competing agents.

The "handedness" of language: Directional symmetry breaking of sign usage in words.

Language, which allows complex ideas to be communicated through symbolic sequences, is a characteristic feature of our species and manifested in a multitude of forms. Using large written corpora for many different languages and scripts, we show that the occurrence probability distributions of signs at the left and right ends of words have a distinct heterogeneous nature. Characterizing this asymmetry using quantitative inequality measures, viz. information entropy and the Gini index, we show that the beginning of a word is less restrictive in sign usage than the end. This property is not simply attributable to the use of common affixes as it is seen even when only word roots are considered. We use the existence of this asymmetry to infer the direction of writing in undeciphered inscriptions that agrees with the archaeological evidence. Unlike traditional investigations of phonotactic constraints which focus on language-specific patterns, our study reveals a property valid across languages and writing systems. As both language and writing are unique aspects of our species, this universal signature may reflect an innate feature of the human cognitive phenomenon.

Modular networks emerge from multiconstraint optimization.

Modular structure is ubiquitous among complex networks. We note that most such systems are subject to multiple structural and functional constraints, e.g., minimizing the average path length and the total number of links, while maximizing robustness against perturbations in node activity. We show that the optimal networks satisfying these three constraints are characterized by the existence of multiple subnetworks (modules) sparsely connected to each other. In addition, these modules have distinct hubs, resulting in an overall heterogeneous degree distribution.