Functional resilience of mutually repressing motifs embedded in larger regulatory networks

Elucidating the design principles of regulatory networks driving cellular decision-making has important implications in understanding cell differentiation and guiding the design of synthetic circuits. Mutually repressing feedback loops between 'master regulators' of cell-fates can exhibit multistable dynamics, thus enabling multiple 'single-positive' phenotypes: (high A, low B) and (low A, high B) for a toggle switch, and (high A, low B, low C), (low A, high B, low C) and (low A, low B, high C) for a toggle triad. However, the dynamics of these two network motifs has been interrogated in isolation in silico, but in vitro and in vivo, they often operate while embedded in larger regulatory networks. Here, we embed these network motifs in complex larger networks of varying sizes and connectivity and identify conditions under which these motifs maintain their canonical dynamical behavior, thus identifying hallmarks of their functional resilience. We show that the in-degree of a motif - defined as the number of incoming edges onto a motif - determines its functional properties. For a smaller in-degree, the functional traits for both these motifs (bimodality, pairwise correlation coefficient(s), and the frequency of 'single-positive' phenotypes) are largely conserved, but increasing the in-degree can lead to a divergence from their stand-alone behaviors. These observations offer insights into design principles of biological networks containing these network motifs, as well as help devise optimal strategies for integration of these motifs into larger synthetic networks.

Robust design of complex socio-technical systems against seasonal effects: a network motif-based approach

Seasonal effects can significantly impact the robustness of socio-technical systems (STS) to demand fluctuations. There is an increasing need to develop novel design approaches that can support capacity planning decisions for enhancing the robustness of STS against seasonal effects. This paper proposes a new network motif-based approach to supporting capacity planning in STS for an improved seasonal robustness. Network motifs are underlying nonrandom subgraphs within a complex network. In this approach, we introduce three motif-based metrics for system performance evaluation and capacity planning decision-making. The first one is the imbalance score of a motif (e.g., a local service network), the second one is the measurement of a motif’s seasonal robustness, and the third one is a capacity planning decision criterion. Based on these three metrics, we validate that the sensitivity of STS performance against seasonal effects is highly correlated with the imbalanced capacity between service nodes in an STS. Correspondingly, we formulate a design optimisation problem to improve the robustness of STS by rebalancing the resources at critical service nodes. To demonstrate the utility of the approach, a case study on Divvy bike-sharing system in Chicago is conducted. With a focus on the size-3 motifs (a subgraph consisting three docked stations), we find that there is a significant correlation between the difference of the number of docks among the stations in a motif and the return/rental performance of such a motif against seasonal changes. Guided by this finding, our design approach can successfully balance out the number of docks between those stations that have caused the most severe seasonal perturbations. The results also imply that the network motifs can be an effective local structural representation in support of STS robust design. Our approach can be generally applied in other STS where the system performances are significantly impacted by seasonal changes, for example, supply chain networks, transportation systems and power grids.

Local interactions and homophily effects in actor collaboration networks for urban resilience governance

Understanding actor collaboration networks and their evolution is essential to promoting collective action in resilience planning and management of interdependent infrastructure systems. Local interactions and choice homophily are two important network evolution mechanisms. Network motifs encode the information of network formation, configuration, and the local structure. Homophily effects, on the other hand, capture whether the network configurations have significant correlations with node properties. The objective of this paper is to explore the extent to which local interactions and homophily effects influence actor collaboration in resilience planning and management of interdependent infrastructure systems. We mapped bipartite actor collaboration network based on a post-Hurricane Harvey stakeholder survey that revealed actor collaborations for hazard mitigation. We examined seven bipartite network motifs for the mapped collaboration network and compared the mapped network to simulated random models with same degree distributions. Then we examined whether the network configurations had significant statistics for node properties using exponential random graph models. The results provide insights about the two mechanisms—local interactions and homophily effect—influencing the formation of actor collaboration in resilience planning and management of interdependent urban systems. The findings have implications for improving network cohesion and actor collaborations from diverse urban sectors.

A connectome of the Drosophila central complex reveals network motifs suitable for flexible navigation and context-dependent action selection

Flexible behaviors over long timescales are thought to engage recurrent neural networks in deep brain regions, which are experimentally challenging to study. In insects, recurrent circuit dynamics in a brain region called the central complex (CX) enable directed locomotion, sleep, and context- and experience-dependent spatial navigation. We describe the first complete electron-microscopy-based connectome of the Drosophila CX, including all its neurons and circuits at synaptic resolution. We identified new CX neuron types, novel sensory and motor pathways, and network motifs that likely enable the CX to extract the fly’s head-direction, maintain it with attractor dynamics, and combine it with other sensorimotor information to perform vector-based navigational computations. We also identified numerous pathways that may facilitate the selection of CX-driven behavioral patterns by context and internal state. The CX connectome provides a comprehensive blueprint necessary for a detailed understanding of network dynamics underlying sleep, flexible navigation, and state-dependent action selection.

Chaotic Resonance in Izhikevich Neural Network Motifs Under Electromagnetic Induction

Chaotic resonance (CR) is the response of a nonlinear system to weak signals enhanced by internal or external chaotic activity (such as the signal derived from Lorenz system). In this paper, the triple-neuron feed-forward loop (FFL) Izhikevich neural network motifs with eight types are constructed as the nonlinear systems, and the effects of EMI on CR phenomenon in FFL neuronal network motifs are studied. It is found that both the single Izhikevich neural model under electromagnetic induction (EMI) and its network motifs exhibit CR phenomenon depending on the chaotic current intensity. There exists an optimal chaotic current intensity ensuring the best detection of weak signal in single Izhikevich neuron or its network motifs via CR. The EMI can enhance the ability of neuron to detect weak signals. For T1-FFL and T2-FFL motifs, the adjustment of EMI parameters makes T2-FFL show a more obvious CR phenomenon than that for T1-FFL motifs, which is different from the impact of system parameters (e.g., the weak signal frequency, the coupling strength, and the time delay) on CR. Another interesting phenomenon is that the variation of CR with time delay exhibits quasi periodic characteristics. Our results showed that CR effect is a robust phenomenon which is observed in both single Izhikevich neuron and network motifs, which might help one understand how to improve the ability of weak signal detection and propagation in neuronal system.

A Mobility Model for Return and Repeated Migration Based on Network Motifs

People changing residence within their own country is the most common type of migration and is one of the main driving forces of a country's demography. Yet, due to a lack of data and tools, some key characteristics of internal migration such as the propensity to remain in the same city or to return to previous locations are frequently ignored. Here, a network-based model of city-to-city migration is constructed, where the movement of individuals is modelled using the frequency of distinct network motifs. We fit this model to longitudinal data on 3.3 million workers in Colombia, including 1.4 million migrations, and compare the motif frequency based on migration and return rates between men and women, and between distinct age and income groups. Results show that the majority of people do not move in general, but that there is a small group which exhibits frequent migration, particularly the young and male. Nearly three out of four times that a person moves, they are going back to a previous city, although women and mature people are less likely to move and more likely to return if they actually move. At a city level, different onward and return migration patterns are observed, whereby people from small secondary towns are more likely to leave and not return than people from large metropolitan areas like Bogotá or Medellín.

Revealing nuclear receptor hub modules from Basal-like breast cancer expression networks

Nuclear receptors are a class of transcriptional factors. Together with their co-regulators, they regulate development, homeostasis, and metabolism in a ligand-dependent manner. Their ability to respond to environmental stimuli rapidly makes them versatile cellular components. Their coordinated activities regulate essential pathways in normal physiology and in disease. Due to their complexity, the challenge remains in understanding their direct associations in cancer development. Basal-like breast cancer is an aggressive form of breast cancer that often lacks ER, PR and Her2. The absence of these receptors limits the treatment for patients to the non-selective cytotoxic and cytostatic drugs. To identify potential drug targets it is essential to identify the most important nuclear receptor association network motifs in Basal-like subtype progression. This research aimed to reveal the transcriptional network patterns, in the hope to capture the underlying molecular state driving Basal-like oncogenesis. In this work, we illustrate a multidisciplinary approach of integrating an unsupervised machine learning clustering method with network modelling to reveal unique transcriptional patterns (network motifs) underlying Basal-like breast cancer. The unsupervised clustering method provides a natural stratification of breast cancer patients, revealing the underlying heterogeneity in Basal-like. Identification of gene correlation networks (GCNs) from Basal-like patients in both the TCGA and METABRIC databases revealed three critical transcriptional regulatory constellations that are enriched in Basal-like. These represent critical NR components implicated in Basal-like breast cancer transcription. This approach is easily adaptable and applicable to reveal critical signalling relationships in other diseases.