Rewiring Process Research Articles

Metabolic Regulation in Mitochondria and Drug Resistance.

Mitochondria are generally considered as a powerhouse in a cell where the majority of the cellular ATP and metabolite productions occur. Metabolic rewiring and reprogramming may be initiated and regulated by mitochondrial enzymes. The hypothesis that cellular metabolic rewiring and reprogramming processes may occur as cellular microenvironment is disturbed, resulting in alteration of cell phenotype, such as cancer cells resistant to therapeutics seems to be now acceptable. Cancer metabolic reprogramming regulated by mitochondrial enzymes is now one of the hallmarks of cancer. This chapter provides an overview of cancer metabolism and summarizes progress made in mitochondria-mediated metabolic regulation in cancer drug resistance.

Coevolution of Cooperation and Partner Rewiring Range in Spatial Social Networks.

In recent years, there has been growing interest in the study of coevolutionary games on networks. Despite much progress, little attention has been paid to spatially embedded networks, where the underlying geographic distance, rather than the graph distance, is an important and relevant aspect of the partner rewiring process. It thus remains largely unclear how individual partner rewiring range preference, local vs. global, emerges and affects cooperation. Here we explicitly address this issue using a coevolutionary model of cooperation and partner rewiring range preference in spatially embedded social networks. In contrast to local rewiring, global rewiring has no distance restriction but incurs a one-time cost upon establishing any long range link. We find that under a wide range of model parameters, global partner switching preference can coevolve with cooperation. Moreover, the resulting partner network is highly degree-heterogeneous with small average shortest path length while maintaining high clustering, thereby possessing small-world properties. We also discover an optimum availability of reputation information for the emergence of global cooperators, who form distant partnerships at a cost to themselves. From the coevolutionary perspective, our work may help explain the ubiquity of small-world topologies arising alongside cooperation in the real world.

Wiring Bacterial Electron Flow for Sensitive Whole-Cell Amperometric Detection of Riboflavin

A whole-cell bioelectrochemical biosensing system for amperometric detection of riboflavin was developed. A "bioelectrochemical wire" (BW) consisting of riboflavin and cytochrome C between Shewanella oneidensis MR-1 and electrode was characterized. Typically, a strong electrochemical response was observed when riboflavin (VB2) was added to reinforce this BW. Impressively, the electrochemical response of riboflavin with this BW was over 200 times higher than that without bacteria. Uniquely, this electron rewiring process enabled the development of a biosensing system for amperometric detection of riboflavin. Remarkably, this amperometric method showed high sensitivity (LOD = 2.2 nM, S/N = 3), wide linear range (5 nM ∼ 10 μM, 3 orders of magnitude), good selectivity, and high resistance to interferences. Additionally, the developed amperometric method featured good stability and reusability. It was further applied for accurate and reliable determination of riboflavin in real conditions including food, pharmaceutical, and clinical samples without pretreatment. Both the cost-effectiveness and robustness make this whole-cell amperometric system ideal for practical applications. This work demonstrated the power of bioelectrochemical signal amplification with exoelectrogen and also provided a new idea for development of versatile whole-cell amperometric biosensors.

Network stratification analysis for identifying function-specific network layers.

A major challenge of systems biology is to capture the rewiring of biological functions (e.g. signaling pathways) in a molecular network. To address this problem, we proposed a novel computational framework, namely network stratification analysis (NetSA), to stratify the whole biological network into various function-specific network layers corresponding to particular functions (e.g. KEGG pathways), which transform the network analysis from the gene level to the functional level by integrating expression data, the gene/protein network and gene ontology information altogether. The application of NetSA in yeast and its comparison with a traditional network-partition both suggest that NetSA can more effectively reveal functional implications of network rewiring and extract significant phenotype-related biological processes. Furthermore, for time-series or stage-wise data, the function-specific network layer obtained by NetSA is also shown to be able to characterize the disease progression in a dynamic manner. In particular, when applying NetSA to hepatocellular carcinoma and type 1 diabetes, we can derive functional spectra regarding the progression of the disease, and capture active biological functions (i.e. active pathways) in different disease stages. The additional comparison between NetSA and SPIA illustrates again that NetSA could discover more complete biological functions during disease progression. Overall, NetSA provides a general framework to stratify a network into various layers of function-specific sub-networks, which can not only analyze a biological network on the functional level but also investigate gene rewiring patterns in biological processes.

Time-varying network models

We introduce the exchangeable rewiring process for modeling time-varying networks. The process fulfills fundamental mathematical and statistical properties and can be easily constructed from the novel operation of random rewiring. We derive basic properties of the model, including consistency under subsampling, exchangeability, and the Feller property. A reversible sub-family related to the Erdős–Rényi model arises as a special case.

Abstract SY19-01: Therapeutic network re-wiring of the DNA damage response can be used to enhance tumor killing by cytotoxic chemotherapy

Abstract Dynamic re-wiring of signaling networks is a prominent mechanism responsible for the development of resistance to many molecular-targeted anti-cancer agents. Here we show how this same dynamic re-wiring process can be used therapeutically to enhance the response of tumors to cytotoxic anti-cancer agents. Using cell lines and murine tumor models of triple-negative breast cancer, non-small cell lung cancer, and head and neck cancer, we show that chronic inhibition of EGFR and/or FGFR driver oncogenes dramatically enhances cell death in response to topoisomerase inhibitors and platinum DNA crosslinking drugs. In marked contrast, no such sensitization is observed when the growth factor receptor inhibitors are co-administered with the cytotoxic agents. The molecular mechanism responsible for this time-dependent growth factor inhibitor-induced tumor cell sensitization was explored using a systems biology-based model of DNA damage signaling in which protein kinase activities, substrate phosphorylation, and phosphoprotein-binding events for multiple signaling pathways were quantitatively measured at densely sampled points in time, and mathematically correlated with tumor cell responses including cell cycle arrest, cytokine production, autophagy, and apoptosis. This analysis revealed that sustained EGFR/FGFR suppression unmasks an apoptotic network involving Caspase-8 that is normally suppressed by oncogene addiction, resulting in an enhanced apoptotic response to equivalent amounts of DNA damage. This discovery demonstrates that the timing interval between administration of different drugs in combination chemotherapy can have profound effects on the tumor response through the dynamic re-wiring of cell signaling pathways in real time. Finally, we take advantage of this dynamic re-wiring process by developing tumor-targeted time-staggered release nanoparticles that deliver EGFR inhibitors at early times followed by the delayed release of doxorubicin. We show that these nanoparticles cause dramatic regression of murine NSCLC and TNBC tumor xenografts in vivo, substantiating the utility of therapeutic network re-wiring for anti-cancer therapy in the clinic. Citation Format: Michael J. Lee, Yogesh Dayma, Anne-Margriet Heijinks, Stephen W. Morton, Erik C. Dreaden, Paula T. Hammond, Michael B. Yaffe. Therapeutic network re-wiring of the DNA damage response can be used to enhance tumor killing by cytotoxic chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY19-01. doi:10.1158/1538-7445.AM2015-SY19-01

3D optical coherence tomography: new insights into the process of optimal rewiring of side branches during bifurcational stenting

We describe three-dimensional optical coherence tomography (3D-OCT) guided bifurcation stenting and the clinical utility of 3D-OCT. Twenty-two consecutive patients who underwent OCT examination to confirm the recrossing position after stent implantation in a bifurcation lesion were enrolled. Frequency domain OCT images were obtained to check the recrossing position and 3D reconstructions were performed off-line. The recrossing position was clearly visualised in 18/22 (81.8%) cases. In 13 cases, serial 3D-OCT could be assessed both before and after final kissing balloon post-dilation (FKBD). We divided these cases into two groups according to the presence of the link between hoops at the carina: free carina type (n=7) and connecting to carina type (n=6). All free carina types complied with the distal rewiring. The percentage of incomplete stent apposition (%ISA) of free carina type at the bifurcation segment after FKBD was significantly smaller than that of the connecting to carina type (0.7±0.9% vs. 12.2±6.5%, p=0.0074). 3D-OCT confirmation of the recrossing into the jailed side branch is feasible during PCI and may help to achieve distal rewiring and favourable stent positioning against the side branch ostium, leading to reduction in ISA and potentially better clinical outcomes.

Impact of constrained rewiring on network structure and node dynamics.

In this paper, we study an adaptive spatial network. We consider a susceptible-infected-susceptible (SIS) epidemic on the network, with a link or contact rewiring process constrained by spatial proximity. In particular, we assume that susceptible nodes break links with infected nodes independently of distance and reconnect at random to susceptible nodes available within a given radius. By systematically manipulating this radius we investigate the impact of rewiring on the structure of the network and characteristics of the epidemic. We adopt a step-by-step approach whereby we first study the impact of rewiring on the network structure in the absence of an epidemic, then with nodes assigned a disease status but without disease dynamics, and finally running network and epidemic dynamics simultaneously. In the case of no labeling and no epidemic dynamics, we provide both analytic and semianalytic formulas for the value of clustering achieved in the network. Our results also show that the rewiring radius and the network's initial structure have a pronounced effect on the endemic equilibrium, with increasingly large rewiring radiuses yielding smaller disease prevalence.

Synaptic plasticity and sensory-motor improvement following fibrin sealant dorsal root reimplantation and mononuclear cell therapy.

Root lesions may affect both dorsal and ventral roots. However, due to the possibility of generating further inflammation and neuropathic pain, surgical procedures do not prioritize the repair of the afferent component. The loss of such sensorial input directly disturbs the spinal circuits thus affecting the functionality of the injuried limb. The present study evaluated the motor and sensory improvement following dorsal root reimplantation with fibrin sealant (FS) plus bone marrow mononuclear cells (MC) after dorsal rhizotomy. MC were used to enhance the repair process. We also analyzed changes in the glial response and synaptic circuits within the spinal cord. Female Lewis rats (6–8 weeks old) were divided in three groups: rhizotomy (RZ group), rhizotomy repaired with FS (RZ+FS group) and rhizotomy repaired with FS and MC (RZ+FS+MC group). The behavioral tests electronic von-Frey and Walking track test were carried out. For immunohistochemistry we used markers to detect different synapse profiles as well as glial reaction. The behavioral results showed a significant decrease in sensory and motor function after lesion. The reimplantation decreased glial reaction and improved synaptic plasticity of afferent inputs. Cell therapy further enhanced the rewiring process. In addition, both reimplanted groups presented twice as much motor control compared to the non-treated group. In conclusion, the reimplantation with FS and MC is efficient and may be considered an approach to improve sensory-motor recovery following dorsal rhizotomy.

Rewiring Mid1p-Independent Medial Division in Fission Yeast

Correct positioning of the cell division machinery is key togenome stability. Schizosaccharomyces pombe is an attractive organism to study cytokinesis as it, like higher eukaryotes, divides using a contractile actomyosin ring. In S.pombe, many actomyosin ring components assemble atthe medial cortex into node-like structures before coalescing into a ring [1, 2]. Assembly of cytokinetic nodes requires Mid1p, which recruits IQGAP-related Rng2p to the division site, after which other node components accumulate at the division site in a characteristic sequence [3-6]. How cytokinetic nodes assemble, whether the order of assembly of ring components is important, and whether Mid1p solely participates in ring positioning are poorly understood. Here, we show that synthetic targeting of IQGAP-related Rng2p, formin-Cdc12p, and myosin II (Myo2p) restores medial division in mid1 mutants, suggesting that ring proteins need not assemble at the division site in an invariant order. Unlike in wild-type cells, actomyosin rings in cells rewired to divide medially in the absence of Mid1p assemble late in anaphase. Furthermore, the rewiring process affects the ability of the actomyosin ring to track the nucleus upon perturbation of nuclear position. Our work reveals the power of synthetic rewiring studies in deciphering roles performed by multifunctional proteins.

Emergence and persistence of communities in coevolutionary networks

We investigate the emergence and persistence of communities through a recently proposed mechanism of adaptive rewiring in coevolutionary networks. We characterize the topological structures arising in a coevolutionary network subject to an adaptive rewiring process and a node dynamics given by a simple voter-like rule. We find that, for some values of the parameters describing the adaptive rewiring process, a community structure emerges on a connected network. We show that the emergence of communities is associated to a decrease in the number of active links in the system, i.e. links that connect two nodes in different states. The lifetime of the community structure state scales exponentially with the size of the system. Additionally, we find that a small noise in the node dynamics can sustain a diversity of states and a community structure in time in a finite size system. Thus, large system size and/or local noise can explain the persistence of communities and diversity in many real systems.

Unraveling the Role of FOXQ1 in Colorectal Cancer Metastasis

Malignant cell transformation, invasion, and metastasis are dependent on the coordinated rewiring of gene expression. A major component in the scaffold of these reprogramming events is one in which epithelial cells lose intercellular connections and polarity to adopt a more motile mesenchymal phenotype, which is largely supported by a robust transcriptional machinery consisting mostly of developmental transcription factors. This study demonstrates that the winged helix transcription factor, FOXQ1, contributes to this rewiring process, in part by directly modulating the transcription of TWIST1, itself a key mediator of metastasis that transcriptionally regulates the expression of important molecules involved in epithelial-to-mesenchymal transition. Forced expression and RNA-mediated silencing of FOXQ1 led to enhanced and suppressed mRNA and protein levels of TWIST1, respectively. Mechanistically, FOXQ1 enhanced the reporter activity of TWIST1 and directly interacted with its promoter. Furthermore, enhanced expression of FOXQ1 resulted in increased migration and invasion in colorectal cancer cell lines, whereas knockdown studies showed the opposite effect. Moreover, using the in vivo chicken chorioallantoic membrane metastasis assay model, FOXQ1 significantly enhanced distant metastasis with minimal effects on tumor growth. These findings reveal FOXQ1 as a modulator of TWIST1-mediated metastatic phenotypes and support its potential as a biomarker of metastasis.

IMPROVING NETWORK TRANSPORT EFFICIENCY BY EDGE REWIRING

Considering the heterogeneous structure of scale-free networks causing low traffic capacity of network, we propose to improve the network transport efficiency by rewiring a fraction of edges for the network. In this paper, six edge rewiring strategies are discussed and extensive simulations on Barabási–Albert (BA) scale-free networks confirm the effectiveness of these strategies. From another perspective, rewiring edges for scale-free networks directly reuse the removed edges under some edge-removal strategies [Z. Liu, M. B. Hu, R. Jiang, W. X. Wang and Q. S. Wu, Phys. Rev. E76 (2007) 037101; G. Q. Zhang, D. Wang and G. J. Li, Phys. Rev. E76 (2007) 017101], and can significantly enhance the traffic capacity of the network at the expense of increasing a little average path length. After the edge rewiring process, the network structure becomes significantly homogeneous. This work is helpful for network design and network performance optimization.

Graph theoretical analysis of developmental patterns of the white matter network

Understanding the development of human brain organization is critical for gaining insight into how the enhancement of cognitive processes is related to the fine-tuning of the brain network. However, the developmental trajectory of the large-scale white matter (WM) network is not fully understood. Here, using graph theory, we examine developmental changes in the organization of WM networks in 180 typically-developing participants. WM networks were constructed using whole brain tractography and 78 cortical regions of interest were extracted from each participant. The subjects were first divided into 5 equal sample size (n = 36) groups (early childhood: 6.0–9.7 years; late childhood: 9.8–12.7 years; adolescence: 12.9–17.5 years; young adult: 17.6–21.8 years; adult: 21.9–29.6 years). Most prominent changes in the topological properties of developing brain networks occur at late childhood and adolescence. During late childhood period, the structural brain network showed significant increase in the global efficiency but decrease in modularity, suggesting a shift of topological organization toward a more randomized configuration. However, while preserving most topological features, there was a significant increase in the local efficiency at adolescence, suggesting the dynamic process of rewiring and rebalancing brain connections at different growth stages. In addition, several pivotal hubs were identified that are vital for the global coordination of information flow over the whole brain network across all age groups. Significant increases of nodal efficiency were present in several regions such as precuneus at late childhood. Finally, a stable and functionally/anatomically related modular organization was identified throughout the development of the WM network. This study used network analysis to elucidate the topological changes in brain maturation, paving the way for developing novel methods for analyzing disrupted brain connectivity in neurodevelopmental disorders.

Modified Penna bit-string network evolution model for scale-free networks with assortative mixing

Motivated by biological aging dynamics, we introduce a network evolution model for social interaction networks. In order to study the effect of social interactions originating from biological and sociological reasons on the topological properties of networks, we introduce the activitydependent rewiring process. From the numerical simulations, we show that the degree distribution of the obtained networks follows a power-law distribution with an exponentially decaying tail, P(k) ∼ (k + c)−γ exp(−k/k 0). The obtained value of γ is in the range 2 < γ s 3, which is consistent with the values for real social networks. Moreover, we also show that the degree-degree correlation of the network is positive, which is a characteristic of social interaction networks. The possible applications of our model to real systems are also discussed.

On the topology of synchrony optimized networks of a Kuramoto-model with non-identical oscillators

We study synchrony optimized networks. In particular, we focus on the Kuramoto model with non-identical native frequencies on a random graph. In a first step, we generate synchrony optimized networks using a dynamic breeding algorithm, whereby an initial network is successively rewired toward increased synchronization. These networks are characterized by a large anti-correlation between neighbouring frequencies. In a second step, the central part of our paper, we show that synchrony optimized networks can be generated much more cost efficiently by minimization of an energy-like quantity E and subsequent random rewires to control the average path length. We demonstrate that synchrony optimized networks are characterized by a balance between two opposing structural properties: A large number of links between positive and negative frequencies of equal magnitude and a small average path length. Remarkably, these networks show the same synchronization behaviour as those networks generated by the dynamic rewiring process. Interestingly, synchrony-optimized network also exhibit significantly enhanced synchronization behaviour for weak coupling, below the onset of global synchronization, with linear growth of the order parameter with increasing coupling strength. We identify the underlying dynamical and topological structures, which give rise to this atypical local synchronization, and provide a simple analytical argument for its explanation.

Nongrowing Preferential Attachment Random Graphs

We consider an edge rewiring process that is widely used to model the dynamics of scale-free weblike networks. This process uses preferential attachment and operates on sparse multigraphs with _n_ vertices and _m_ edges. We prove that its mixing time is optimal and develop a framework that simplifies the calculation of graph properties in the steady state. The applicability of this framework is demonstrated by calculating the degree distribution, the number of self-loops, and the threshold for the appearance of the giant component.

Flat-head power-law, size-independent clustering, and scaling of coevolutionary scale-free networks

Scale-free topology and high clustering coexist in some real networks, and keep invariant for growing sizes of the systems. Previous models could hardly give out size-independent clustering with selforganized mechanism when succeeded in producing power-law degree distributions. Always ignored, some empirical statistic results display flat-head power-law behaviors. We modify our recent coevolutionary model to explain such phenomena with the inert property of nodes to retain small portion of unfavorable links in self-organized rewiring process. Flat-head power-law and size-independent clustering are induced as the new characteristics by this modification. In addition, a new scaling relation is found as the result of interplay between node state growth and adaptive variation of connections.

Dynamical Rewiring Processes in Binary Decision Networks

We present a dynamical binary opinion model for the emergence of collective decision making based on a generalization of the majority and the minority principle. The network consists of N interacting agents, whose connectivity structure is dynamic, governed by a rewiring process controlled by the actual network state. With the aid of damage spreading techniques we show how the dynamical stability of these models can be largely enhanced by self-organized feedback loops between the network topology and the intrinsic network dynamics. The model provides possible explanations for social behaviour, in particular for the stability and instability of the individual and global opinion during an electoral campaign.

Emergence of heterogeneous structures in chemical reaction-diffusion networks

This paper suggests that reaction-diffusion processes, rather than pure topological rules, are responsible for the emergence of heterogeneous structures of complex chemical reaction networks. In such a network, chemical substances react in each node and diffuse between connected nodes. At the same time, each node is able to sense the difference between its own state and the environmental conditions and can rearrange its neighbors via a local rewiring process so as to eliminate the sensed difference. Then, the network, even originally homogeneous, will develop a heterogeneous structure under certain environmental conditions. Such a resultant heterogeneous network may be disassortative, highly clustering, and small world as well. This implies that the reaction-diffusion equilibrium can be statistically controlled by slightly changing the structure of the underlying network. This structure-control mechanism may be especially useful in the situations where some other macroscopic measurements, such as temperature and pressure, are not allowed to be changed through the process.