It has been a challenge in systems biology to unravel relationships between structural properties and dynamic behaviors of biological networks. A Cytoscape plugin named NetDS was recently proposed to analyze the robustness-related dynamics and feed-forward/feedback loop structures of biological networks. Despite such a useful function, limitations on the network size that can be analyzed exist due to high computational costs. In addition, the plugin cannot verify an intrinsic property which can be induced by an observed result because it has no function to simulate the observation on a large number of random networks. To overcome these limitations, we have developed a novel software tool, PANET. First, the time-consuming parts of NetDS were redesigned to be processed in parallel using the OpenCL library. This approach utilizes the full computing power of multi-core central processing units and graphics processing units. Eventually, this made it possible to investigate a large-scale network such as a human signaling network with 1,609 nodes and 5,063 links. We also developed a new function to perform a batch-mode simulation where it generates a lot of random networks and conducts robustness calculations and feed-forward/feedback loop examinations of them. This helps us to determine if the findings in real biological networks are valid in arbitrary random networks or not. We tested our plugin in two case studies based on two large-scale signaling networks and found interesting results regarding relationships between coherently coupled feed-forward/feedback loops and robustness. In addition, we verified whether or not those findings are consistently conserved in random networks through batch-mode simulations. Taken together, our plugin is expected to effectively investigate various relationships between dynamics and structural properties in large-scale networks. Our software tool, user manual and example datasets are freely available at http://panet-csc.sourceforge.net/.

Supplementary data are available at Bioinformatics online.

Background: Many previous clinical studies have found that accumulated sequential mutations are statistically related to tumorigenesis. However, they are limited in fully elucidating the significance of the ordered-mutation because they did not focus on the network dynamics. Therefore, there is a pressing need to investigate the dynamics characteristics induced by ordered-mutations.Methods: To quantify the ordered-mutation-inducing dynamics, we defined the mutation-sensitivity and the orderspecificity that represent if the network is sensitive against a double knockout mutation and if mutation-sensitivity is specific to the mutation order, respectively, using a Boolean network model.Results: Through intensive investigations, we found that a signaling network is more sensitive when a doublemutation occurs in the direction order inducing a longer path and a smaller number of paths than in the reverse order. In addition, feedback loops involving a gene pair decreased both the mutation-sensitivity and the orderspecificity. Next, we investigated relationships of functionally important genes with ordered-mutation-inducing dynamics. The network is more sensitive to mutations subject to drug-targets, whereas it is less specific to the mutation order. Both the sensitivity and specificity are increased when different-drug-targeted genes are mutated. Further, we found that tumor suppressors can efficiently suppress the amplification of oncogenes when the former are mutated earlier than the latter.Conclusion: Taken together, our results help to understand the importance of the order of mutations with respect to the dynamical effects in complex biological systems.

Motivation It is a challenging problem in systems biology to infer both the network structure and dynamics of a gene regulatory network from steady-state gene expression data. Some methods based on Boolean or differential equation models have been proposed but they were not efficient in inference of large-scale networks. Therefore, it is necessary to develop a method to infer the network structure and dynamics accurately on large-scale networks using steady-state expression. Results In this study, we propose a novel constrained genetic algorithm-based Boolean network inference (CGA-BNI) method where a Boolean canalyzing update rule scheme was employed to capture coarse-grained dynamics. Given steady-state gene expression data as an input, CGA-BNI identifies a set of path consistency-based constraints by comparing the gene expression level between the wild-type and the mutant experiments. It then searches Boolean networks which satisfy the constraints and induce attractors most similar to steady-state expressions. We devised a heuristic mutation operation for faster convergence and implemented a parallel evaluation routine for execution time reduction. Through extensive simulations on the artificial and the real gene expression datasets, CGA-BNI showed better performance than four other existing methods in terms of both structural and dynamics prediction accuracies. Taken together, CGA-BNI is a promising tool to predict both the structure and the dynamics of a gene regulatory network when a highest accuracy is needed at the cost of sacrificing the execution time. Availability and implementation Source code and data are freely available at https://github.com/csclab/CGA-BNI. Supplementary information Supplementary data are available at Bioinformatics online.

Machinery diagnostics and prognostics usually involve the prediction process of fault-types and remaining useful life (RUL) of a machine, respectively. The process of developing a data-driven diagnostics and prognostics method involves some fundamental subtasks such as data rebalancing, feature extraction, dimension reduction, and machine learning. In general, the best performing algorithm and the optimal hyper-parameters suitable for each subtask are varied across the characteristics of datasets. Therefore, it is challenging to develop a general diagnostic/prognostic framework that can automatically identify the best subtask algorithms and the optimal involved parameters for a given dataset. To resolve this problem, we propose a new framework based on an ensemble of genetic algorithms (GAs) that can be used for both the fault-type classification and RUL prediction. Our GA is combined with a specific machine-learning method and then tries to select the best algorithm and optimize the involved parameter values in each subtask. In addition, our method constructs an ensemble of various prediction models found by the GAs. Our method was compared to a traditional grid-search over three benchmark datasets of the fault-type classification and the RUL prediction problems and showed a significantly better performance than the latter. Taken together, our framework can be an effective approach for the fault-type and RUL prediction of various machinery systems.

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BackgroundIdentification of novel gene-gene relations is a crucial issue to understand system-level biological phenomena. To this end, many methods based on a correlation analysis of gene expressions or structural analysis of molecular interaction networks have been proposed. They have a limitation in identifying more complicated gene-gene dynamical relations, though.ResultsTo overcome this limitation, we proposed a measure to quantify a gene-gene dynamical influence (GDI) using a Boolean network model and constructed a GDI network to indicate existence of a dynamical influence for every ordered pair of genes. It represents how much a state trajectory of a target gene is changed by a knockout mutation subject to a source gene in a gene-gene molecular interaction (GMI) network. Through a topological comparison between GDI and GMI networks, we observed that the former network is denser than the latter network, which implies that there exist many gene pairs of dynamically influencing but molecularly non-interacting relations. In addition, a larger number of hub genes were generated in the GDI network. On the other hand, there was a correlation between these networks such that the degree value of a node was positively correlated to each other. We further investigated the relationships of the GDI value with structural properties and found that there are negative and positive correlations with the length of a shortest path and the number of paths, respectively. In addition, a GDI network could predict a set of genes whose steady-state expression is affected in E. coli gene-knockout experiments. More interestingly, we found that the drug-targets with side-effects have a larger number of outgoing links than the other genes in the GDI network, which implies that they are more likely to influence the dynamics of other genes. Finally, we found biological evidences showing that the gene pairs which are not molecularly interacting but dynamically influential can be considered for novel gene-gene relationships.ConclusionTaken together, construction and analysis of the GDI network can be a useful approach to identify novel gene-gene relationships in terms of the dynamical influence.Electronic supplementary materialThe online version of this article (10.1186/s12918-017-0509-y) contains supplementary material, which is available to authorized users.

There have been many in silico studies based on a Boolean network model to investigate network sensitivity against gene or interaction mutations. However, there are no proper tools to examine the network sensitivity against many different types of mutations, including user-defined ones. To address this issue, we developed RMut, which is an R package to analyze the Boolean network-based sensitivity by efficiently employing not only many well-known node-based and edgetic mutations but also novel user-defined mutations. In addition, RMut can specify the mutation area and the duration time for more precise analysis. RMut can be used to analyze large-scale networks because it is implemented in a parallel algorithm using the OpenCL library. In the first case study, we observed that the real biological networks were most sensitive to overexpression/state-flip and edge-addition/-reverse mutations among node-based and edgetic mutations, respectively. In the second case study, we showed that edgetic mutations can predict drug-targets better than node-based mutations. Finally, we examined the network sensitivity to double edge-removal mutations and found an interesting synergistic effect. Taken together, these findings indicate that RMut is a flexible R package to efficiently analyze network sensitivity to various types of mutations. RMut is available at https://github.com/csclab/RMut.