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1.  Combining Machine Learning Systems and Multiple Docking Simulation Packages to Improve Docking Prediction Reliability for Network Pharmacology 
PLoS ONE  2013;8(12):e83922.
Increased availability of bioinformatics resources is creating opportunities for the application of network pharmacology to predict drug effects and toxicity resulting from multi-target interactions. Here we present a high-precision computational prediction approach that combines two elaborately built machine learning systems and multiple molecular docking tools to assess binding potentials of a test compound against proteins involved in a complex molecular network. One of the two machine learning systems is a re-scoring function to evaluate binding modes generated by docking tools. The second is a binding mode selection function to identify the most predictive binding mode. Results from a series of benchmark validations and a case study show that this approach surpasses the prediction reliability of other techniques and that it also identifies either primary or off-targets of kinase inhibitors. Integrating this approach with molecular network maps makes it possible to address drug safety issues by comprehensively investigating network-dependent effects of a drug or drug candidate.
doi:10.1371/journal.pone.0083922
PMCID: PMC3877102  PMID: 24391846
2.  Harnessing Diversity towards the Reconstructing of Large Scale Gene Regulatory Networks 
PLoS Computational Biology  2013;9(11):e1003361.
Elucidating gene regulatory network (GRN) from large scale experimental data remains a central challenge in systems biology. Recently, numerous techniques, particularly consensus driven approaches combining different algorithms, have become a potentially promising strategy to infer accurate GRNs. Here, we develop a novel consensus inference algorithm, TopkNet that can integrate multiple algorithms to infer GRNs. Comprehensive performance benchmarking on a cloud computing framework demonstrated that (i) a simple strategy to combine many algorithms does not always lead to performance improvement compared to the cost of consensus and (ii) TopkNet integrating only high-performance algorithms provide significant performance improvement compared to the best individual algorithms and community prediction. These results suggest that a priori determination of high-performance algorithms is a key to reconstruct an unknown regulatory network. Similarity among gene-expression datasets can be useful to determine potential optimal algorithms for reconstruction of unknown regulatory networks, i.e., if expression-data associated with known regulatory network is similar to that with unknown regulatory network, optimal algorithms determined for the known regulatory network can be repurposed to infer the unknown regulatory network. Based on this observation, we developed a quantitative measure of similarity among gene-expression datasets and demonstrated that, if similarity between the two expression datasets is high, TopkNet integrating algorithms that are optimal for known dataset perform well on the unknown dataset. The consensus framework, TopkNet, together with the similarity measure proposed in this study provides a powerful strategy towards harnessing the wisdom of the crowds in reconstruction of unknown regulatory networks.
Author Summary
Elucidating gene regulatory networks is crucial to understand disease mechanisms at the system level. A large number of algorithms have been developed to infer gene regulatory networks from gene-expression datasets. If you remember the success of IBM's Watson in ”Jeopardy!„ quiz show, the critical features of Watson were the use of very large numbers of heterogeneous algorithms generating various hypotheses and to select one of which as the answer. We took similar approach, “TopkNet”, to see if “Wisdom of Crowd” approach can be applied for network reconstruction. We discovered that “Wisdom of Crowd” is a powerful approach where integration of optimal algorithms for a given dataset can achieve better results than the best individual algorithm. However, such an analysis begs the question “How to choose optimal algorithms for a given dataset?” We found that similarity among gene-expression datasets is a key to select optimal algorithms, i.e., if dataset A for which optimal algorithms are known is similar to dataset B, the optimal algorithms for dataset A may be also optimal for dataset B. Thus, our “TopkNet” together with similarity measure among datasets can provide a powerful strategy towards harnessing “Wisdom of Crowd” in high-quality reconstruction of gene regulatory networks.
doi:10.1371/journal.pcbi.1003361
PMCID: PMC3836705  PMID: 24278007
3.  A comprehensive map of the influenza A virus replication cycle 
BMC Systems Biology  2013;7:97.
Background
Influenza is a common infectious disease caused by influenza viruses. Annual epidemics cause severe illnesses, deaths, and economic loss around the world. To better defend against influenza viral infection, it is essential to understand its mechanisms and associated host responses. Many studies have been conducted to elucidate these mechanisms, however, the overall picture remains incompletely understood. A systematic understanding of influenza viral infection in host cells is needed to facilitate the identification of influential host response mechanisms and potential drug targets.
Description
We constructed a comprehensive map of the influenza A virus (‘IAV’) life cycle (‘FluMap’) by undertaking a literature-based, manual curation approach. Based on information obtained from publicly available pathway databases, updated with literature-based information and input from expert virologists and immunologists, FluMap is currently composed of 960 factors (i.e., proteins, mRNAs etc.) and 456 reactions, and is annotated with ~500 papers and curation comments. In addition to detailing the type of molecular interactions, isolate/strain specific data are also available. The FluMap was built with the pathway editor CellDesigner in standard SBML (Systems Biology Markup Language) format and visualized as an SBGN (Systems Biology Graphical Notation) diagram. It is also available as a web service (online map) based on the iPathways+ system to enable community discussion by influenza researchers. We also demonstrate computational network analyses to identify targets using the FluMap.
Conclusion
The FluMap is a comprehensive pathway map that can serve as a graphically presented knowledge-base and as a platform to analyze functional interactions between IAV and host factors. Publicly available webtools will allow continuous updating to ensure the most reliable representation of the host-virus interaction network. The FluMap is available at http://www.influenza-x.org/flumap/.
doi:10.1186/1752-0509-7-97
PMCID: PMC3819658  PMID: 24088197
Drug targets; FluMap; Host factors; Influenza virus; Pathways
4.  Modeling of Rifampicin-Induced CYP3A4 Activation Dynamics for the Prediction of Clinical Drug-Drug Interactions from In Vitro Data 
PLoS ONE  2013;8(9):e70330.
Induction of cytochrome P450 3A4 (CYP3A4) expression is often implicated in clinically relevant drug-drug interactions (DDI), as metabolism catalyzed by this enzyme is the dominant route of elimination for many drugs. Although several DDI models have been proposed, none have comprehensively considered the effects of enzyme transcription/translation dynamics on induction-based DDI. Rifampicin is a well-known CYP3A4 inducer, and is commonly used as a positive control for evaluating the CYP3A4 induction potential of test compounds. Herein, we report the compilation of in vitro induction data for CYP3A4 by rifampicin in human hepatocytes, and the transcription/translation model developed for this enzyme using an extended least squares method that can account for inherent inter-individual variability. We also developed physiologically based pharmacokinetic (PBPK) models for the CYP3A4 inducer and CYP3A4 substrates. Finally, we demonstrated that rifampicin-induced DDI can be predicted with reasonable accuracy, and that a static model can be used to simulate DDI once the blood concentration of the inducer reaches a steady state following repeated dosing. This dynamic PBPK-based DDI model was implemented on a new multi-hierarchical physiology simulation platform named PhysioDesigner.
doi:10.1371/journal.pone.0070330
PMCID: PMC3782498  PMID: 24086247
5.  Adding Protein Context to the Human Protein-Protein Interaction Network to Reveal Meaningful Interactions 
PLoS Computational Biology  2013;9(1):e1002860.
Interactions of proteins regulate signaling, catalysis, gene expression and many other cellular functions. Therefore, characterizing the entire human interactome is a key effort in current proteomics research. This challenge is complicated by the dynamic nature of protein-protein interactions (PPIs), which are conditional on the cellular context: both interacting proteins must be expressed in the same cell and localized in the same organelle to meet. Additionally, interactions underlie a delicate control of signaling pathways, e.g. by post-translational modifications of the protein partners - hence, many diseases are caused by the perturbation of these mechanisms. Despite the high degree of cell-state specificity of PPIs, many interactions are measured under artificial conditions (e.g. yeast cells are transfected with human genes in yeast two-hybrid assays) or even if detected in a physiological context, this information is missing from the common PPI databases. To overcome these problems, we developed a method that assigns context information to PPIs inferred from various attributes of the interacting proteins: gene expression, functional and disease annotations, and inferred pathways. We demonstrate that context consistency correlates with the experimental reliability of PPIs, which allows us to generate high-confidence tissue- and function-specific subnetworks. We illustrate how these context-filtered networks are enriched in bona fide pathways and disease proteins to prove the ability of context-filters to highlight meaningful interactions with respect to various biological questions. We use this approach to study the lung-specific pathways used by the influenza virus, pointing to IRAK1, BHLHE40 and TOLLIP as potential regulators of influenza virus pathogenicity, and to study the signalling pathways that play a role in Alzheimer's disease, identifying a pathway involving the altered phosphorylation of the Tau protein. Finally, we provide the annotated human PPI network via a web frontend that allows the construction of context-specific networks in several ways.
Author Summary
Protein-protein-interactions (PPIs) participate in virtually all biological processes. However, the PPI map is not static but the pairs of proteins that interact depends on the type of cell, the subcellular localization and modifications of the participating proteins, among many other factors. Therefore, it is important to understand the specific conditions under which a PPI happens. Unfortunately, experimental methods often do not provide this information or, even worse, measure PPIs under artificial conditions not found in biological systems. We developed a method to infer this missing information from properties of the interacting proteins, such as in which cell types the proteins are found, which functions they fulfill and whether they are known to play a role in disease. We show that PPIs for which we can infer conditions under which they happen have a higher experimental reliability. Also, our inference agrees well with known pathways and disease proteins. Since diseases usually affect specific cell types, we study PPI networks of influenza proteins in lung tissues and of Alzheimer's disease proteins in neural tissues. In both cases, we can highlight interesting interactions potentially playing a role in disease progression.
doi:10.1371/journal.pcbi.1002860
PMCID: PMC3536619  PMID: 23300433
6.  BioPAX support in CellDesigner 
Bioinformatics  2011;27(24):3437-3438.
Motivation: BioPAX is a standard language for representing and exchanging models of biological processes at the molecular and cellular levels. It is widely used by different pathway databases and genomics data analysis software. Currently, the primary source of BioPAX data is direct exports from the curated pathway databases. It is still uncommon for wet-lab biologists to share and exchange pathway knowledge using BioPAX. Instead, pathways are usually represented as informal diagrams in the literature. In order to encourage formal representation of pathways, we describe a software package that allows users to create pathway diagrams using CellDesigner, a user-friendly graphical pathway-editing tool and save the pathway data in BioPAX Level 3 format.
Availability: The plug-in is freely available and can be downloaded at ftp://ftp.pantherdb.org/CellDesigner/plugins/BioPAX/
Contact: huaiyumi@usc.edu
Supplementary Information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btr586
PMCID: PMC3232372  PMID: 22021903
7.  Gene regulatory network analysis supports inflammation as a key neurodegeneration process in prion disease 
BMC Systems Biology  2012;6:132.
Background
The activation of immune cells in the brain is believed to be one of the earliest events in prion disease development, where misfolded PrionSc protein deposits are thought to act as irritants leading to a series of events that culminate in neuronal cell dysfunction and death. The role of these events in prion disease though is still a matter of debate. To elucidate the mechanisms leading from abnormal protein deposition to neuronal injury, we have performed a detailed network analysis of genes differentially expressed in several mouse prion models.
Results
We found a master regulatory core of genes related to immune response controlling other genes involved in prion protein replication and accumulation, and neuronal cell death. This regulatory core determines the existence of two stable states that are consistent with the transcriptome analysis comparing prion infected versus uninfected mouse brain. An in silico perturbation analysis demonstrates that core genes are individually capable of triggering the transition and that the network remains locked once the diseased state is reached.
Conclusions
We hypothesize that this locking may be the cause of the sustained immune response observed in prion disease. Our analysis supports the hypothesis that sustained brain inflammation is the main pathogenic process leading to neuronal dysfunction and loss, which, in turn, leads to clinical symptoms in prion disease.
doi:10.1186/1752-0509-6-132
PMCID: PMC3607922  PMID: 23068602
Prion disease; Inflammation; Neurodegeneration; Gene regulatory network; Perturbation; Stable states
8.  CTen: a web-based platform for identifying enriched cell types from heterogeneous microarray data 
BMC Genomics  2012;13:460.
Background
Interpreting in vivo sampled microarray data is often complicated by changes in the cell population demographics. To put gene expression into its proper biological context, it is necessary to distinguish differential gene transcription from artificial gene expression induced by changes in the cellular demographics.
Results
CTen (cell type enrichment) is a web-based analytical tool which uses our highly expressed, cell specific (HECS) gene database to identify enriched cell types in heterogeneous microarray data. The web interface is designed for differential expression and gene clustering studies, and the enrichment results are presented as heatmaps or downloadable text files.
Conclusions
In this work, we use an independent, cell-specific gene expression data set to assess CTen's performance in accurately identifying the appropriate cell type and provide insight into the suggested level of enrichment to optimally minimize the number of false discoveries. We show that CTen, when applied to microarray data developed from infected lung tissue, can correctly identify the cell signatures of key lymphocytes in a highly heterogeneous environment and compare its performance to another popular bioinformatics tool. Furthermore, we discuss the strong implications cell type enrichment has in the design of effective microarray workflow strategies and show that, by combining CTen with gene expression clustering, we may be able to determine the relative changes in the number of key cell types.
CTen is available at http://www.influenza-x.org/~jshoemaker/cten/
doi:10.1186/1471-2164-13-460
PMCID: PMC3473317  PMID: 22953731
Cell type enrichment; Microarray data; Deconvolution; Influenza; Systems immunology
9.  Integrated network analysis reveals a novel role for the cell cycle in 2009 pandemic influenza virus-induced inflammation in macaque lungs 
BMC Systems Biology  2012;6:117.
Background
Annually, influenza A viruses circulate the world causing wide-spread sickness, economic loss, and death. One way to better defend against influenza virus-induced disease may be to develop novel host-based therapies, targeted at mitigating viral pathogenesis through the management of virus-dysregulated host functions. However, mechanisms that govern aberrant host responses to influenza virus infection remain incompletely understood. We previously showed that the pandemic H1N1 virus influenza A/California/04/2009 (H1N1; CA04) has enhanced pathogenicity in the lungs of cynomolgus macaques relative to a seasonal influenza virus isolate (A/Kawasaki/UTK-4/2009 (H1N1; KUTK4)).
Results
Here, we used microarrays to identify host gene sequences that were highly differentially expressed (DE) in CA04-infected macaque lungs, and we employed a novel strategy – combining functional and pathway enrichment analyses, transcription factor binding site enrichment analysis and protein-protein interaction data – to create a CA04 differentially regulated host response network. This network describes enhanced viral RNA sensing, immune cell signaling and cell cycle arrest in CA04-infected lungs, and highlights a novel, putative role for the MYC-associated zinc finger (MAZ) transcription factor in regulating these processes.
Conclusions
Our findings suggest that the enhanced pathology is the result of a prolonged immune response, despite successful virus clearance. Most interesting, we identify a mechanism which normally suppresses immune cell signaling and inflammation is ineffective in the pH1N1 virus infection; a dyregulatory event also associated with arthritis. This dysregulation offers several opportunities for developing strain-independent, immunomodulatory therapies to protect against future pandemics.
doi:10.1186/1752-0509-6-117
PMCID: PMC3481363  PMID: 22937776
Influenza; Host response; Microarray; pH1N1; Systems biology
10.  Software support for SBGN maps: SBGN-ML and LibSBGN 
Bioinformatics  2012;28(15):2016-2021.
Motivation: LibSBGN is a software library for reading, writing and manipulating Systems Biology Graphical Notation (SBGN) maps stored using the recently developed SBGN-ML file format. The library (available in C++ and Java) makes it easy for developers to add SBGN support to their tools, whereas the file format facilitates the exchange of maps between compatible software applications. The library also supports validation of maps, which simplifies the task of ensuring compliance with the detailed SBGN specifications. With this effort we hope to increase the adoption of SBGN in bioinformatics tools, ultimately enabling more researchers to visualize biological knowledge in a precise and unambiguous manner.
Availability and implementation: Milestone 2 was released in December 2011. Source code, example files and binaries are freely available under the terms of either the LGPL v2.1+ or Apache v2.0 open source licenses from http://libsbgn.sourceforge.net.
Contact: sbgn-libsbgn@lists.sourceforge.net
doi:10.1093/bioinformatics/bts270
PMCID: PMC3400951  PMID: 22581176
11.  A framework for mapping, visualisation and automatic model creation of signal-transduction networks 
An intuitive formalism for reconstructing cellular networks from empirical data is presented, and used to build a comprehensive yeast MAP kinase network. The accompanying rxncon software tool can convert networks to a range of standard graphical formats and mathematical models.
Network mapping at the granularity of empirical data that largely avoids combinatorial complexityAutomatic visualisation and model generation with the rxncon open source software toolVisualisation in a range of formats, including all three SBGN formats, as well as contingency matrix or regulatory graphComprehensive and completely references map of the yeast MAP kinase network in the rxncon format
Intracellular signalling systems are highly complex. This complexity makes handling, analysis and visualisation of available knowledge a major challenge in current signalling research. Here, we present a novel framework for mapping signal-transduction networks that avoids the combinatorial explosion by breaking down the network in reaction and contingency information. It provides two new visualisation methods and automatic export to mathematical models. We use this framework to compile the presently most comprehensive map of the yeast MAP kinase network. Our method improves previous strategies by combining (I) more concise mapping adapted to empirical data, (II) individual referencing for each piece of information, (III) visualisation without simplifications or added uncertainty, (IV) automatic visualisation in multiple formats, (V) automatic export to mathematical models and (VI) compatibility with established formats. The framework is supported by an open source software tool that facilitates integration of the three levels of network analysis: definition, visualisation and mathematical modelling. The framework is species independent and we expect that it will have wider impact in signalling research on any system.
doi:10.1038/msb.2012.12
PMCID: PMC3361003  PMID: 22531118
combinatorial complexity; mathematical modelling; network mapping; signal transduction; visualisation
12.  A proof of the DBRF-MEGN method, an algorithm for deducing minimum equivalent gene networks 
Background
We previously developed the DBRF-MEGN (difference-based regulation finding-minimum equivalent gene network) method, which deduces the most parsimonious signed directed graphs (SDGs) consistent with expression profiles of single-gene deletion mutants. However, until the present study, we have not presented the details of the method's algorithm or a proof of the algorithm.
Results
We describe in detail the algorithm of the DBRF-MEGN method and prove that the algorithm deduces all of the exact solutions of the most parsimonious SDGs consistent with expression profiles of gene deletion mutants.
Conclusions
The DBRF-MEGN method provides all of the exact solutions of the most parsimonious SDGs consistent with expression profiles of gene deletion mutants.
doi:10.1186/1751-0473-6-12
PMCID: PMC3152880  PMID: 21699737
DBRF-MEGN method; proof; algorithm; gene network; expression profiles
13.  A comprehensive map of the mTOR signaling network 
The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation. mTOR signaling is frequently dysregulated in oncogenic cells, and thus an attractive target for anticancer therapy. Using CellDesigner, a modeling support software for graphical notation, we present herein a comprehensive map of the mTOR signaling network, which includes 964 species connected by 777 reactions. The map complies with both the systems biology markup language (SBML) and graphical notation (SBGN) for computational analysis and graphical representation, respectively. As captured in the mTOR map, we review and discuss our current understanding of the mTOR signaling network and highlight the impact of mTOR feedback and crosstalk regulations on drug-based cancer therapy. This map is available on the Payao platform, a Web 2.0 based community-wide interactive process for creating more accurate and information-rich databases. Thus, this comprehensive map of the mTOR network will serve as a tool to facilitate systems-level study of up-to-date mTOR network components and signaling events toward the discovery of novel regulatory processes and therapeutic strategies for cancer.
doi:10.1038/msb.2010.108
PMCID: PMC3018167  PMID: 21179025
cancer; CellDesigner; graphical notation; mTOR; regulatory network
14.  A comprehensive molecular interaction map of the budding yeast cell cycle 
With the accumulation of data on complex molecular machineries coordinating cell-cycle dynamics, coupled with its central function in disease patho-physiologies, it is becoming increasingly important to collate the disparate knowledge sources into a comprehensive molecular network amenable to systems-level analyses. In this work, we present a comprehensive map of the budding yeast cell-cycle, curating reactions from ∼600 original papers. Toward leveraging the map as a framework to explore the underlying network architecture, we abstract the molecular components into three planes—signaling, cell-cycle core and structural planes. The planar view together with topological analyses facilitates network-centric identification of functions and control mechanisms. Further, we perform a comparative motif analysis to identify around 194 motifs including feed-forward, mutual inhibitory and feedback mechanisms contributing to cell-cycle robustness. We envisage the open access, comprehensive cell-cycle map to open roads toward community-based deeper understanding of cell-cycle dynamics.
doi:10.1038/msb.2010.73
PMCID: PMC2964125  PMID: 20865008
comprehensive map; large-scale network; yeast cell cycle
15.  Drug-Induced Regulation of Target Expression 
PLoS Computational Biology  2010;6(9):e1000925.
Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug-induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments. In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention.
Author Summary
Many drug targets thought to be suitable for therapeutic purposes are subjected to positive or negative feedback loops upon chemical perturbations which might even account for the development of drug tolerance. In this study, we carried out the first systematic analysis of drug-induced differential expression of drug targets using the Connectivity Map, a resource that contains the genome-wide expression profiles of 1309 bioactive small molecules performed on four cultured human cells. The main obstacle in analyzing such a large set of profiles is the non-biological experimental variation across batches. We overcame this by developing a pipeline for strict filtering and state-of-the-art normalization and were able to utilize the Connectivity Map for assessing the drug-induced differential regulation of drug targets. Using the normalized data, we found that at least 8% of the drug-induced drug targets studied are differentially regulated in three cell lines; some of these confirm previous observations in other cell lines. Our work not only quantifies the amount of target expression feedback loops in three human cell lines, but also identifies so far unknown drug-induced target expression changes; some of them can be linked to the development of drug tolerance in patients.
doi:10.1371/journal.pcbi.1000925
PMCID: PMC2936514  PMID: 20838579
16.  Consistent design schematics for biological systems: standardization of representation in biological engineering 
Journal of the Royal Society Interface  2009;6(Suppl 4):S393-S404.
The discovery by design paradigm driving research in synthetic biology entails the engineering of de novo biological constructs with well-characterized input–output behaviours and interfaces. The construction of biological circuits requires iterative phases of design, simulation and assembly, leading to the fabrication of a biological device. In order to represent engineered models in a consistent visual format and further simulating them in silico, standardization of representation and model formalism is imperative. In this article, we review different efforts for standardization, particularly standards for graphical visualization and simulation/annotation schemata adopted in systems biology. We identify the importance of integrating the different standardization efforts and provide insights into potential avenues for developing a common framework for model visualization, simulation and sharing across various tools. We envision that such a synergistic approach would lead to the development of global, standardized schemata in biology, empowering deeper understanding of molecular mechanisms as well as engineering of novel biological systems.
doi:10.1098/rsif.2009.0046.focus
PMCID: PMC2843967  PMID: 19493898
systems biology; standardization; biological engineering; graphical notation
17.  Large-Scale Analysis of Network Bistability for Human Cancers 
PLoS Computational Biology  2010;6(7):e1000851.
Protein–protein interaction and gene regulatory networks are likely to be locked in a state corresponding to a disease by the behavior of one or more bistable circuits exhibiting switch-like behavior. Sets of genes could be over-expressed or repressed when anomalies due to disease appear, and the circuits responsible for this over- or under-expression might persist for as long as the disease state continues. This paper shows how a large-scale analysis of network bistability for various human cancers can identify genes that can potentially serve as drug targets or diagnosis biomarkers.
Author Summary
Since most disease states exhibit a certain level of resilience against therapeutic interventions, each disease state can be considered to be homeostatic to some extent. There must be one or more mechanisms that cause the gene-regulatory network to maintain a certain state, and one such mechanism is a bistable switch. In this work, bistable switch networks were constructed and their ON(upregulated)/OFF(downregulated) states were compared between human cancers and healthy control samples. Changes in the ON/OFF state with the progression of cancer were demonstrated. A series of genes that might serve as a drug target or diagnosis biomarker was identified. The approach presented here should provide useful insights into the states of biological networks, which may lead to the discovery of novel drug targets and therapeutic interventions.
doi:10.1371/journal.pcbi.1000851
PMCID: PMC2900289  PMID: 20628618
18.  Violations of robustness trade-offs 
Biological robustness is a principle that may shed light on system-level characteristics of biological systems. One intriguing aspect of the concept of biological robustness is the possible existence of intrinsic trade-offs among robustness, fragility, performance, and so on. At the same time, whether such trade-offs hold regardless of the situation or hold only under specific conditions warrants careful investigation. In this paper, we reassess this concept and argue that biological robustness may hold only when a system is sufficiently optimized and that it may not be conserved when there is room for optimization in its design. Several testable predictions and implications for cell culture experiments are presented.
doi:10.1038/msb.2010.40
PMCID: PMC2913402  PMID: 20571533
evolution; portfolio selection; robustness; suboptimality; trade-offs
19.  PathText: a text mining integrator for biological pathway visualizations 
Bioinformatics  2010;26(12):i374-i381.
Motivation: Metabolic and signaling pathways are an increasingly important part of organizing knowledge in systems biology. They serve to integrate collective interpretations of facts scattered throughout literature. Biologists construct a pathway by reading a large number of articles and interpreting them as a consistent network, but most of the models constructed currently lack direct links to those articles. Biologists who want to check the original articles have to spend substantial amounts of time to collect relevant articles and identify the sections relevant to the pathway. Furthermore, with the scientific literature expanding by several thousand papers per week, keeping a model relevant requires a continuous curation effort. In this article, we present a system designed to integrate a pathway visualizer, text mining systems and annotation tools into a seamless environment. This will enable biologists to freely move between parts of a pathway and relevant sections of articles, as well as identify relevant papers from large text bases. The system, PathText, is developed by Systems Biology Institute, Okinawa Institute of Science and Technology, National Centre for Text Mining (University of Manchester) and the University of Tokyo, and is being used by groups of biologists from these locations.
Contact: brian@monrovian.com.
doi:10.1093/bioinformatics/btq221
PMCID: PMC2881405  PMID: 20529930
20.  Grand Challenges in Systems Physiology 
doi:10.3389/fphys.2010.00003
PMCID: PMC3059972  PMID: 21423346
21.  Fragilities Caused by Dosage Imbalance in Regulation of the Budding Yeast Cell Cycle 
PLoS Genetics  2010;6(4):e1000919.
Cells can maintain their functions despite fluctuations in intracellular parameters, such as protein activities and gene expression levels. This commonly observed biological property of cells is called robustness. On the other hand, these parameters have different limitations, each reflecting the property of the subsystem containing the parameter. The budding yeast cell cycle is quite fragile upon overexpression of CDC14, but is robust upon overexpression of ESP1. The gene products of both CDC14 and ESP1 are regulated by 1∶1 binding with their inhibitors (Net1 and Pds1), and a mathematical model predicts the extreme fragility of the cell cycle upon overexpression of CDC14 and ESP1 caused by dosage imbalance between these genes. However, it has not been experimentally shown that dosage imbalance causes fragility of the cell cycle. In this study, we measured the quantitative genetic interactions of these genes by performing combinatorial “genetic tug-of-war” experiments. We first showed experimental evidence that dosage imbalance between CDC14 and NET1 causes fragility. We also showed that fragility arising from dosage imbalance between ESP1 and PDS1 is masked by CDH1 and CLB2. The masking function of CLB2 was stabilization of Pds1 by its phosphorylation. We finally modified Chen's model according to our findings. We thus propose that dosage imbalance causes fragility in biological systems.
Author Summary
Normal cell functioning is dependent on balance between protein interactions and gene regulations. Although the balance is often perturbed by environmental changes, mutations, and noise in biochemical reactions, cellular systems can maintain their function despite these perturbations. This property of cells, called robustness, is now considered to be a design principle of biological systems and has become a central theme for systems biology. We previously developed an experimental method designated “genetic tug-of-war,” in which we assessed the robustness of cellular systems upon overexpression of certain genes, especially that of the budding yeast cell cycle. Although the yeast cell cycle can be maintained despite significant overexpression of most genes within the system, the cell cycle halts upon just two-fold overexpression of M phase phosphatase CDC14. In this study, we experimentally showed that this fragility is caused by dosage imbalance between CDC14 and NET1. Interestingly, fragility of regulation of separase gene ESP1, potentially caused by dosage imbalance, was masked by regulation of other factors such as CDH1 and CLB2. We thus propose that dosage imbalance causes fragility in biological systems.
doi:10.1371/journal.pgen.1000919
PMCID: PMC2858678  PMID: 20421994
22.  Payao: a community platform for SBML pathway model curation 
Bioinformatics  2010;26(10):1381-1383.
Summary: Payao is a community-based, collaborative web service platform for gene-regulatory and biochemical pathway model curation. The system combines Web 2.0 technologies and online model visualization functions to enable a collaborative community to annotate and curate biological models. Payao reads the models in Systems Biology Markup Language format, displays them with CellDesigner, a process diagram editor, which complies with the Systems Biology Graphical Notation, and provides an interface for model enrichment (adding tags and comments to the models) for the access-controlled community members.
Availability and implementation: Freely available for model curation service at http://www.payaologue.org. Web site implemented in Seaser Framework 2.0 with S2Flex2, MySQL 5.0 and Tomcat 5.5, with all major browsers supported.
Contact: kitano@sbi.jp
doi:10.1093/bioinformatics/btq143
PMCID: PMC2865864  PMID: 20371497
23.  Predicted Functions of MdmX in Fine-Tuning the Response of p53 to DNA Damage 
PLoS Computational Biology  2010;6(2):e1000665.
Tumor suppressor protein p53 is regulated by two structurally homologous proteins, Mdm2 and MdmX. In contrast to Mdm2, MdmX lacks ubiquitin ligase activity. Although the essential interactions of MdmX are known, it is not clear how they function to regulate p53. The regulation of tumor suppressor p53 by Mdm2 and MdmX in response to DNA damage was investigated by mathematical modeling of a simplified network. The simplified network model was derived from a detailed molecular interaction map (MIM) that exhibited four coherent DNA damage response pathways. The results suggest that MdmX may amplify or stabilize DNA damage-induced p53 responses via non-enzymatic interactions. Transient effects of MdmX are mediated by reservoirs of p53∶MdmX and Mdm2∶MdmX heterodimers, with MdmX buffering the concentrations of p53 and/or Mdm2. A survey of kinetic parameter space disclosed regions of switch-like behavior stemming from such reservoir-based transients. During an early response to DNA damage, MdmX positively or negatively regulated p53 activity, depending on the level of Mdm2; this led to amplification of p53 activity and switch-like response. During a late response to DNA damage, MdmX could dampen oscillations of p53 activity. A possible role of MdmX may be to dampen such oscillations that otherwise could produce erratic cell behavior. Our study suggests how MdmX may participate in the response of p53 to DNA damage either by increasing dependency of p53 on Mdm2 or by dampening oscillations of p53 activity and presents a model for experimental investigation.
Author Summary
A Molecular Interaction Map (MIM) akin to a circuit diagram of an electric device can give a comprehensive view of cellular processes and help understand complex protein functions in cells. To this end, we generated a MIM focused on the p53-Mdm2-MdmX network proteins and performed computer simulations to help understand how Mdm2 and MdmX may regulate p53. Proper regulation of p53 is important for cell survival: elevated levels of p53 can lead to cell death, and decreased levels of p53 can lead to cancer. Mdm2 and MdmX are structurally homologous proteins that regulate p53. Mdm2 negatively regulates p53 by degradation, but MdmX regulation of p53 is not well understood. Recently, Mdm2 and MdmX have been recognized as potential cancer therapeutic targets. In an effort to better understand how MdmX can alter the p53 activity under various conditions, we used mathematical models based on the MIM network to generate hypotheses that can be tested by experiments. Our simulations suggest that MdmX may increase the dependency of p53 on Mdm2 or dampen p53 oscillations during DNA damage response.
doi:10.1371/journal.pcbi.1000665
PMCID: PMC2824598  PMID: 20174603
24.  Structure of Protein Interaction Networks and Their Implications on Drug Design 
PLoS Computational Biology  2009;5(10):e1000550.
Protein-protein interaction networks (PINs) are rich sources of information that enable the network properties of biological systems to be understood. A study of the topological and statistical properties of budding yeast and human PINs revealed that they are scale-rich and configured as highly optimized tolerance (HOT) networks that are similar to the router-level topology of the Internet. This is different from claims that such networks are scale-free and configured through simple preferential-attachment processes. Further analysis revealed that there are extensive interconnections among middle-degree nodes that form the backbone of the networks. Degree distributions of essential genes, synthetic lethal genes, synthetic sick genes, and human drug-target genes indicate that there are advantageous drug targets among nodes with middle- to low-degree nodes. Such network properties provide the rationale for combinatorial drugs that target less prominent nodes to increase synergetic efficacy and create fewer side effects.
Author Summary
Genome-wide data on interactions between proteins are now available, and networks of protein interactions are the keys to understanding diseases and finding accurate drug targets. This study revealed that the architectural properties of the backbones of protein interaction networks (PINs) were similar to those of the Internet router-level topology by using statistical analyses of genome-wide budding yeast and human PINs. This type of network is known as a highly optimized tolerance (HOT) network that is robust against failures in its components and that ensures high levels of communication. Moreover, we also found that a large number of the most successful drug-target proteins are on the backbone of the human PIN. We made a list of proteins on the backbone of the human PIN, which may help drug companies to search more efficiently for new drug targets.
doi:10.1371/journal.pcbi.1000550
PMCID: PMC2760708  PMID: 19876376
25.  Robustness and fragility in the yeast high osmolarity glycerol (HOG) signal-transduction pathway 
Cellular signalling networks integrate environmental stimuli with the information on cellular status. These networks must be robust against stochastic fluctuations in stimuli as well as in the amounts of signalling components. Here, we challenge the yeast HOG signal-transduction pathway with systematic perturbations in components' expression levels under various external conditions in search for nodes of fragility. We observe a substantially higher frequency of fragile nodes in this signal-transduction pathway than that has been observed for other cellular processes. These fragilities disperse without any clear pattern over biochemical functions or location in pathway topology and they are largely independent of pathway activation by external stimuli. However, the strongest toxicities are caused by pathway hyperactivation. In silico analysis highlights the impact of model structure on in silico robustness, and suggests complex formation and scaffolding as important contributors to the observed fragility patterns. Thus, in vivo robustness data can be used to discriminate and improve mathematical models.
doi:10.1038/msb.2009.36
PMCID: PMC2710867  PMID: 19536204
gTow; HOG; robustness; signal transduction; systems biology

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