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1.  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
2.  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
3.  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
4.  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
5.  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
6.  AlzPathway: a comprehensive map of signaling pathways of Alzheimer’s disease 
BMC Systems Biology  2012;6:52.
Background
Alzheimer’s disease (AD) is the most common cause of dementia among the elderly. To clarify pathogenesis of AD, thousands of reports have been accumulating. However, knowledge of signaling pathways in the field of AD has not been compiled as a database before.
Description
Here, we have constructed a publicly available pathway map called “AlzPathway” that comprehensively catalogs signaling pathways in the field of AD. We have collected and manually curated over 100 review articles related to AD, and have built an AD pathway map using CellDesigner. AlzPathway is currently composed of 1347 molecules and 1070 reactions in neuron, brain blood barrier, presynaptic, postsynaptic, astrocyte, and microglial cells and their cellular localizations. AlzPathway is available as both the SBML (Systems Biology Markup Language) map for CellDesigner and the high resolution image map. AlzPathway is also available as a web service (online map) based on Payao system, a community-based, collaborative web service platform for pathway model curation, enabling continuous updates by AD researchers.
Conclusions
AlzPathway is the first comprehensive map of intra, inter and extra cellular AD signaling pathways which can enable mechanistic deciphering of AD pathogenesis. The AlzPathway map is accessible at http://alzpathway.org/.
doi:10.1186/1752-0509-6-52
PMCID: PMC3411424  PMID: 22647208
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  A comprehensive pathway map of epidermal growth factor receptor signaling 
Molecular Systems Biology  2005;1:2005.0010.
The epidermal growth factor receptor (EGFR) signaling pathway is one of the most important pathways that regulate growth, survival, proliferation, and differentiation in mammalian cells. Reflecting this importance, it is one of the best-investigated signaling systems, both experimentally and computationally, and several computational models have been developed for dynamic analysis. A map of molecular interactions of the EGFR signaling system is a valuable resource for research in this area. In this paper, we present a comprehensive pathway map of EGFR signaling and other related pathways. The map reveals that the overall architecture of the pathway is a bow-tie (or hourglass) structure with several feedback loops. The map is created using CellDesigner software that enables us to graphically represent interactions using a well-defined and consistent graphical notation, and to store it in Systems Biology Markup Language (SBML).
doi:10.1038/msb4100014
PMCID: PMC1681468  PMID: 16729045
bow-tie structure; comprehensive pathway map; epidermal growth factor receptor; graphical notation; Systems Biology Markup Language (SBML)

Results 1-13 (13)