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Pathways for exploratory data analysis.

<p>Biological pathways are powerful visualization tools for data exploration, focused on finding the right question.</p

miRNA regulation of genes associated with <i>diabetes mellitus</i>.

<p>Genes and miRNAs are visualised as grey circles and yellow rounded rectangles, respectively. The names of the genes and miRNAs are displayed on the nodes. The genes linked to the MeSH term <i>diabetes mellitus</i> were obtained using Gene2MeSH (<a href="http://gene2mesh.ncibi.org/" target="_blank">http://gene2mesh.ncibi.org/</a>). The molecular interactions between the genes were obtained from the STRING database and are visualised in black. The MTIs originate from microCosm (486), TargetScan (207), miRTarBase (5) and miRecords (2), and are coloured in blue, orange, red and purple, respectively.The overlap threshold function was applied to show only MTIs present in at least two RegINs.</p

CyTargetLinker workflow.

<p><b>Step 1:</b> Four miRNAs known to be involved in prostate cancer <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082160#pone.0082160-Heneghan1" target="_blank">[27]</a> are visualised in a Cytoscape network (A). The miRNAs are annotated with miRBase accession numbers and ids. <b>Step 2:</b> The regulatory interaction networks (RegINs) harbouring miRNA-target interactions (MTIs), either validated (miRecords and miRTarBase) or predicted (microCosm and TargetScan), are downloaded from <a href="http://projects.bigcat.unimaas.nl/cytargetlinker/regins" target="_blank">http://projects.bigcat.unimaas.nl/cytargetlinker/regins</a>. <b>Step 3:</b> Known targets are integrated (B) after specifying the miRBase accession number column, the RegINs directory and the direction “<i>Add Targets</i>” in the CyTargetLinker dialog. In the resulting network miRNAs and target genes are defined as grey circles and pink hexagons, respectively. The predicted MTIs are visualised in orange (TargetScan: 4239) and blue (microCosm: 2800) and the validated MTIs in red (miRTarBase: 59) and purple (miRecords: 24), as shown in the control panel. <b>Step 4:</b> The hide/show and overlap threshold functions were used to visualise validated interactions exclusively or to show the overlap in MTI coverage. In the validated network only the MTIs in miRecords and miRTarBase are visualised by hiding MTIs in TargetScan and microCosm (C). In the overlap network the MTIs present in two or more RegINs are shown by setting the threshold to 2 (D).</p

Comparison of available Cytoscape apps.

<p>Overview of four Cytoscape apps that are most related to CyTargetLinker. This table provides a comparison of the availability and data used in the apps.</p

Regulatory interaction network files.

<p>Subset of the RegINs (regulatory interaction networks) available for download on the CyTargetLinker website. All RegIN networks support the following identifier systems: (i) for genes/proteins Ensembl, NCBI gene, UniProt, (ii) for miRNAs miRBase accession number and ids, and (iii) for drugs DrugBank. (* Redistribution of data not allowed, but RegIN can be created with our provided conversion script).</p

Meta network of the ErbB signaling pathway containing miRNA, TF and drug regulation.

<p>The ErbB signaling pathway (<a href="http://wikipathways.org/index.php/Pathway:WP673" target="_blank">http://wikipathways.org/index.php/Pathway:WP673</a>) from WikiPathways was extended with TFs, miRNAs and drugs regulating the elements in the pathway. The nodes from the original pathway are coloured in grey, TFs in green, miRNAs in yellow and drugs in purple. 258 TF-gene interactions from ENCODE, 162 miRNA-target interactions from the two validated miRNA-target RegINs (miRTarBase and miRecords) and 138 drug-target interactions from DrugBank were added to the network. The edges are coloured based on the RegIN source, purple and orange for ENCODE (proximal and distal), blue and red for miRTarBase and miRecords, and green for DrugBank.</p

Extend a GeneMania network with TF data from the ENCODE project.

<p>A set of known DNA repair genes (grey circled nodes) were used as input for the GeneMania app in Cytoscape. Physical interactions (black) between the query genes were added by GeneMania. Every node in a GeneMania network has an attribute “Entrez gene identifier” which was used by the CyTargetLinker app to extend the network with TF-gene interactions from the ENCODE networks. The integration direction was selected as “<i>Add regulators</i>”, indicating that the app should look for interactions that target the input genes. The colours and shapes of the TFs are based on the provided TF family information in the ENCODE project <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082160#pone.0082160-Gerstein1" target="_blank">[3]</a>. The ENCODE project studied proximal and distal TF regulation which are indicated in this figure as blue and red edges.</p

WikiPathways can be accessed by end-users from the wiki-style website.

<p>In addition, the WikiPathways web service provides a programmatic interface that can be used in many programming languages, including R, python, Java and perl and in workflow tools such as Taverna. Using this interface, new pathway analysis tools can be built and existing bioinformatics tools can be extended with pathway-based functionality.</p

Two Models for Managing Biological Data

<p>Current biological databases provide the community with data submission forms or tools and access to the compiled data via websites, FTP sites, and, sometimes, programmatic interfaces (API). Internal curation teams organize and update the data. A wiki model for biological databases, such as WikiPathways, provides a single, intuitive interface for submitting, updating, organizing, and accessing data, allowing the community to participate in the curation process and keep up with the influx of new data. The widths of the arrows represent the relative capacity for data management in the two models.</p