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Cytoscape An Open Source Platform for Biological Network Analysis and Visualization 2/22/2013 @University of Tokyo HGC Keiichiro Ono Cytoscape Core Developer Team University of California, San Diego Trey Ideker Lab

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Thanks for Attending! - Keiichiro Ono - Cytoscape Core Developer since 2005 - Core modules design & implementation - Release management - Area of Interest: Data Integration & Visualization - University of California, San Diego Trey Ideker Lab

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Made with:

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Outline - What is Cytoscape? - How Cytoscape helps your research projects - Cytoscape Ecosystem

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What is Cytoscape?

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Cytoscape - Open source platform for biological network data integration, analysis, and visualization

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- Free! (open source, LGPL) - Developed and maintained by universities, companies, and research institutions - De-facto standard software in biological network research community - Expandable by Apps

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Network?

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reaction-modifier reaction-modifier reaction-modifier reaction-modifier reaction-reactant reaction-modifier reaction-product reaction-reactant reaction-product reaction-modifier reaction-modifier reaction-modifier reaction-reactant reaction-product reaction-modifier reaction-reactant reaction-modifier reaction-product reaction-modifier reaction-modifier reaction-product reaction-reactant reaction-modifier reaction-modifier reaction-reactant reaction-reactant reaction-modifier reaction-product reaction-product reaction-modifier reaction-modifier reaction-modifier reaction-modifier MEK v3 v1 v4 v2 v5 MpY MpT M v6 MKP3 v7 Mpp

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Network = Nodes + Edges

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Nodes and Edges in Biology - Protein - Protein - Protein - DNA - Genetic (Epistasis) - Synthetic lethality - Biochemical Reactions - Compound - Enzyme - Compound Cartoon representation of a complex between DNA and the protein p53 Node Node Edge

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Human-Curated Pathways KEGG Pathway Visualized by Cytoscape

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Undirected Network - Protein - Protein Interaction

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Directed Network KEGG Pathway (TCA Cycle) visualized by Cytoscape KGMLReader

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KEGG Global Map Visualized by Cytoscape

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Network Appears Everywhere

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Twitter Visualization

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M20 M10 M18 M9 M19 M12 M7 M6 M17 M2 M15 M5 M11 M4 M8 M1 M3 M16 M13 M14 Network of Networks

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The Challenge

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BioGRID Mouse Network Release 3.2.95 - 5.5k nodes / 13k edges ?

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Biological Networks - Tell us anything by themselves - Big hairball (or small galaxy...)

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Tool for Hacking Hairballs - Biologists need a tool to extract meaningful biological modules from the huge hairballs - Cytoscape is focussing that area of problem

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In Other Words...

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Networks

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Genes of Interest

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List of Drug Targets Other knowledge

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Cytoscape Core is NOT a... - Simulator - Pathway diagram (SBGN) editor - Statistical network analysis tool suite - Still, you can implement these as Apps though

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Our Focus

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Large-Scale Network Analysis and Visualization Human Interactome data from BioGRID visualized by Cytoscape

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How Big? - Protein-Protein: ~10k nodes/ ~20k edges - Genetic: ~Millions - And more flood of data is coming - Microbiomes - Co-expression of SNPs - ...

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Pick a Right Tool NetworkX

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Advantages of Open Platform - Write a bridge App and use other applications‘ features - Web Service API, etc... - Cytoscape as a part of your workflow

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Summary - Cytoscape is a platform for: - Data integration: networks & known annotations, experimental/clinical data - Analysis: filter/search/module extraction - Visualization: Helps you to understand the data

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Introduction to Biological Network Analysis Using Cytoscape

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1.Load Networks (Get network data)‏ 2.Load Attributes (Get data about networks)‏ 3.Analyze and Visualize Networks 4.Prepare for Publication - A specific example of this workflow: − Cline, et al. “Integration of biological networks and gene expression data using Cytoscape”, Nature Protocols, 2, 2366-2382 (2007). Cytoscape Workflow

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Network Data Annotated Networks Attributes Analyzed Data Apps

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79 0 9 167 18 75 8 12 26 210 29 320 Import Networks

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Network Data Formats - SIF - GML - XGMML - GraphML - BioPAX - PSI-MI - SBML - KGML (KEGG) - Excel - Delimited Text Table - CSV - Tab

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I Don’t Have a Network! - Don’t worry - There are tons of public interaction data sets - Cytoscape can import those public data sets directly via Internet.

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Which Database? - Protein - Protein - STRING, IntAct - Genetic - BioGRID - Protein - Compound - ChEMBL - Human-Curated Pathways - KEGG, Reactome, PathwayCommons

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PSICQUIC - Standardized mechanism to access public interaction data sets - In short, you can search multiple databases at once

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Import Attributes

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What are Attributes? - Any data that describes or provides details about nodes, edges, and networks.

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BRCA1 NCBI Gene ID 672 On Chromosome 17 GO Terms: DNA Repair Cell Cycle DNA Binding Ensemble ID ENSG00000012048

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Why we need attributes? - Analysis - It is hard to get biologically meaningful analysis result only from network topology (= structure) - Meaningful Visualization - Expression values - Node Color - Gene Function - Node Shape - etc.

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Node Attributes - Gene Expression Data - Human-readable gene names - Gene Ontology Terms

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Edge Attributes - Interaction Detection Methods - Y2H, NMR, affinity chromatography, etc. - Interaction Type - Physical, genetic, predicted - Publication ID

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Network Attributes - Experiment details - Pathway Metadata - Description - Publication ID

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Public Data Source - Access directly from Cytoscape, or - Import as Table (Text/Excel)

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Your Data Sets - Anything saved as a table cam be loaded into Cytoscape - Excel - Tab Delimited Document - CSV - As long as proper mapping key is available, Cytoscape can map them to your networks.

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Mapping Key in the Network Mapping Key in the Table

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Analysis

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Network Analysis - Filtering - Calculate network statistics by Network Analyzer - Degree distribution,centrality, etc. - Advanced analysis by Apps

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Filtering - Find nodes and edges with specific conditions - Pick nodes with degree > 5 - Select edges extracted from publication X - Find nodes annotated by GO term ID Y

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Visualization

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Layouts

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Biological Data Visualization - Help others to understand your data - Emphasize what you want to tell by the image - Use color, shape, size of objects effectively! - Excellent resource for data visualization - Tamara Munzner’s Web Site: http://www.cs.ubc.ca/~tmm/

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Visualization Core Idea - Map values to visual properties - Expression Value to Node Color - Edge Weight to Width - Degree to Node Size - Node Type to Shape

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Map Attributes to Visual Properties

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Visual Style - Collection of mappings from Attributes to Visual Properties

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Default View Editor Discrete Mapping Editor Continuous Mapping Editor

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Prepare for Publication - Network images can be exported as PDF/ PS/PNG/JPG. - Use PDF for your publications

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Real World Examples http://cytoscape-publications.tumblr.com

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Expanding Cytoscape with Apps

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Cytoscape Apps - Were called Plugins - Add new features to Cytoscape - Large app developer/user community - This is the reason why Cytoscape is so popular!

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http://apps.cytoscape.org

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AllegroMCODE APCluster APID2NET BioQualiPlugin BLAST2SimilarityGraph BNMatch CABIN CalculateNodeDegree CentiScaPe ChemViz clusterExplorerPlugin clusterMaker ClusterONE ClusterViz COMA CommFinder CyClus3D CyOog cytoHubba Cytomcl DualLayout dynamicXpr EnhancedSearch EnrichmentMap ExprEssence GraMoFoNe GraphletCounter HiderSlider jActiveModules mcl-new MCODE MINE NeMo NetAtlas NetCirChro netMatch NetworkAnalyzer NetworkEvolution OmicsAnalyzer OmicsViz OrthoNets PanGIA PerturbationAnalyzer PinnacleZ RandomNetworks RDFScsape Reactome FIs RemainingDegreeDistribution ReOrientPlugin ShortestPath Plugin SimTrek structureViz TransClust VennDiagramGenerator VistaClaraPlugin WordCloud BiNoM bioCycPlugin BiogridPlugin BiomartClient BioNetBuilder BisoGenet ConsensusPathDBplugin CoryneRegNetLoader CyThesaurus-ID-Mapping CytoSQL DroID Genoscape GPML-Plugin GraphMLReader IntActWSClient iRefScape KGMLReader MetScape MiMIplugin NCBIClient NCBIEntrezGeneUserInterface Pathintegrator PhosphositePlus Web Service Client Module PICRClient PSICQUICUniversalClient ReConn SessionForWeb SFLDLoader StringWSClient Superpathways-Plugin 3DScape AgilentLiteratureSearch Cytoprophet DisGeNET DomainGraph ExpressionCorrelation GeneMANIA MetaNetter MONET BiNGO BubbleRouter ClueGO CommonAttributes DisplayNetworkFromFlatFile FluxViz FunNetViz HyperEdgeEditor PiNGO CyGoose CytoscapeRPC GroovyScriptingEngine JavaScriptEngine MiSink PythonScriptingEngine RubyScriptingEngine ScriptEngineManager addParentNeighbors AdvancedNetworkMerge batchTool BiLayout commandTool coreCommands CyAnimator edgeLengthPlugin edgeLister EpiTrace FERN FM3 GoogleChartFunctions GroupTool MetaNodePlugin2 MultilevelLayoutPlugin NamedSelection NatureProtocolsWorkflow NeighborHighlight NetLink nodeCharts PhyloTree VennDiagrams 140+ Apps

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A Must Read A travel guide to Cytoscape plugins Rintaro Saito, Michael E Smoot, Keiichiro Ono, Johannes Ruscheinski, Peng- Liang Wang, Samad Lotia, Alexander R Pico, Gary D Bader, Trey Ideker (2012) Nature Methods 9 (11) p. 1069-1076

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Rintaro Saito et al: a travel guide to cytoscape plugins Nature Methods 9 (11) p. 1069-1076

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Cytoscape Family

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Cytoscape Family - Version 2.x - Production version - Version 3.x - Next generation - 3.0.x - Maintenance - 3.1.x - Next release with new features - cytoscape.js - Library for web applications

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Cytoscape 2

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Next Generation

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Cytoscape 3

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ENSG00000234012 PIK3CA CNA1 ATRX ABL1 MED1 KPNA3 HRAS PTEN FAM175A CDK8 ARIH1 CHGA ELAC2 FBXW4 FGF11 FBXW11 MAP3K1 MLH1 CDC6 GTF2E1 IP1 TRIM28 NCOA2 RPS6KB2 HSD17B1 FOS NBN TAF2G PLK1 FBXO4 AURKA T1 MAGED2 PLK3 JUN CDK1 FAM175B ERBB2 POLL RAD54B GTF2H4 PMS2 STK11 SMAD3 TFDP2 RFC1 RAD51 TP53 DPPA3 AR DCLRE1C RBBP4 FANCF MYC FANCE FANCC D FANCL FG W NBR2 NFYA SMAD1 MAP4K4 FBXO9 RPA1 WWP1 ANTXR1 PALB2 PEG3 JUND AP2B1 FLI1 TOPBP1 FANCB TSPAN9 DCUN1D1 FBXO25 CDC25A RNF31 CDK4 PPP1CA SMARCB1 SMARCC2 FBXO11 HYRC SMC1A MED24 CHTF18 RBL2 PIAS4 2F6 CDK5 BRCA2 JAK2 MDC1 KAT2A BATF MAD2L1 CHEK1 R 3H FBXL5 RAD51AP1 PIAS1 RNF20 FBXO8 FANCM MPP3 FBXO24 ELK1 MELK UBB LMO7 WT1 NBR1 ERCC4 ERCC1 XRCC5 MRE11A WRN NMI SHFM1 EZH2 ERCC TUBB2A MAP3K4 PML DCAF11 CDKN1A APLP2 CDC45 TSPAN17 NUP153 EGFR FBXL3 CTCFL SMARCE1 GATA3 CHEK2 TOP3A EIF4G1 DDB1 PAX6 TUBA4A IGF1R RNF168 BRCA1 PPM1D JUNB MED21 F CDKN1B RAD9A

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MED13 SMARCC1 EP300 MAP3K3 GFI1B NUFIP1 GTF2F1 ENSG00000234012 G5A EP400 CBLL1 RAD51 CHGB ID4 WHSC2 FBXW4 BAP1 BRE CDK8 NCK1 8KDE69BZMi87N7sAF1369Ab14So-2 Q8NHQ3 Brca2 uBEqgVbNZFpKdFvwcyL6sloSw0g9606 GSTP1 Ncoa2 FANCL LDpqfKYgCfLDptQIUCIlr9Yfwb49606 UBB Dd2vI8mq8orSfrL52KvLX4sD/Ho-2 BRCA1 SMAD4 PPP1CA 2099 3725 2005 9972 10111 1487 9606.ENSP00000358154 3838 9412 9093 140690 4609 PAXIP1 JUN RNF2 CSTF2 GPR3 ENSG00000137337 MZT1 BMI1 VCP G5A MGF BARS RPB2 RBBP4 RIM PP-1A EWS-ATF1 JUND OSRC RCC JTK3 RBBP3 X2HRIP110 DKFZp686B04100 IPOA1 BRAP LMO4 CLSPN DHX9 RBBP7 E2F4 hRad50 HDAC2 MAP3K3 hSNF2a DBP AURKB HIST1H4L FA-H MLH1 BLM JAK2 LCFS2 HD1 LAT H2A/X WNT2B UBE2I UBE3A UbcM4 HSPA8 MRPL39 TRIP2 SP1 DKFZp686L20222 PEG3 DKFZp686N23123 DDIT1 SMARCA4 MDC1 DEF1 TRRAP hSNF2b BRCC1 NUP120 TERF2 PP1425 FIP p85-ALPHA CCNA MGC131997 XRCC3 SKP2 RSTS 6657 BRCA2 010204 000008035 6 6 FP00000007136 00000012830 SAP Cdk1 Ccnd1 Ercc1 Racgap1 Topbp1 Aspm RPA2 Immp2l FANCD1 Aurkb peptide-linker Birc5 HNRNPL efqpO06SDGYmzwbMpJ+t06UDlsY MPP-2 JXK67Oy2Ny+i96e1jAFkVJTCF50 DD2eG+gmXMcK4KCVbtT54i9U1xc9606 USF1 2lutkxFaFwUJS+5PatDg/qCXa/8 JsH9sHdvJhJOYXW58i3HjQWBu0E FANCD2 WDR16 +2eXiWJK61JwsRevyDVe+z6LKIg UBE2D1 NUP188 RPL31 MAP4K4 ABL1 MED17 TERF1 Q8IZU3 NUP2 C13orf15 dl6L440zevhf86Ba5SdPQ3cStkQ9606 ZNF350 HMG20B Bap1 PDS5B MED21 bAL7aWxtvUXKdB1zZ+HHMKM9FT89606 FLI1 ELK4 KIF1B MLP2 RPA1 MTA2 SMC3L1 CCR4 FYN MTA2 NEK1 XRCC9 ETS1 OQtyYL8HGbvuX0heZ5qCycS8zI8 kEU79P2/HWd7/1I2NJOLvFiSlBQ nDnqwbN+UgKzMvfaP0EIekAhiZQ Cyclin 02nZZfkeIi3mdZR6KqEjgW4gIO0 MAPK14 CCNE1 ERBB2 SMAD3 PGR XRCC3 HMMR PSMD14 ERCC1 PSMB3 NCOA2 MPP3 FLNA CAMKK1 E2F6 BRD7 FBXO8 FBXO10 FGFR2 MLH1 GADD45A RAD51AP1 PTEN SMAD1 HIC1 UBC RAD52 AURKB CBX1 MEN1 MAD1L1 JAK2 MDC1 SLC4A7 C11orf58 RASEF ACVR1B MAP2K4 TSSK3 OPTC PLEC LPHN3 PALLD BCCIP MLH3 XPA PHF21A SP1 ATRX NFKB1 CHEK1 MSH3 PMS2 RAD54B TP53 CHEK2 DEPDC1B FANCB PLK1 NBN BACH1 CDH1 RB1 ESR1 RAD50 FANCM MCPH1 DPH1 PARP1 HRAS MAP3K1 LIG3 ERCC4 STAT5A BLM 2962 207 SIAH3 RNASEL 7503 CCND1 BUB1B DMC1 Mad2l1 Fancc Rad51l1 Dmc1 SUMO1 Mgmt Ppp2r5b Bub1 Pten Bard1 Brca2 Cdca7 Trp53 Prdx2 Tcp1 Chek1 Fanca Rb1 1 qo2 Nfkb1 Slco4a1 Hmmr LSP1 NEK10 UBE2D3 ATM FANCI CCNA2 TP53BP1 AR FANCD2 H2AFX RPA2 PMS1 FHIT RAD51L3 PIK3CA LIG4 ELAC2 9448 XPC XRCC4 CDKN1A MSH6 SMAD4 RAD51C FANCA CDKN2A TIPARP BRCC3 SMAD2 AURKA INSC XRCC1 RAD51 TWSG1 PALB2 MRE11A BUB1 STK11 HYRC CDK1 C17orf70 UBA52 CYP17A1 641 C11orf30 MSH2 C19orf40 TOX3 FBXL7 WRN KLHDC8B 7321 ECHDC1 XRCC2 6597 10499 C5orf4 UIMC1 FAM175A 51720 59348 595 GATA3 FANCC XRCC6 FANCF XRCC5 Uba52 Men1 Pes1 Brca1 Nme2 Cdc45l Fam175a Twsg1 KPNA6 Fancm Sumo2 GCGR Terf2 DHX9 DNAH8 NEK2 Ezh1 Trp53bp1 ASPM Lmo4 853808 3717 PRDX2 SRD5A2 PPP2R5B CDCA7 COX11 3716 KIF4A NCOA3 HSD17B4 PSMD3 ZMYND11 RNF146 ZNF217 RBBP8 TOP2A TGFBR2 CSNK2B WDR16 ARL11 MND1 ZAR1L SERPINH1 ARIH1 CNTLN EZH1 851212 855055 CDKL4 RNF20 ASB9 DHX32 RAD23B USP11 PSMD6 GGNBP1 UBE2H UBE2L6 PRSS1 SKP2 SERAC1 DAPK1 BRAF RAD51L1 6599 9969 BRCA2 ECD BRCA1 6772 000024255 SCAFP00000026442 GALK1 9615.ENSCAFP00000023980 5.ENSCAFP00000028394 0028192 9615.ENSCAFP00000025953 9615.ENSCAFP00000035179 9615.ENSCAFP00000024343 BRCA1 9615.ENSCAFP00000030064 9615.ENSCAFP00000029451 POLR2A 9615.ENSCAFP00000030922 9615.ENSCAFP00000028763 Cks2 Obox3 Pik3ca 9615.ENSCAFP00000007566 Shfm1 9615.ENSCAFP00000006799 Tiparp Lphn3 9615.ENSCAFP00000027562 AFP00000023734 9615.ENSCAFP00000025994 9615.ENSCAFP00000028888 ADRA2B CCNA1 CREB1 CCNB1 TUBG MSH6 ATM MGC163290 3312 VCP 367 BRCC3 CDK4 BACH1 CSNK2A1 NCOA2 NMI 9555 PPP1CB POU2F1 HsT16930 ORC2 PDS5B CTCFL CCDC DNAJA3 Anti Zuai-1 FLNA VIM HMG20B PLK1 NCKalpha SMARCA2 EMSY HIST2H2AC SMARCC2 KAT2A SMAD3 PPP1CA RBL1 RBL2 UBA1 SMARCB1 AR H2AFY ACACA ABL1 SUB1 POLR2A MED23 GTF2H4 PRKDC NPM1 TOP2A MSH3 SMARCD2 CDK5 MED24 FANCD2 FHL2 ARNT CSTF2 CDKN2D TRP53 NF-kappaB FLJ12847 852199 ATR p150 853957 KPNA2 CDK8 851470 CCND1 SUMO1 853811 APLP2 HIST2H3A SRC MRPL36 6603 GTF2F1 MGC141879 Piasg SPT5 SPT4 DKFZp762J2115 oJw0JiiF0ME7x7eSGqUXn1ujDsg 79728 1020 OPD1 7415 898 UCpeqyqxh zU q6W0BO8vHuuZh PRM TzbYjLhQfYYis5ZHoOIz1MogPM CCNA2 CHEK2 ATDC DHX9 MYC AKT1 BRIP1 ZCCHC8 6601 2968 SSK1 PALB2 MGC45350 TOK1 S3 TP53 STAT5A DSS1 BARD1 CDK2 Ifi204 UQCC RFC1 NUP170 DHH1 FANCE ETS1 POM34 1019 USP1 RAD23A ROCK2 B3GALTL ZFHX3 TBX2 eKcZNhe4o3Sj9t+CWeVB2UBxvgk9606 9862 BRCC2 8202 9439 2Nu9AAWbBoSXW1y9FPjEO6691mU9606 CDK1 5981 983 BRCA1 KIAA0204 SGA-113M HHR23A RPA1 CDK16 Brca2 GTF2E1 ESR1 ASH RNF11 891 NUP153 SHFM1 NUP133 ASM4 KAT2B FANCG 1874 4800 CDC45 dJ199H16.1MGC149819 RAD21 6595 2175 HjbdLaovED6ZlK/153JO9Hsm86o FN+kJjmaxWZr/lWSN4mXugd0TPc 5GNzWn6eJ41h8viIYZEnxs7GUYI vDCqLkifRBymdYzE8Q8boNEF1ZY Vhaq0CUSlWCGivG2ObT5Xa7IB+E BUB1B p65 MCPH1 BCCIP FLNA CHK1 USP11 CCNE1

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What’s New in 3? - New Visualization features - Edge Bend, Background Images - Server-side applications - Headless Mode (Command-line) - More advanced visualization by new rendering engines - For developers: Cleaner API

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Release Schedule - 3.0.0 is (finally) available! - For more information, please visit: http://www.cytoscape.org/cy3.html - 3.0.1 will be available shortly - We will release more frequently

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cytoscape.js - JavaScript version of Cytoscape for network visualization on the web browsers - Take advantage of HTML5/Canvas - Sharing core concepts - Visual Style, Layouts, etc. - A building block for web apps, NOT a complete web application

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Collaboration

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Collaboration - National Resources for Network Biology (NRNB) - Always open for new collaboration! - Scientific Research - Application / Tool Development - nrnb.org

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Countries of origin for each App based on contact e-mail addresses and affiliations Where is Japan...?

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github.com/cytoscape

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Where to Start? - Cytoscape Web Site - cytoscape.org - Open Tutorials - opentutorials.cgl.ucsf.edu/ index.php/Main_Page

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Getting Help - Two Google Groups - [email protected] - [email protected] - ANY question is OK!

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NIH GM070743-01 P01 HG005062 P41 RR031228 (NRNB)

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www.cytoscape.org

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2013 Keiichiro Ono [email protected]