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BioUML
0100100010011101
ISB0100100010011101
ISB
Fedor Kolpakov
Institute of Systems Biology(spin-off of DevelopmentOnTheEdge.com)
Laboratory of Bioinformatics,Design Technological Institute of Digital Techniques
Novosibirsk, Russia
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Agenda
• Part 1: overview of BioUML workbench
• Cafe break
• Part 2: new concepts and possibilities(versions 0.8.0 – 0.8.3)
• Further development
• Questions and discussion
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Part 1: overview of BioUML workbenchOverview• Main concepts• Meta model• Architecture overview• Diagram types• Database module
concepts• Full text search• Graph search• Simulation engine• BioUML server• BMOND/Biopath database
Live demonstration:•Installation of BioUML workbench•Creating and simulating simple model•SBML - Biomodels module•BioPAX import•BMOND database web interface•JavaScript shell
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Part 2: new concepts and possibilities
Overview• Reconstruction as
solitaire game• Levels of biological
information• BioHub concept• Composite database
module• Composite diagram• Experiment concept• Graphic notation editor• Microarray data analysis
Live demonstration•Loading database modules from server•Text search•Graph search•Creating of composite database module•Creating of composite diagram•Experiment•Graphic notation editor•Microarray data analysis
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Useful resourceshttp://www.biouml.org/demo
Flash movies that demonstrates how to work with BioUML workbench
http://www.biouml.org/user/help/index.html
http://www.biouml.org/download/0.7.8/manual.doc
Useguide, >200 pages
- HTML version
- MS Word document
http://bmond.biouml.org
Examples of pathway annotation:
BMOND – Biological Models aNd Diagrams database
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Part 1
Overview of BioUML workbench
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Main BioUML concepts and ideas• Visual modeling
o Meta model – problem domain neutral level of abstraction that describes system as compartmentalized graph
o Diagram type concept – formally defines graphical notation and provides its incorporation into BioUML workbench.
o Automated code generation for model simulation.• Database module concept - allows developer to incorporate
databases on biological pathways into BioUML workbench taking into account database peculiarities.
• Plug-in based architecture (Eclipse platform runtime from IBM company).
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Biological databases
Data search and retrieving
Visual modeling
Automated code generation for model simulation of model behavior
Formal description of structure of biological system
MATLAB code Java code
Simulating using MATLAB.JMatLink allows to BioUML
workbench to start MATLAB and retrieve simulations results
Java simulation plug-in.Contains ODE solvers ported from odeToJava and methods
for hybrid models support.
… code
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Meta model
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][1 Akdt
dA
][2][1 BkAkdt
dB
][2 Bkdt
dC
Corresponding mathematical model:
Example: system from two chemical reactions
A B-k1[A] k1[A]
R1C
-k2[B] K2[B]
R2100 0 0
k1 - reaction rate for R1k2 – reaction rate for R2
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A B
-k1[A] k1[A]
R1 C
-k2[B] k2[B]
R2
100 0 0
System structure is described as a graph
Mathematical modelof the system
Description of system components in the database
ID ACC .....//
ID R1A->B
...//
ID BCC .....//
ID R2B->C
...//
ID CCC .....//
A B-k1[A] k1[A]
R1C
-k2[B] k2[B]
R2100 0 0
Meta-model: example of formal description of system from two chemical reactions
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Suggested approach can be applied for modeling biological systems using:– Systems of ordinary differential equations– Systems of algebra-differential equations– State and transition diagrams– Hybrid models– Boolean and logical networks– Petri nets– Markov chains– Stochastic models– Cellular automates– …
Some limitations– Spatial models– PDE– …
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BioUML architecture
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Plug-in based architecture
Plug-in- plugin.xml
- Java jar files
A plug-in is the smallest unit of BioUML workbench function that can be developed and delivered separately into BioUML workbench. A plug-in is described in an XML manifest file, called plugin.xml. The parsed contents of plug-in manifest files are made available programmatically through a plug-in registry API provided by Eclipse runtime.
- extension points are well-defined function points in the system where other plug-ins can contribute functionality.
- extension is a specific contribution to an extension point. Plug-ins can define their own extension points, so that other plug-ins can integrate tightly with them.
Plug-in - plugin.xml
- Java jar filesPlug-in
- plugin.xml- etc.
Eclipse platform runtime
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Meta model
Executable model
Graph structure
Standard module
Database
Database adapter
Java objects
Gene Protein …
Diagram types- Semantic map- Pathway- Pathway simulation
Eclipse platform runtime Workbench UI
Diagram editor
Analysistools
Simulation tools
Other tools
Views, editors
Menus, toolbars, etc.
GeneNet module
KEGG/pathwaysmodule
TRANSPATHmodule
SBML module
Perspectives
Diagram view part
Diagram editor part
DiagramType-semantic controller-diagram view builder-diagram filter
ModuleType-diagram types-data categories-query engine
Query engine
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Formal description and modeling of biological systems require coordinated efforts of different group of researchers:
• programmers - they should provide computer tools for this task.
• problem domain experts - they should specify what and how should be described.
• experimenters and annotators - they should describe corresponding data following to these rules.
• mathematicians - they should provide methods for models analysis and simulations.
BioUML architecture separates these tasks so they can be effectively solved by corresponding group of researchers and provides simple contract how these groups and corresponding software parts should communicate.
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Diagram types
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Diagram type conceptDiagram type defines:
· types of biological components and their interactions that can be shown on the diagram;
· diagram view builder - it is used to generate view for each diagram element taking into account problem domain peculiarities;
· semantic controller - provides semantic integrity of the diagram during its editing;
· filters – hide or highlight diagram elements according to some selection criteria.
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Reconstruction and formal description of biological systems using different diagram types
1. Semantic network
2. Pathway diagram(semantic network + gene network or metabolic pathway)
3. Metabolic pathway 4. Gene network
5. Pathway simulation(mathematical model)
Formality,details Semi-structured
data
Structured data(reactions and its components)
Kinetic data(kinetic laws, constants,
initial values
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Graphic notation
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Stimulus activating NF-kappaB(semantic network, ontology)
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NF-kappaB family (semantic network, ontology)
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Function of human DNA methyltransferases (pathway diagram)
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The biosynthesis of catecholamines(metabolic pathway)
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Cell cycle model of mammalian G1/S transition control with E2F feedback loops
(pathway simulation diagram)
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DGR0356 “NF-kB model” (Hoffmann et al., 2002)
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NF-kB dynamics in nucleus and cytoplasm before and after TNF-alpha stimulation (Hoffmann et al., 2002)
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Regulation of caspase-3 activation and degradation (Stucki and Simon, 2005 )
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Database module conceptThe database module concept allows to
developer define new diagram types and incorporate other databases on biological pathways into BioUML framework.
The database module defines mapping of database content into diagram elements and diagram types that can be used with the database.
Module also provides query engine that can be used by BioUML workbench to find interactiong components of the system.
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BioUML database modulesBioUML standard module
Databases• EBI databases: Ensembl, UniProt, ChEBI, GeneOntology• Biopath/BMOND (http://biopath.biouml.org)• KEGG/Ligand (http://www.kegg.com)• TRANSPATH (http://www.biobase.de) • GeneNet (http://wwwmgs.bionet.nsc.ru)
Formats• SBML – Systems Biology Markup Language, level 1, 2
(http:// www.sbml.org)• CellML – Cell Markup Language (http://www.cellml.org)• BioPax – Biological Pathways Exchange (http://www.biopax.org)• PSI-MI• OBO• GXL - Graph eXchange Language (http://www.gupro.de/GXL)
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KEGG pathway
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CellML model
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SBML model
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Full text search
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User interface for full text search: 1) pop-up menu; 2) menu buttons for selected entity; 3) full text search pane.
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Full text search (uses Lucene engine)
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Graph search
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Graph search engine
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Simulation engine
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Biological databases
Data search and retrieving
Visual modeling
Automated code generation for model simulation of model behavior
Formal description of structure of biological system
MATLAB code Java code
Simulating using MATLAB.JMatLink allows to BioUML
workbench to start MATLAB and retrieve simulations results
Java simulation plug-in.Contains ODE solvers ported from odeToJava and methods
for hybrid models support.
… code
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%script for 'CellCycle_1991Gol' model simulation
%constants declarationglobal Reaction1_vi Reaction2_kd Reaction4_K1 Reaction4_Kc Reaction4_VM1 Reaction5_K3
Reaction5_VM3 Reaction6_K2 Reaction6_V2 Reaction7_K4 Reaction7_V4Reaction1_vi = 0.023Reaction2_kd = 0.00333Reaction4_K1 = 0.1Reaction4_Kc = 0.3Reaction4_VM1 = 0.5Reaction5_K3 = 0.1Reaction5_VM3 = 0.2Reaction6_K2 = 0.1Reaction6_V2 = 0.167Reaction7_K4 = 0.1Reaction7_V4 = 0.1
%Model rate variables and their initial valuesy = []y(1) = 0.0 % y(1) - $cytoplasm.Cy(2) = 0.0 % y(2) - $cytoplasm.EmptySety(3) = 0.0 % y(3) - $cytoplasm.My(4) = 0.0 % y(4) - $cytoplasm.X
%numeric equation solving[t,y] = ode23('CellCycle_1991Gol_dy',[0 100],y)
%plot the solver outputplot(t,y(:,1),'-',t,y(:,2),'-',t,y(:,3),'-',t,y(:,4),'-')title ('Solving Goldbeter problem')ylabel ('y(t)')xlabel ('x(t)')legend('$cytoplasm.C','$cytoplasm.EmptySet','$cytoplasm.M','$cytoplasm.X');
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Function to calculate dy/dt for the model
function dy = CellCycle_1991Gol_dy(t, y)% Calculates dy/dt for 'CellCycle_1991Gol' model.
%constants declarationglobal Reaction1_vi Reaction2_kd Reaction4_K1 Reaction4_Kc Reaction4_VM1 Reaction5_K3
Reaction5_VM3 Reaction6_K2 Reaction6_V2 Reaction7_K4 Reaction7_V4
% write rules to calculate some eqution parametersrateOfReaction1 = Reaction1_vi;rateOfReaction4 = ((1 - y(3))*Reaction4_VM1*y(1))/((1 + Reaction4_K1 -
y(3))*(Reaction4_Kc + y(1)));rateOfReaction5 = (Reaction5_VM3*(1 - y(4))*y(3))/(1 + Reaction5_K3 - y(4));rateOfReaction6 = (y(3)*Reaction6_V2)/(Reaction6_K2 + y(3));rateOfReaction7 = (Reaction7_V4*y(4))/(Reaction7_K4 + y(4));rateOfReaction2 = y(1)*Reaction2_kd;
% calculates dy/dt for 'CellCycle-1991Gol.xml' modeldy = [ + rateOfReaction1 - rateOfReaction2 - rateOfReaction1 - rateOfReaction4 - rateOfReaction5 + rateOfReaction6 +
rateOfReaction7 + rateOfReaction2 + rateOfReaction4 - rateOfReaction6 + rateOfReaction5 - rateOfReaction7]
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Results of SBML semantic tests
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BioModels – comparison BioUML simulation
results with other simulators
http://www.biouml.org/_biomodels/
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Simulators comparison criteriaPassed – CSV file was generated by simulator
interval criteria no difference - 0.999 * min < x < 1.001 * max or x < ZERO and max < ZERO small difference – 0.5 * min < x < 1.5 * max significant difference - otherwise
median criteria no difference - abs((x – median)/median) < 0.01 or x < ZERO and median < ZERO small difference - abs((x – median)/median) < 0.5 significant difference – otherwise
x – variable value provided by compared simulatormin, max, median – calculated from values provided by other simulators with
which the specified simulator is being compared.
Implementation note: if result file was not generated by BioUML, then other simulators can be compared one to each other.
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BioUML Enterprise Edition:BioUML server
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BioUML workbench
Servlet container: Tomcat
BioUML EE architecture
MySQL database
Web browser
JDBC
BeanExplorerEnterprise Edition
Client side:
Server side:
Database module
BioUML servlet
JDBC DB module
Lucene full textsearch engine
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BMOND Biological MOdels aNd Diagrams
database
(former name – Biopath)
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BioUML workbench
Servlet container: Tomcat
BMOND system architecture
BiopathMySQL database
Web browser
JDBC
BeanExplorerEnterprise Edition
Client side:
Server side:
Biopath module
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Figure 4. G1/S entry model (Kel et al., 2000) described using BioUML technology.
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BMOND web interfacelive demonstration
http://bmond.biouml.org
- Interface overview- View diagrams- View diagram components- List of diagram components- Categories (classification)- Filter- Dynamic columns- Web forms for components editing
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Part 2
New concepts and possibilities
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Part 2: new concepts and possibilities
Overview• Reconstruction as
solitaire game• Levels of biological
information• BioHub concept• Composite database
module• Composite diagram• Experiment concept• Graphic notation editor• Microarray data analysis
Live demonstration•Loading database modules from server•Text search•Graph search•Creating of composite database module•Creating of composite diagram•Experiment•Graphic notation editor•Microarray data analysis
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Metaphor: biological systems reconstruction as solitaire (patience) game
Desk – BioUML editor
Solitaire – biological pathway
Cards – biological objects(genes, proteins, lipids, etc.)
Pack of cards – different biological databases
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UniProtEnsembl ChEBI GOLevel 1: Catalogs
Level 2: Pathways,models
GeneModels
Biological objects
Levels of biological information
refers
Level 3: Problem specific
Cyclonet- leads- actions- targets
refers refers
LipidNetclassifications:- lipids- genes
refers
UbiProtclassifications:E1, E2, E3, …
Main idea for data integration and pathway reconstruction: - escape information duplication- classify components of biological pathways by levels- each next level should refer but do not duplicate information from previous levels- use free EBI databases whenever it is possible.
BMOND
refers
wiki
wiki
wiki
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Add-on technologyThis approach should help us to solve difficulties with usage of external catalogs when external catalog does not contain needed entity (for example gene or substance) or when we would like to add some information to existing entity description. Example for BMOND2, gene: special table allow us to add new entity to BMOND2 if such entity missing in corresponding external catalog.
Gene catalogEnsembl
Geneadd-on table
Synonyms
Description
DB references
Literature references
Classification
SQL query
BioUML
BeanExplorerWeb interface
Java object
Lucene
Document
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BioHub
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BioHub concept• BioHUB – an approach link information from different databases.
Main usage:– binding microarray (omics) data to pathway diagrams– graph search– DBReferences editor– microarray (omics) data analysis
• Follows to MIRIAM standard:– References to database objects– Relationships between biological objects
• Simple Java API
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BioHub structure Entities- DB_ID- version- ID- AC- species- description- key words
Relations- DB_ID_1- DB_version_1- ID_1- DB_ID_2- DB_version_2- ID_2- relation- evidence- comment
Databases- DB_ID- name- description- URL- url_patern_ID- url_patern_AC
RelationTypes- relation- description- backwardRelation- comment
RelationInfo- DB_ID_1- DB_ID_2- relation- comment
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UniProtEnsembl ChEBI GOLevel 1: Catalogs
Level 2: Pathways,models
GeneModels
Biological objects
Linking with experimental data and results of analysis
refers
Level 3: Problem specific
BMOND
refers
Experimental data,results of analysis
BioHUB
OMICS data
Results of analysis
MSigDB GeneAtlas,NCI60
Cyclonet- leads- actions- targets
refers refers
LipidNetclassifications:- lipids- genes
refers
UbiProtclassifications:E1, E2, E3, …
wiki
wiki
wiki
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UniProtEnsembl ChEBI GOLevel 1: Catalogs
Level 2: Pathways,models
GeneModels
Biological objects
Linking with external databases
refers
Level 3: Problem specific
BMOND
refers
Experimental data,results of analysis
BioHUB
OMICS data
Results of analysis
MSigDB GeneAtlas,NCI60
External databases:- KEGG- LipidMap, LipidBank- Reactome, …
Cyclonet- leads- actions- targets
refers refers
LipidNetclassifications:- lipids- genes
refers
UbiProtclassifications:E1, E2, E3, …
wiki
wiki
wiki
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Coloring diagram according to microarray data.Each bar corresponds to one value from corresponding microarray series.
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Coloring diagram according to omics data
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BioHub usage: graph search engine
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Composite database module
Flash movie: XML_module.exe
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Composite database module is defined formally as XML document. It allows:• specify dependencies from other database modules• specify data types that can be used from external database modules• describe dynamic properties for add-on technology• specify what dynamic properties can be added to data types from external modules. This information will be stored in local module and merged dynamically with information from external modules. By this way user can add information to external catalogs like Ensembl, UniPropt, etc.• specify data types used by local module• specify diagram types used by local module• specify QueryEngine
Composite database module
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DTD
<!ELEMENT dbModule (jdbcConnection, properties?, dependencies?, types?)>
<!ATTLIST dbModule > name CDATA #REQUIRED title CDATA #REQUIRED description PCDATA version CDATA "0.8.0" type CDATA text|SQL databaseType CDATA databaseVersion CDATA databaseName CDATA >
<!ELEMENT jdbcConnection><!ATTLIST jdbcConnection> name CDATA #REQUIRED jdbcDriverClass CDATA #REQUIRED jdbcURL CDATA #REQUIRED jdbcUser CDATA jdbcPassword CDATA>
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<!-- ================================================================ --><!-- Properties - definition of properties for all types of diagram --><!-- elements used by the graphic notation. --><!-- --><!-- Possible property types: --><!-- - simple types: boolean, int, double, String --><!-- - array --><!-- - composite --><!-- ================================================================ --><!ELEMENT properties (property*)><!ELEMENT property (tags?)><!ATTLIST property name CDATA #REQUIRED type CDATA #REQUIRED short-description CDATA #IMPLIED value CDATA ><!ELEMENT tags (tag+)><!ELEMENT tag><!ATTLIST tag name CDATA #REQUIRED value CDATA #IMPLIED ><!ELEMENT propertyRef><!ATTLIST propertyRef name CDATA #REQUIRED value CDATA >
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<!-- ================================================================--><!-- Dependencies from other databases and modules --><!-- Graphic notations can be defined in the specialized module --><!-- =============================================================== -->
<!ELEMENT dependencies (dbModule*, graphicNotation*)><!ELEMENT dbModule (externalType+)><!ATTLIST dbModule> name CDATA #REQUIRED ><!ELEMENT externalType (propertyRef*)><!ATTLIST externalType name CDATA #REQUIRED readOnly CDATA true|false ><!ELEMENT graphicNotation><!ATTLIST graphicNotation> name CDATA #REQUIRED type CDATA Java|XML class CDATA path CDATA>
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<!-- ================================================================ --><!-- Internal data types for this module --><!-- Description of internal type should provide all information to --><!-- create corresponding DataCollection --><!-- ================================================================ -->
<!ELEMENT types (internalType*)><!ELEMENT internalType (querySystem, propertyRef*)><!ATTLIST internalType> section CDATA #REQUIRED name CDATA #REQUIRED class CDATA #REQUIRED transformer CDATA #REQUIRED ><!ELEMENT querySystem (index*)><!ATTLIST querySystem> class CDATA #REQUIRED luceneIndexes CDATA><!ELEMENT index><!ATTLIST index> class CDATA #REQUIRED table CDATA>
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Editor for composite database module
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Editor for composite database module
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Editor for composite database module
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Editor for composite database module
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Current status:Implemented:• Database modules (initial version):
Ensembl, UniProt, ChEBI, GO,IntAct, Reactome, BioModels
• Composite module (external referencies)– Defined as XML– Composite module editor
• Selecting and loading modules from server
In process:• BioHUB• Protein state concept• Add-on technology• BMOND2 – redesigned version of BMOND.
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From huge theory to practical output
Automated language translation
Practical output• electronic dictionaries• spell checkers
Biological data
integrations
Practical output• catalogs (Ensembl, UniProt, CheBI)• controlled vocabularies, ontologies• hubs
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Model composition
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Composite diagram: main conceptsblock (EModel)dx/dt = f1dy/dt = f2z = f3
block 2 (EModel)dx/dt = f5dy/dt = f6 + z k+z+f4 = 0
x x
y y
subdiagram (EModel)
Rs1 s2
e
x
e
block 3 (EModel)dx/dt = f5 dy/dt = f6 + block2.k k+z+f4 = 0
Indirect linkx
xforbidden
Rs2 s3
s1
s1
f(x)
s4direct participation of subdiagram elementin a reaction
Block types:1) block – only mathematical equations. Used mainly for physiological models;2) subdiagram – other diagram
Connection types:1) directed – input output. Transformation function can be used;2) undirected – contact. Indicates that 2 nodes in mode is the same entity.
Semantic constraints:There are semantic constraints, for example: block can have only one input for each variable. Two inputs are forbidden for the same variable.
Flat model:Before Matlab or Java code generation composite model is transformed into flat model and usual genertions routines are used.
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Experiment
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Experiment
To make a virtual experiment it is frequently needed to modify initial model.
Typical modifications (changes) are:• changing of initial values• changing of model parameters to imitate different conditions or mutations• deleting of some model elements to imitate knock-out mutations• adding events to imitate external influences on the model
To skip model duplications for each virtual experiment we introduce “changes” concept.
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Graphic notation
formal definition as XML document
http://www.biouml.org/sbgn.shtmlFlash movie: Graphic_Notations_Editor.exe
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Graphic notation versus graph layout
• allows edit diagram• allows to create new diagram• different graphic notations can be applied
to the same SBML model• allows formally define SBGN and use it in
SBML models• allows to reuse graphic notation by many
tools
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Graphic notation can be defined formally as XML document• properties – formal definition of properties that can be used as properties of nodes and
edges (for example, title, multimer, etc.). Definition of property includes:– name– type– short description– controlled vocabulary (optional)
• node types – definition of node includes:– name– icon – properties– view function (JavaScript)– short description
• edge types – definition of edge includes:– name– icon – properties– view function (JavaScript)– short description
• semantic controller – defines rules for semantic control of diagram integrity. For this purpose it defines following functions:
– canAccept (JavaScript)– isResizable (JavaScript)– move (JavaScript)
• Examples – a set of diagrams that can be used as test cases, legend and examples for the graphic notation. DML - Diagram Markup Language – is used for this purpose.
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SBML …
Diagram
Model API
BioPAX Layoutinformation
Graphic notation
Layout APINotation API
Rendering engine JavaScript functions:
- build node/edge view
- semantic control
Initial data
JavaScriptAPI for
data access
Rendering APIJavaScript API for creating primitives
similar with SBML layout extension
Basic software architecture for rendering of biological models according to specified graphic notation and layout information
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Formal definition of graphic notation as XML document and integration with SBML format
Graphic notation components
Defined as SBML
Object types XML <annotations> Object properties XML <annotations> User defined properties XML <annotations> Rules for visualization JavaScript Rules for semantic control JavaScript Test cases XML model, module
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Graphic notation editormain concepts
• graphic notation is defined formally as XML document• graphic notation editor provides user friendly interface for
XML document editing• SBGN graphic notation (prototype) is implemented• BioUML workbench allows to create and edit diagrams
using graphic notation defined as XML document• May be graphic editor will be useful for SBGN
community for:– improving SBGN specification– for testing SBGN specification by creating different diagrams
Details: http://www.biouml.org/sbgn.shtml
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BioUML workbech
Select ‘Data’ tab to see the tab with a listwith available graphic notations
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Click right mouse button onselected graphic notation to open it Graphic Notation Editor
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Graphic Notation Editor
Main sections of formal definitionof graphic notation
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List of specific propertiesthat are used by graphic notation
Properties editor
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User can click right mouse button on Properties node to create new property
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Nodes – contains list of all node typesused by graphic notation
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For each node type user can define:- name- properties- icon- view function (JavaScript)
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By clicking right mouse button on “Nodes”user can create new node type
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By the same way user can define edge type:- name- properties- icon- view function (JavaScript)
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“Examples” nodecontains a set of diagrams that demonstrates usage of graphic notation.
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User can create and edit such diagram.
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When user selects some element on the diagram he can edit:- object properties- JavaScript that builds a view for selected diagram element
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“Semantic controller” nodecontains list of JavaScript functions that provide semantic constraints and semantic integrity of the diagram.
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Graphic notation defined as XML document can be used by BioUML workbench to create corresponding diagram.
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Graphic Notation Editor
SBGN examplescreated in BioUML
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Skins
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Microarray plug-in(alpha version)
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Microarray plug-in- Import microarray data in tab delimited format- Show data as a table- Filter data by different criteria- Microarray data analysis
- Revealing up/down regulated genes- Meta-analyses
- Binding with diagram nodes by ID- Coloring diagrams- JavaScript functions
- Data manipulation (filter, join, intersect, trim, etc.)- Statistical analysis
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Microarray plug-inCurrent work:- Powerful user interface for coloring diagrams- Support of other formats for microarray data and results
of analyses- Sophisticated binding algorithm using different database
references and ID (gene hub)
Further work:- Server module that will provide access to ArrayExpress
data
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BioUML workbench.
Data tab contains section “Microarray”.User can import microarray data in tab delimited format into this section.
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Possibility to filter probe sets:- by column values - selecting only those probe sets that can be linked to the specified diagram
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Microarray analysis
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Coloring diagram according to microarray data.Each bar corresponds to one value from corresponding microarray series.
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Coloring diagram according to omics data
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Further development:
Protein state
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BioUML workbench: further development• Protein states• Complexes
• Improving team work on annotation– Login, single sign on– Editing history (what data were modified, whom and when)– Passing of changes from server to client
• Sequence analysis and visualization
• Agent based modeling
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Protein state
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Modification• The functions of macromolecular entities (mainly proteins)
are often determined not only by their primary sequences, but by chemical modifications they have undergone.
• In BMOND2 unmodified and modified forms of a protein refer to the same entity in UniProt database
• List of possible modifications is extracted from UniProt Feature Table
• BMOND2 modifications table– allows to describe modifications that are not described in UniProt.
These modifications are automatically added to the protein, referred from BMOND2.
• Modification type – control vocabulary that describes possible modification types (for example, phosphorylation, acetylation, ubiqutination)
• To take into account protein modifications State concept is used.
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UniProt Feature Table•FT CHAIN 1 561 Cytosolic purine 5'-nucleotidase.•FT /FTId=PRO_0000064389.•FT REGION 202 210 Substrate binding (Potential).•FT COMPBIAS 549 561 Asp/Glu-rich (acidic).•FT ACT_SITE 52 52 Nucleophile.•FT ACT_SITE 54 54 Proton donor.•FT METAL 52 52 Magnesium.•FT METAL 54 54 Magnesium (via carbonyl oxygen).•FT METAL 351 351 Magnesium.•FT BINDING 127 127 Allosteric activator 1.•FT BINDING 154 154 Allosteric activator 2.•FT BINDING 354 354 Allosteric activator 2.•FT BINDING 436 436 Allosteric activator 1; via carbonyl•FT oxygen.•FT BINDING 453 453 Allosteric activator 2.•FT MOD_RES 527 527 Phosphoserine (By similarity).•FT VARIANT 3 3 T -> A (in dbSNP:rs10883841).•FT /FTId=VAR_024244.•FT VARIANT 136 136 Q -> R (in dbSNP:rs12262171).•FT /FTId=VAR_030242.
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Modification
• position
• amynoacid
• modification type (controlled vocabulary)
• evidenceexperimental, by similarity, predicted
• comment
• Publication reference
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State concept• State – describes states of all amino acids available for
modifications• possible values:
– ? – unknown, not specified– * – any– - – unmodified– p – phoshporylated– ac – acetylated– … – from controlled vocabulary
• Protein states are described in BMOND2 states table• Reaction – user should specify protein state• Diagram – user should specify protein state
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State table
• module (database)
• id
• state – short name (like TRANSPATH)
• position
• modification
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SBGN
Mapping: BMOND2 -- SBGNmodification – state variablestate – state of macromolecule
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Complex concept
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Complex concept
• A complex is s a biochemical entity composed of other biochemical entities, whether macromolecules, small molecules, multimers, or themselves complexes.
• Complex is specified as a set of units• Complex modifications
– all possible modifications of its units (some of them can not occur due to physical interactions between units – how we can take it into account)
• Complex state– var.1 – list of modifications for its subunits– var. 2 – list of states for its units
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Complex tables• Complex
– ID– title (short name)– complete name– species– synonyms– comment
• References:– States– Synonyms– Structure– DBReferences– Publications
• Complex Units– complexDB– complexID– unitDB– unitID– multimer
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SBGN
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Reaction• Reaction components
– component identification• DB• id• [state]• [compartment]
• Reaction– [compartment]
• Reaction dialog– specie state– specie compartment– reaction compartment
• Tables– Reaction
• compartment– Reaction
components• state• compartment
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Diagrams
• Macromolecule state– “New diagram element” dialog
• Graphic notation– BioUML
• states – right label, one modification• complexes
– SBGN skin
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AcknowledgementsPart of this work was partially supported by following grants: • European Committee grant №037590 “Net2Drug”• Siberian Branch of Russian Academy of Sciences
(interdisciplinary projects № 46)• Volkswagen-Stiftung (I/75941), • INTAS Nr. 03-51-5218• RFBR Nr. 04-04-49826-а
Author is grateful to for useful comments, discussions and technical support
Alexander Kel Sergey Zhatchenko
Software developers Annotators Nikita Tolstyh Mikhail Puzanov Ruslan Sharipov Sergey Lapukhov Ilya Kiselev Ivan YevshinAlexander Magdysyuk Denis Ryumin Elena CheremushkinaVlad Zhvaleev Alexandr Koshukov Ekaterina Kalashnikova Vasiliy Hudyakov Igor Tyazhev Sergey Graschenko Oleg Onegov