Overview of Biochemical Pathways

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Overview of Biochemical Pathways
Academia Sinica Taiwan International Graduate
Program

• Chun-nan Chi
• Ph.D. Student of TIGP
• Academia Sinica
• cnchi_at_iis.sinica.edu.tw

2
Outlines

• Biological Backgrounds
• Study Fields in Biochemical Pathways
• Competitors
• Trends of Pathway Research
• Reference
• Q A

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Biological Backgrounds

• What is Biochemical Pathways
• Types of Biochemical Pathways
• How Pathways work Together
• Why Pathway Studies is Important

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What is Biochemical Pathways

• A map of the biological mechanism of an organism

Fig 1. Metabolic Pathways ExPASy,
http//www.expasy.org/cgi-bin/show_thumbnails.pl,
founded by Roche Applied Science.
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Types of Biochemical Pathways
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How Pathways work Together
Signal Transduction
1 Glucoses 2 ATP
Metabolism
4 ATP 2 Pyruvate 2 NADH
Regulation
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Why Pathway Studies is Important
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Study Fields in Biochemical Pathways

• Overviews of Pathway Studies
• Literature Mining
• Pathway Diagrams
• Graphical Modelers
• Pathway Databases
• Pathway Representation
• Management Tools for Pathway
• Database Integration
• Standard for Exchanging Pathways
• Pathway Querying Reasoning
• Simulation

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Overviews of Pathway Studies
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Literature Mining
ACTIVATOR activate ACTIVATEE

• RAF6 activates NF-kappaB.
• Lck is activated by autophosphorylation at Tyr
  394.
• Anandamide induces vasodilation by activating
  vanilloid receptors.
• the activation of Rap1 by C3G
• the GTPase-activating protein rhoGAP
• the stress-activated group of MAP kinases

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Literature Mining

• Current Methodologies

Text Mining
Alexander S. Yeh et al. (2003) Evaluation of
text data mining for database curation
lessons learned from the KDD Challenge
Cup Bioinformatics, Vol. 19 Suppl. 1 2003, pages
i331i339
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Literature Mining

• For more details

Very Good Seminar You shouldnt miss!
Title Literature mining for biomedical
text Speaker Dr. Ting-Yi Sung Date 2004/11/08
Monday 1030 AM 1200 PM Location Auditorium
106 at new IIS Building
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Pathway Diagrams

• Static Images of Pathways (Primary)
• BBID 2001 (Biological Biochemical Image
  Database)
• The search engine finding the figures on many
  textbooks or journals
• BPC 2001 (Biochemical Pathway Chart)
• A poster-liked handmade static image that
  describes the metabolic pathways and cellular /
  molecular processes.
• BioCarta 2001
• A database that store the pathway information
  with static image format. Can be browsed by
  categories and searched by keywords. Hosted by a
  commercial company.
• KEGG 2001 (Kyoto Encyclopedia of Genes and
  Genomes)
• It is a very famous database that specially
  focuses on storing metabolic pathways
  information. All proteins are categorized in
  their functions by EC (Enzyme Classification)
  Number system.
• BRIDE 2001 (Biomolecular Relations in
  Information Transmission Expression)
• It is a binary relation search engine based on
  KEGG database. It can search the binary
  interaction between genes, proteins, or other
  biological molecules.

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Pathway Diagrams

• Static Images of Pathways (Minor)
• SPAD 2001 (Signal PAthway Database)
• It is a database for genetic information and
  signal transduction pathways. The site is
  unfinished and seems to stop the construction.
• KMIM 1999 (Kohn Molecular Interaction Map)
• It is an interaction map for representing the
  network of multi-protein complexes, protein
  modifications, and enzymes for reactions.

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Pathway Diagrams

• Dynamic Images of Pathways
• BioCyc 2002
• This is a database that contains metabolic
  pathway information for 17 species. It presents
  a pathway chart dynamically.
• STKE (Signal Transduction Knowledge Environment)
• This is the site hosted by Science Magazine. It
  collects pathways related to signal transduction
  and is searchable by keywords.

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Pathway Diagrams

• Important Papers

Ogata 1998 Computation with the KEGG pathway
database Ogata H, Goto S, Fujibuchi W, Kanehisa
M.Computation with the KEGG pathway
databaseBiosystems. 1998 Jun-Jul47(1-2)119-28.
http//igs-server.cnrs-mrs.fr/ogata/Paper/ogata98
BioSys.html
Karp 2000 The EcoCyc and MetaCyc
databases Peter D. Karp, Monica Riley, Milton
Saier, Ian T. Paulsen, Suzanne M. Paley, Alida
Pellegrini-Toole"The EcoCyc and MetaCyc
databases"Nucleic Acids Research, Vol. 28, No.
1, pp. 56-59http//nar.oupjournals.org/cgi/reprin
t/28/1/56
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Pathway Diagrams

• Important Sites for Pathway Diagrams

Metabolic Pathways
Signal Transduction Pathways
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Graphical Modelers

• What is the Graphical Modeler?

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Graphical Modelers

• Some Graphical Modelers

CellDesigner
BioUML
JDesigner
PathwayBuilder
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Graphical Modelers

• Output Format for those Graphical Modelers

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Graphical Modelers

• Do we solve the problems for modeling pathways?

Problem 1

• No graphical modelers can represent different
  knowledge granularities of pathways.
• No graphical modelers can represent the
  incomplete knowledge of pathways.

Solution 1

• Use Compound Graph Fukuda 2001
• Use recursive representation of pathways
  Demir 2002

Fig 2. TGF-ß / Smad Signal Transduction
Pathway Fukuda et al. (2001) Knowledge
Representation of Signal Transduction Pathways.
Bioinformatics, Vol. 17 no.9, 829-837
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Graphical Modelers

• Do we solve the problems for modeling pathways?

Problem 2

• No way to annotate the metadata of a pathway
  for the following information - Species -
  Tissues or Cell Type - Environmental Condition
  (pH, Tempetc.) - Developmental Stage of
  Organism

Fig 3. AKT Signaling Pathway Biocarta,
http//www.biocarta.com/pathfiles/h_aktPathway.asp

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Graphical Modelers

• Do we solve the problems for modeling pathways?

Problem 3

• Hard to represent the following architectures
  of pathways - Pre-conditions Post-conditions
  (Especially for Signal Transduction Pathways
  - Concurrency

Solution 3

• Petri Net could be a good solution - BioPNML
  (Bio Petri Net Markup Language) - Chen 2003
  Quantitative Petri Net model - Matsuno 2000
  Hybrid Petri Net - Hofestädt 1998
  Quantitative Modeling

Fig 3. An Example of Petri Net Hubert Becker
(2001) Logistik - Ein Überblick (Logistics An
Overview) http//home.t-online.de/home/becker2/pet
rinet.gif
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Graphical Modelers

• Do we solve the problems for modeling pathways?

Problem 4

• No tool has a good representation for modeling
  sequence information including - DNA Sequence
  - RNA Sequence - Protein Sequence

Not Yet!!
Fig 4. DNA Double Strand Structure Ian Stansfield
(2001) Web resources for sequence
analysis http//www.abdn.ac.uk/mbi094/dna.gif
Do we solve the modeling problems?
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Graphical Modelers

• What we need to solve the modeling problems?

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Pathway Databases

• Most famous metabolic pathway databases

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Pathway Databases

• Other metabolic pathway databases

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Pathway Databases

• Some signaling transduction pathway databases

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Pathway Databases

• Some gene regulatory network databases

DBTBS
SPAD
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Pathway Representation

• Can we create a model to represent all the
  situations of pathways?

?
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Pathway Representation

• What is a good representation model for pathways?

• Attributes - List of reactions - Synonyms,
  Species
• Characteristics - Concurrence - Cyclic -
  Incomplete

• Types Reactants, Products, Catalysts,
  Inhibitors, Sequences
• Attributes Synonyms, Location, Concentration,
  other Substrates

Pathway
Substrate

• Types Synthesis, Degrade, Transport,
  Denatured, Transform, Decomposition
• Attributes - List of reactants, products,
  modifiers - Conditions before / after the
  reaction - Kinetic Functions (Forward /
  Backward) - Synonyms

• Types Nucleus, Cytosol, Inner membrane, cell,
  organ, body
• Attribute Synonyms, Temperature, Size, Local
  Time
• Characteristics - Pass-thru (e.g.
  trans-membrane)

Reaction
Compartment
Event
Function
Timer
All have the Class-Instance concept
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Pathway Representation

• The important papers for pathway modeling

• Fukuda 2001
• Compound Graph

• Demir 2002
• Incomplete Pathways

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Pathway Representation

• How to implement the pathway model?

Relational Database is not enough! We need
stronger relations between entities.
Use Ontology instead!!
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Pathway Representation

• What is Ontology?
• A set of vocabularies and their relationships

Mary
Mary ate an apple
apple
eat
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Pathway Representation

• The Compound Graph Fukuda 2001
• Compound Graph CG (G, T)
• G Interaction Graph
• T Decomposition Tree
• Interaction Graph G (V, EG)
• V Vertex that represent concepts of knowledge
• EG Edge in Interaction Graph
• Decomposition Tree T (V, ET, r)
• V Vertex that represent concepts of knowledge
• EG Edge in Interaction Graph
• r The root node of the decomposition tree T

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Pathway Representation

• The Compound Graph Fukuda 2001

Petri Net

Decomposition Tree
Interaction Graph
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Management Tools for Pathway

• The well-known Ontology editor

• Protégé 2000
• It is a tool which allows user to construct a
  domain ontology
• It can import the existing ontology with RDFS,
  OWL, or CLIP format.
• It provides a set of API for developers to
  create their own plug-ins
• It was developed by SRI (Stanford Research
  Institute)

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Management Tools for Pathway

• The screenshot of Protégé 2000

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Database Integration

• Current public databases related to pathways

Gene Database
Metabolic Pathways
Signaling Pathways
Regulatory Pathways
Transcription Factors Database
Disease Database
Microarray Database
Protein- Protein Interaction
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Database Integration

• What database we are going to integrate?

Gene Symbols
Enzymes
Enzymes
DNA Transcription Factors
Transcription Splicing
Translation Protein Info
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Database Integration

• Interesting Problem 1
• Predict new pathways according the genome
  databases

• Paley 2002
• PathoLogic
• Predict new pathways from a genome database
  based on the known model pathway database

• Yamanishi 2004
• Predict new pathways from 4 different genomic
  databases

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Database Integration

• Interesting Problem 2
• Find the sequence of pathways based on Microarray
  database in terms of time

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Standard for Exchanging Pathways

• Too many specific file formats to exchange the
  knowledge of pathways

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Standard for Exchanging Pathways

• Current famous formats for pathway

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Standard for Exchanging Pathways

• What is SBML

System Biology Markup Language
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Standard for Exchanging Pathways

• The main structure for SBML

lt?xml version"1.0" encoding"UTF-8"?gt ltsbml
xmlns"http//www.sbml.org/sbml/level2" level"2"
version"1"gt ltmodelgt lt/listOfParametersgt
lt/listOfParametersgt ltlistOfUnitDefinitionsgt
lt/listOfUnitDefinitionsgt ltlistOfCompartmentsgt
lt/listOfCompartmentsgt ltlistOfSpeciesgt
lt/listOfSpeciesgt ltlistOfReactionsgt
lt/listOfReactionsgt ltlistOfFunctionDefinitionsgt
lt/listOfFunctionDefinitionsgt
lt/listOfRulesgt lt/listOfRulesgt
ltlistOfEventsgt lt/listOfEventsgt lt/modelgt
lt/sbmlgt

• Variables
• Units
• Compartments
• Substances
• Reactions
• Functions
• Rules
• Triggers

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Standard for Exchanging Pathways

• Who is in SBML Project?

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Standard for Exchanging Pathways

• Advantages of SBML
• Good for quantitative analysis
• Good for simulation
• Disadvantages of SBML
• Can not represent the following relationships
  between reactions (Which is bad for representing
  pathways)
• Sequential Relationships
• Conditional Branch
• Iterative Relationships

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Standard for Exchanging Pathways

• How many tools support SBML?

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Standard for Exchanging Pathways

• What is BioPAX

Biological Pathways Exchange
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Standard for Exchanging Pathways

• Application of BioPAX

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Standard for Exchanging Pathways

• The Classes Hierarchy of BioPAX

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Standard for Exchanging Pathways

• Who is in BioPAX Project?

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Standard for Exchanging Pathways

• Advantages of BioPAX
• Good for pathways knowledge management
• Good for qualitative inference
• Disadvantages of BioPAX
• Only support metabolic pathways
• No quantitative information can be stored in
  BioPAX

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Standard for Exchanging Pathways

• How many tools can support BioPAX
• Protégé 2000 with the OWL Plug-in

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Standard for Exchanging Pathways

• Roadmap of BioPAX

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Pathway Querying Reasoning

• Basic Queries

Protein Name
Protein Sequence
Neighborhood Navigation
Route Suggestion
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Pathway Querying Reasoning

• Some reasoning examples

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Pathway Querying Reasoning

• Other reasoning idea 1 Find all crosstalk
  pathways in a specific cell type
• Given a set of genes, tell me all the pathways
  that will influence these genes including
  following information
• Species
• Cell line / Cell type
• From what tissue?
• From what age of the organism?
• Treatment
• Reacting period
• All crosstalk pathways of the candidate pathways

Literature Mining
Time-course Microarray Data
Computational Method
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Pathway Querying Reasoning

• Other reasoning idea 2 Pathway Construction
  Helper

Pathway Database
A ? C
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Simulation

• Why simulation?

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Simulation

• Previous works in Simulation
• Simulate the Kinetics of Biochemical Metabolic
  Pathway
• METAMODEL (Cornish-Bowden and Hofmeyr, 1991)
• Contain up to 20 reactions (enzyme) and up to 30
  metabolites as well as its concentration
• SCAMP (Sauro, 1993)
• A general purpose simulator of metabolic and
  chemical networks
• GEPASI (Mendes, 1993, 1997)
• Simulate the kinetics of biochemical reactions
• KINSIM (Barshop et al., 1993 Dang Frieden,
  1997)
• Good tool to simulate the Kinetics of
  biochemistry
• MIST (Ehlde Zacchi, 1995)
• A software package which can be used for dynamic
  simulations, stoichiometric calculations and
  control analysis of metabolic pathways

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Simulation

• Previous works in Simulation
• Simulate Gene Regulation Expression
• Meyers and Friedland, "Knowledge-based simulation
  of genetic regulation in bacteriophage lambda",
  Nucleic Acids Research, January 1984
• K. Koile and GC Overton. "A qualitative model for
  gene expression." In Proceedings of the 1989
  Summer. Computer Simulation Conference, pages
  415-421, 1989
• Peter D. Karp(1993), "A Qualitative Biochemistry
  and Its Application to the Regulation of the
  Tryptophan Operon"
• Arita, M., Hagiya, M. and Shiratori, T. (1994),
  "GEISHA SYSTEM an environment for simulating
  protein interaction"
• McAdams and Shapiro (1995), "Circuit Simulation
  of Genetic Networks", Science, 269, 650-656

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Simulation

• Previous works in Simulation
• Simulate Cell Division Cycle
• Tyson,J.J. (1991), "Modeling the cell division
  cycle cdc2 and cyclin interactions"
• Novak,B. and Tyson,J.J. (1995), "Quantitative
  analysis of a molecular model of mitotic control
  in fission yeast
• Simulate Signal Transduction Mechanisms
• Bray D, Bourret R B, Simon M I. Computer
  Simulation of the Phosphorylation Cascade
  Controlling Bacterial Chemotaxis., Molecular
  Biology of the Cell. VOL.4, PAGE.469-482 (1993)

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Simulation

• Previous works in Simulation
• The whole cell simulation

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Competitors

• Peter Karp (USA)
• Minoru Kanehisa (Japan)

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Peter Karp (USA)
Peter D. Karp Director Bioinformatics Research
Group Artificial Intelligence Center Stanford
Research Institute
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Minoru Kanehisa (Japan)
Minoru Kanehisa (?? ?) Director Bioinformatics
Center Institute for Chemical ResearchKyoto
University
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Trends of Pathway Research

• DB Represent.
• Integration
• Exchange

• Text mining
• Graphical Modeler

Pathway Database
Annotation
Data Acquisition
Mechanism Understanding
Function Prediction
Re-annotation
DB Management

• Mngmt. Tools
• Inference

Ouzounis CA, Karp PD. (2002) The past, present
and future of genome-wide re-annotation. Genome
Biol. 20023(2)COMMENT2001. Epub 2002 Jan 31.
70
Reference

• Alexander S. Yeh et al. (2003) "Evaluation of
  text data mining for database curation lessons
  learned from the KDD Challenge Cup"
  Bioinformatics, Vol. 19 Suppl. 1 2003, pages
  i331i339
• Ogata H, Goto S, Fujibuchi W, Kanehisa
  M."Computation with the KEGG pathway
  database."Biosystems. 1998 Jun-Jul47(1-2)119-28
  .
• Peter D. Karp, Monica Riley, Milton Saier, Ian T.
  Paulsen, Suzanne M. Paley, Alida
  Pellegrini-Toole"The EcoCyc and MetaCyc
  databases"Nucleic Acids Research, Vol. 28, No.
  1, pp. 56-59
• Ken-ichiro Fukuda and Toshihisa Takagi,
  "Knowledge representation of signal transduction
  pathways." Bioinformatics, Vol 17, No. 9, 2001
• E. Demir, O. Babur, U. Dogrusoz, A. Gursoy, G.
  Nisanci, R. Cetin-Atalay, M. Ozturk, "PATIKA an
  integrated visual environment for collaborative
  constrcution and analysis of cellular pathways."
  Bioinformatics, Vol. 18 no. 7 2002, Pages
  996-1003
• Natalya Fridman Noy, Ray W. Fergerson, Mark A.
  Musen, "The Knowledge Model of Protege 2000
  combining interoperatability and flexibility."
  2th International Conference on Knowledge
  Engineering and Knowledge Management (EKAW'2000),
  Juan-les-Pins, France, 2000.
• Yoshihiro Yamanishi, Jean-Philippe Vert, Minoru
  Kanehisa, "Protein network inference from
  multiple genomic data a supervised approach."
  Bioinformatics, Vol. 20, Suppl. 1, 2004, pp.
  i363-i370
• Suzanne M. Paley, Peter D. Karp, "Evaluation of
  Computational Metabolic-Pathway Predictions for
  Helicobacter pylori." Bioinformatics, Vol. 18,
  no. 5, 2002, pp. 715-724
• Ouzounis CA, Karp PD. (2002) The past, present
  and future of genome-wide re-annotation. Genome
  Biol. 20023(2)COMMENT2001. Epub 2002 Jan 31.
• Tomita,M., Hashimoto,K., Shimizu,T.S.,
  Matsuzaki,Y., Miyoshi,F., Saito,K., Tanida,S.,
  Yugi,K., Venter,J.C. and Hutchison,III,C.A.
  (1999)"E-CELL software environment for
  whole-cell simulation."Bioinformatics, 15, 72-84
• Schaff,J.C. and Loew,L.M. (1999) "The virtual
  cell" In Altman,R.B., Dunker,A.K., Hunter,L. and
  Klein,T.E. (eds), Pacific Symposium on
  Biocomputing, volume 4, World Scientific,
  Singapore, pp. 228-239

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Q A