1program前付け A4版4 - Systems Biology · programs, ICSB-2006 presents the most comprehensive...
Transcript of 1program前付け A4版4 - Systems Biology · programs, ICSB-2006 presents the most comprehensive...
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ICSB-2006
The 7th International Conference on Systems BiologyOctober 8 - 13, 2006
Pacifico Yokohama, Yokohama, Japan
CONTENTSWelcome to ICSB-2006 ..............................................................................2
Committees ..............................................................................................3
Program Day 1 (October 9) .................................................................4
Day 2 (October 10) ................................................................5
Day 3 (October 11) ................................................................6
Program At-A-Glance .................................................................................9
Student Session (October 10) ..................................................................10
Session Abstracts
Plenary Talk Abstracts .........................................................................11
I Systems Biology for Medicine .......................................................13
II Systems Biology of Basic Biological Systems ...............................19
III Fronts in Systems Biology .............................................................27
Poster Session .........................................................................................34
Tutorial Program (October 8) ...................................................................48
Workshops (October 7,12,13) .................................................................49
Access ............................................................................................50
Floor Plan ............................................................................................51
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Welcome to ICSB-2006
Welcome to the Seventh International Conference on Systems Biology!
The International Conference on Systems Biology (ICSB) started in 2000 in Tokyo, and traveled around the world—Pasadena, Stockholm, St. Louis, Heidelberg, and Boston. Owing to the efforts of organizers, sponsors, and participants, the conference has grown into the main conference in the field. This year, ICSB employed parallel sessions for the first time, and invited over 65 distinguished speakers in the field reflecting the overall landscape of systems biology today. With about 400 posters, 12 tutorial sessions, and 5 workshop programs, ICSB-2006 presents the most comprehensive program to date. The program was enabled by generous support from several government agencies and sponsor companies for which we, as the systems biology community, are very grateful.
When the f irst ICSB was held in 2000 at Tokyo with the support of Japan Science and Technology Corporation (JST), systems biology was yet to be recognized as a serious area of study. Nevertheless, it attracted over 300 attendees, over a half of them from outside of Japan. That year featured Prof. Sydney Brenner, a Nobel Laureate in physiology or medicine in 2002, as a banquet speaker. Systems biology is now gaining serious attention world-wide and a number of major research programs and centers have been created. It is my great pleasure that ICSB has grown into the main forum of scientific discussions in systems biology, and has contributed to the field’s progress. However, we should remind ourselves that the field is still in its infancy and much more needs to be done in all areas of research to bring still more maturity to the field. Given the long history of pioneering research leading to the modern form of systems biology, the field may have finally arrived to the point of experiencing a steep learning curve. A scientific problem, experimental techniques, computational analysis, and theoretical frameworks all have to be aligned to address significant questions in biology and decipher their system-level properties and principles. You will witness the growth and future of systems biology at ICSB-2006.
Please enjoy the conference and beautiful Japan!
Sincerely yours,
Hiroaki KitanoConference Chair, The Seventh International Conference on Systems Biology
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Committees*alphabetical order by region
Program CommitteeAsia:Uri Alon (Weitzman Institute of Science, Israel)Upi Bhalla (National Centre for Biological Science, India)Kwang-Hyun Cho (Seoul National Univ., Korea)Hsuan-Cheng Huang (National Yang-Ming University,
Taiwan)Akira Funahashi (SBI & JST ERATO-SORST Kitano
Project, Japan)Mariko Hatakeyama (RIKEN GSC, Japan)Yoshihide Hayashizaki (RIKEN GSC, Japan)Do Han Kim (Gwangju Institute of Science and Technology,
Korea)Hiroaki Kitano (SBI & Sony CSL, Japan) Conference
ChairShinya Kuroda (Univ. of Tokyo, Japan)Sang Yup Lee (Korea Advanced Institute of Science and
Technology, Korea)Edison Liu (Genome Institute of Singapore, Singapore)Douglas Murray (SBI & JST ERATO-SORST Kitano
Project, Japan)Shuichi Onami (Keio Univ., Japan)Reiko Tanaka (RIKEN BioMimetic Center, Japan)Masaru Tomita (Keio Univ., Japan)Hiroki Ueda (RIKEN CDB, Japan)
Europe:Lilla Alberghina (Univ. of Milano-Bicocca, Italy)Marta Cascante (Univ. of Barcelona, Spain)Roland Eils (DFKI (=German Cancer Research Center),
Germany)Peter Ghazal (GTI (=Scottish Centre for Genomic
Technology and Informatics), UK)Igor Goryanin (Univ. of Edinburgh, UK)Stefan Hohmann (Goteborg Univ., Sweden)Douglas Kell (Univ. of Manchester, UK)Edda Klipp (Max-Planck Institute for Molecular Genetics,
Germany)Pierre De Meyts (Hagedorn Research Institute, Denmark
and Novo Nordisk A/S)Jens Nielsen (DTU (=Technical Univ. of Denmark), Denmark)Staffan Normark (Karolinska Institute, Sweden)Nicolas Le Novere (EBI (=European Bioinformatics
Institute), UK)Klaus Prank (GlaxoSmithKline)Hans Westerhoff (Univ. of Amsterdam, the Netherlands)
North America:Adam Arkin (Lawrence Berkeley National Lab., USA)Frederick Cross (Rockefeller Univ., USA)Marie Csete (Emory Univ. USA)Francis Doyle (UCSB, USA)John Doyle (Caltech, USA)Joe Gray (Lawrence Berkeley National Lab. USA)Mike Hucka (Caltech, USA)Trey Ideker (UCSD, USA)Boris Kholodenko (Thomas Jefferson Univ., USA )Douglas Lauffenburger (MIT, USA)Pedro Mendes (Virginia Tech., USA)Bernhard Palsson (UCSD, USA)John Tyson (Virginia Tech., USA)Marc Vidal (Dana-Farber Cancer Institute, USA)Tau-Mu Yi (UCI, USA)
Student Session Organizer:Satya Arjunan (Keio Univ., Japan)John Cumbers (Brown Univ., USA)
Advisory CommitteeSydney Brenner (Founding President, Okinawa Institute of
Science and Technology & The Salk Institute)Kiyoshi Kurokawa (President, The Science Council of
Japan)Koichi Kitazawa (Senior Executive-Director, Japan
Science and Technology Agency)Yoshiyuki Sakaki (Director, RIKEN GSC)Sin-ichi Nishikawa (Deputy Director, Laboratory for
Stem Cell Biology, Center for Developmental Biology, RIKEN)
Yoshiki Hotta (President, Research Organization of Information and Systems)
Shigetada Nakanishi (Director, Osaka Bioscience Institute)
Executive CommitteeKazuyuki Aihara (Univ. of Tokyo and JST ERATO Aihara
Project)Akiyasu Fujii (SBI)Ken Fukuda (AIST)Akira Funahashi (SBI & JST ERATO-SORST Kitano
Project)Mariko Hatakeyama (RIKEN GSC)Hiroaki Kitano (SBI & Sony CSL)Tatsuhiko Kodama (Univ. of Tokyo)Shinya Kuroda (Univ. of Tokyo)Yukiko Matsuoka (SBI & JST ERATO-SORST Kitano
Project)Satoru Miyano (Univ. of Tokyo)Masahiko Noda (Japan Science and Technology Agency)Makoto Suematsu (Keio Univ. School of Medicine)Hiroki Ueda (RIKEN CDB)Toru Yao (RIKEN GSC)
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Program
Day 1: Monday, October 9, 2006
9:30 Opening 1F Main HallSpeaker
Hiroaki Kitano, The Systems Biology Institute, Sony Computer Science Laboratories, Inc.
10:00 P1 Plenary Session 1 1F Main HallElectricity meets Chemistry: Fast and Slow Signaling in Memory
Upinder S. Bhalla, National Centre of Biological Sciences
10:30 P2 Plenary Session 2 1F Main HallSpatio-temporal Patterns of Intracellular Signaling
Atsushi Miyawaki, RIKEN Brain Science Institute
11:00 Break
11:30 P3 Plenary Session 3 1F Main HallBiological Large Scale Integration
Stephen R. Quake, Stanford University / HHMI
12:00 P4 Plenary Session 4 1F Main HallEvolvability and hierarchy in rewired bacterial gene networks
Luis Serrano, European Molecular Biology Laboratory
12:30 Lunch Session Talks
14:00 S1a Systems Biology for Drug Discovery 1F Main Hall
Chairs John Morser, Nihon Schering Research Center Osamu Sato, Dai-ichi Pharmaceuticals
SpeakersFrom Molecular Events to Clinical Outcome: Computational Systems Biology in the Pharmaceutical Industry
Klaus Prank, GlaxoSmithKlineHarnessing Systems Biology Using Chemical Synergies
Joseph Lehár, CombinatoRX, Inc.Application of Systems Biology for Pharmaceutical Drug Development
Jeff Trimmer, Entelos Inc.Systems Biology in Drug Discovery and Development: Impact and Challenges
Didier Scherrer, AstraZenecaTechnological breakthrough for cell-based target discovery
Masato Miyake, CytoPathfinder Inc.
14:00 S1b Cyclic and Dynamic Behaviours 5F Sub Hall 1
Chairs Hiroki Ueda, RIKEN Center for Developmental Biology Lilia Alberghina, University of Milano-Bicocca
SpeakersA Generic Model of Cell Cycle Regulation in Eukaryotes
John J. Tyson, Virginia TechProbing structure and dynamics of cell cycle in budding yeast
Lilia Alberghina, University of Milano-BicoccaCircadian Systems of Cyanobacheria
Takao Kondo, Nagoya UniversityAnalysis and Synthesis of Mammalian Circadian Clocks
Hiroki Ueda, RIKEN Center for Developmental BiologyMulti-loop Architecture in Clock Circuits
Andrew J. Millar, University of Edinburgh
16:30 -18:00
Poster Session I 4F
18:00 Welcome Reception 5F
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Day 2: Tuesday, October 10, 2006
9:30 P5 Plenary Session 5 1F Main HallDealing with the complexity of a 'simple' eukaryotic cellStephen G. Oliver, The University of Manchester
10:00 Break Session Talks
10:30 S2a Cardiovascular Systems Biology 1F Main Hall
Chair Do Han Kim, Gwangju Institute of Science and Technology
Speakers Cardiac Systems Biology
Giovanni Paternostro, Burnham Institute for Medical Research, La Jolla, CAKyoto Model, a comprehensive cardiac cell model
Akinori Noma, Kyoto University, Graduate School of MedicineCardiomyopathy in Mice and Men
Jonathan Seidman, Harvard Medical SchoolDirect observation of transcription in the human cell using tiling array
Tatsuhiko Kodama, The University of Tokyo
10:30 S2b Yeast Systems Biology 5F Sub Hall 1
Chairs Stefan Hohmann, Goteborg University Stephen G. Oliver, The University of Manchester
Speakers Dynamic Modeling of Stress Response of Yeast Cells
Edda Klipp, Max Planck Institute for Molecular GeneticsQuantitative physiology of a cellular information sensing and relaying system
Roger Brent, The Molecular Sciences InstituteInterrogation of cellular networks
Mike Tyers, Samuel Lunenfeld Research InstituteSources and control of cell to cell variation in the response of yeast to mating pheromone
Alejandro Colman-Lerner, The Molecular Sciences Institute
10:30 S2e Network Biology 5F Sub Hall 2
Chairs Marc Vidal, Dana-Farber Cancer Institute / Harvard Medical School Yoshihide Hayashizaki, RIKEN Yokohama Institute
Speakers Interactome Networks
Marc Vidal, Dana-Farber Cancer Institute / Harvard Medical SchoolProtein Network Comparative Genomics
Trey Ideker, University of California, San DiegoGenome Network Project in Japan
Yoshihide Hayashizaki, RIKEN Yokohama InstituteSingle molecule imaging of motor proteins in living cells - deciphering physical networks of molecular motions
Hideo Higuchi, Tohoku University
12:30 Lunch Session Talks
14:00 S2d Systems Immunology 1F Main Hall
Chair Marie Csete, Emory University
Speakers Evolution and divergence of herpesviral protein interaction networks
Juergen Haas, University of MunichPathway Biology Approach to the Interferon System
Peter Ghazal, University of Edinburgh Medical SchoolThe Center for Inflammation and Regenerative Medicine: a service model
Gilles Clermont, University of PittsburghTo Kill or not to Kill - Decision making in Natural Killer Cells
Roland Eils, German Cancer Research Center (DKFZ), HeidelbergStem Cells and Pain: Linking Immunity to Regeneration
Marie Csete, Emory University
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14:00 S2c Metabolomics and Bioprocess 5F Sub Hall 1
Chairs Sang Yup Lee, KAIST Marta Cascante, University of Barcelona
Speakers Bottom-up Reconstruction of the Human Metabolic Network based on Build-35 and Bibliomic Data
Bernhard Palsson, University of California, San DiegoSystems Level Analysis and Engineering of Industrial Bacteria
Sang Yup Lee, KAISTMetabolome Analysis and Synthetic Biology
Masaru Tomita, Keio UniversityA Systems Biology Approach to Identify and Therapeutically Exploit the Weakness of the Robust Tumour Metabolism
Marta Cascante, University of Barcelona
14:00 S2f Student Session 5F Sub Hall 2
Chair Marc Vidal, Dana-Farber Cancer Institute / Harvard Medical School
Speakers Silvia Jantos, EMBLMikael Andersen, Technical University of DenmarkYusuke Maeda, The University of TokyoDale Muzzey, MIT- Harvard Alexander Fletcher, University of OxfordAriosto Silva, Centro Infantil Boldrini
16:30-18:30
Poster Session II 4F
19:00 Banquet Pan Pacific Hotel
Day 3: Wednesday, October 11, 2006Session Talks
9:15 S3a Systems Biology of Diabetes (Novo Nordisk-sponsored) 1F Main Hall
Chair Pierre De Meyts, Hagedorn Research Institute
Speakers Understanding diabetes pathogenesis: the need for systems biology
Pierre De Meyts, Hagedorn Research InstituteA Systems Biology Approach to Type 1 Diabetes
Allan E. Karlsen, Novo Nordisk A/SThe transcriptome as a window into pathogenesis of type 1 diabetes
Nathan Goodman, Institute for Systems Biology
9:15 S3b Developmental Systems Biology 5F Sub Hall 1
Chairs Shuichi Onami, RIKEN Genomic Sciences Center Fabio Piano, New York University
SpeakersC. elegans early embryogenesis: global, local and evolutionary views
Fabio Piano, New York UniversityInteractions among the Pigment Cells of Zebrafish Give Rise to Turing Pattern
Shigeru Kondo, Nagoya UniversityQuantitative analysis of C. elegans embryogenesis
Shuichi Onami, RIKEN Genomic Sciences Center
9:15 S3c Complex Systems Biology 5F Sub Hall 2
Chairs Kwang-Hyun Cho, Seoul National University Sree N. Sreenath, Case Western Reserve University
Speakers Interaction Balance Coordination as Organizing Principle in Complex Systems Biology
Mihajlo D. Mesarovic, Case Western Reserve UniversityCoordination of Gene Expression by RNA Operons
Jack Donald Keene, Duke University Medical CenterApplications of Complex Systems Biology to the Study of Neural Systems
Kenneth Alan Loparo, Case Western Reserve University
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10:30 Break Session Talks
11:00 S3d Cancer Systems Biology 1F Main Hall
Chairs Roland Eils, German Cancer Research Center (DKFZ), Heidelberg Charles Auffray, CNRS and Pierre & Marie Curie University
Speakers Design Principles of the JAK-STAT Signaling Pathway
Ursula Klingmüller, German Cancer Research Center (DKFZ), HeidelbergPredicting the Outcome of Chemotherapy through Pathway Modelling
Charles Auffray, CNRS and Pierre & Marie Curie UniversityFrom Simulation to Therapy: A Systems Biology Approach to Oncogene Detection
Avijit Ghosh, Drexel University
11:00 S3e Systems Neurobiology 5F Sub Hall 1
Chairs Upinder S. Bhalla, National Centre of Biological Sciences Boris N. Kholodenko, Thomas Jefferson University Nicolas Le Novere, EMBL-EBI
Speakers Understanding Molecular Complexity at the Neuronal Synapse
August B. Smit, Vrije Universiteit AmsterdamModelling Structure and Function of the Post-Synaptic Proteome
James Douglas Armstrong, University of EdinburghSystems Analysis of Spike-Timing Dependent Synaptic Plasticity
Shinya Kuroda, The University of Tokyo
11:00 S3f Control and System Theory for Systems Biology 5F Sub Hall 2
Chairs Francis J. Doyle, University of California, Santa Barbara Rudi Gunawan, National University of Singapore
Speakers Robustness Analysis of Biological Networks Using Sensitivity Measures
Francis J. Doyle, University of California, Santa BarbaraFeedback Control Regulation of Cell Division
Pablo A. Iglesias, The Johns Hopkins UniversityThe Architecture of Cellular Regulation
John Doyle, California Institute of Technology
12:30 Lunch Session Talks
14:00 S3g Synthetic Biology 1F Main Hall
Chair Drew Endy, Massachusetts Institute of Technology
Speakers Languages and Grammars for Programming in DNA
Drew Endy, Massachusetts Institute of TechnologyApplications in Systems and Synthetic Biology
Adam Arkin, University of California, BerkeleyImpact of a Whole Genome Cloning on Systems Biology
Mitsuhiro Itaya, Keio UniversityAdaptive Response of a Gene Network to Environmental Changes by Fittness-induced Attractor Selection
Tetsuya Yomo, Graduate School of Information Science and Technology, Osaka UniversityProgrammable Bacterial Catalysts
Vitor Martins dos Santos, Helmholtz Centre for Infection Research
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14:00 S3h Signal Transduction 5F Sub Hall 1
Chairs Philippe Bastiaens, EMBL Heidelberg Boris N. Kholodenko, Thomas Jefferson University Shinya Kuroda, The University of Tokyo
Speakers Cell-signaling Dynamics in Time and Space
Boris N. Kholodenko, Thomas Jefferson UniversityEmerging Principles of Living Systems
Hans V. Westerhoff, Manchester Centre for Integrative Systems Biology and Biocentre AmsterdamLigand-dependent Cell Fate Control of ErbB Signaling Network in Breast Cancer Cells
Mariko Hatakeyama, RIKEN Genomic Sciences CenterRules for Modeling Signal-transduction Systems
William S. Hlavacek, Los Alamos National LaboratoryReaction Cycles in the Spatial and Temporal Organization of Cell Signaling
Philippe Bastiaens, EMBL Heidelberg
14:00 S3i Novel Computational Environments for Systems Biology 5F Sub Hall 2Chairs Douglas Kell, The University of Manchester
Pedro Mendes, Virginia Tech.
Speakers Linking Text with Knowledge - Challenges in Text Mining for Biology
Junichi Tsujii, The University of TokyoGoing with the Flow: Distributed Computing for Systems Biology using Taverna
Carole Anne Goble, The University of ManchesterThe DREAM project: Establishing a Community-based Gold Standard for Systems Biology
Andrea Califano, Columbia University Medical CenterThe Systems Biology Markup Language (SBML): Where It's Been and Where It's Going
Michael Hucka, California Institute of TechnologyMIRIAM and BioModels DB: Curation and Exchange of Quantitative Models
Nicolas Le Novere, EMBL-EBI
16:30 Break
17:00 Panel Discussion 1F Main Hall
Perspective on Systems Biology in National Research Agenda
Chairs Hiroaki Kitano Stefan Hohmann
17:30 Closing 1F Main Hall
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SundayOctober 8
Pacifico Yokohama411 + 412 413 414 + 415 416 417 418 419
9:30 T2:SignalingNetwork(CellNetAnalyzer)
T1:Design Principle
T3:New Math Method
T12:SBML
T8:Copasi Basic
T11:PottersWheel
T7:Virtual Cell
12:3014:00
T4:MatLab
T5:Teranode
T 6:E-Cell
T9:Copasi Advanced
T10:CellDesigner
17:00
MondayOctober 9
Pacifico Yokohama1F Main Hall 4F 5F Sub Hall 1 5F
9:00
Poster Display
9:30 Opening10:00 P1
Upinder S. Bhalla10:30 P2
Atsushi Miyawaki11:00 Break11:30 P3
Stephen Quake12:00 P4
Luis Serrano12:30 Lunch14:00 S1a
Drug DiscoveryS1b
Cyclic and Dynamic Behaviours
16:30 Poster Session
18:00 Welcome Reception19:3021:00
TuesdayOctober 10
Pacifico Yokohama Pan PacificHotel1F Main Hall 4F 5F Sub Hall 1 5F Sub Hall 2
9:00
Poster Display
9:30 P5Stephen Oliver
10:00 Break10:30 S2a
Cardiovascular Systems BiologyS2b
Yeast Systems BiologyS2e
Network Biology
12:30 Lunch Lunch Lunch14:00 S2d
Systems ImmunologyS2c
Metabolomics and BioprocessS2f
Student Session
16:30 Poster Session
18:3019:00 Banquet21:00
WednesdayOctober 11
Pacifico Yokohama1F Main Hall 4F 5F Sub Hall 1 5F Sub Hall 2
9:15 S3aSystems Biology of Diabetes
S3bDevelopmental Systems Biology
S3cComplex Systems Biology
10:30 Break11:00 S3d
Cancer Systems BiologyS3e
Systems Neurobiology
S3fControl and System Theory for
Systems Biology12:30 Lunch14:00 S3g
Synthetic BiologyS3h
Signal Transduction
S3iNovel computational environments
for systems biology16:30 Break17:00 Panel Discussion
Closing18:00
ThursdayOctober 12
Miraikan AISTMiraikan Hall Meeting Room 1 Meeting Room 2 Meeting Room
Synthetic BiologySystems Biology and the Human
Health Risks of EnvironmentalChemicals
SBML Forum RTK Workshop
FridayOctober 13
Miraikan AISTMiraikan Hall Meeting Room 1 Meeting Room 2 Meeting Room
SBML Forum RTK Workshop
Tutorial
Conference
Workshop
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Student Session
Venue: Pacifico Yokohama, 5F Sub Hall 2Date: Tuesday, October 10, 2006, 14:00-16:30
Chair: Marc Vidal, Dana-Farber Cancer Institute
SpeakersThe following Speakers will give an oral presentation on their Posters. These Speakers' posters were selected by the Student Session Review Committee as the best poster abstracts submitted in the Student Category.
MAPK signaling network properties giving rise to specific cellular fate decisions (BS24)Silvia Santos, Philippe BastiaensEMBL
Applied genome-scale modelling of Aspergillus niger (FI58)Mikael Andersen, Michael L. Nielsen, Jens NielsenTechnical University of Denmark
Regulatory Dynamics of Synthetic Gene Networks with Positive Feedback (FS06)Yusuke Maeda, Masaki SanoThe University of Tokyo
Monitoring MAPK osmo-signaling in individual yeast cells (BS09)Dale Muzzey, Carlos Gomez-Uribe, Jerome Mettetal, Alexander van OudenaardenMIT-Harvard
Mathematical modelling of the role of HIF-1 in tumour growth (FN27)Alexander Fletcher, Jonathan Chapman, Christopher BrewardUniversity of Oxford
Study of Dependency of Synchronization of Beta-cells Insulin Secretion on Size of Langerhans Islets (MD04)Ariosto Silva, Jose YunesCentro Infantil Boldrini
The following scientists reviewed the abstracts for the Student Session:- Hsuan-Cheng Huang, National Yang-Ming University, Taiwan- Bruce Shapiro, California Institute of Technology- Tau Mu Yi, UCI- Upinder Bhalla, National Centre for Biological Sciences, Bangalore, India- Marie Csete, Emory University School of Medicine- Martin Robert, Keio University
Organizers:Satya Arjunan, Keio UniversityJohn Cumbers, Brown University
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P1 10:00-10:30, October 9 Main HallElectricity meets chemistry: fast and slow signaling in memoryUpinder S. BhallaNational Centre for Biological Sciences, TIFR, Bangalore, IndiaContacts: [email protected]
Deliberations on memory mechanisms often seem to proceed on at least three independent tracks. One of these involves biochemical mechanisms for plasticity, including feedback loops and cellular activation. Space is another dimension, and is the arena for interactions between synapses, and propagation of signals between synapses, dendrites, and the cell body. Finally, electrical activity is a function of cell as well as network dynamics, and here too feedback may play a role through reverberating activity in network loops. It is an interesting process to develop models that impinge on all of these levels, because of the wide range of timescales, numerical techniques, and sheer computational load. It is especially tricky to get parameters for such models. I will describe a study where we have used coupled electrical and biochemical compartmental modeling, and weeded out several candidate models by comparing their predictions to our experiments. The surviving models incorporate chemical, spatial and electrical ingredients. They exhibit network-activity controlled single-cell reverberating activation, with interesting spatial consequences. We suggest that this is a form of short-term and spatially defined memory. It sits at the interface between individual synapses and dendrites, and also between network and cellular attributes of memory.
http://www.ncbs.res.in/~bhalla/index.html
P2 10:30-11:00, October 9 Main HallSpatio-temporal patterns of intracellular signalingAtsushi MiyawakiRIKEN Brain Science InstituteContacts: [email protected]
"Why bio-imaging, i.e. real time fluorescence imaging?" Currently, this is a topic of great interest in the bioscience community. Many molecules involved in signal transduction have been identified, and the hierarchy among those molecules has also been elucidated. It is not uncommon to see a signal transduction diagram in which arrows are used to link molecules to show enzyme reactions and intermolecular interactions. To obtain a further understanding of a signal transduction system, however, the diagram must contain the three axes in space as well as a fourth dimension, time, because all events are controlled ingeniously in space and time. Since the isolation of green fluorescent protein (GFP) from the bioluminescent jellyfish in 1992 and later with its relatives, researchers have been awaiting the development of a tool, which enables the direct visualization of biological functions. This has been increasingly enhanced by the marriage of GFP with fluorescence resonance energy transfer (FRET) or fluorescence cross-correlation spectroscopy (FCCS), and is further expanded upon by the need for "post-genomic analyses." It is not my intent to discourage the trend seeking the visualization of biological function. I would like to propose that it is time to evaluate the true asset of "bio-imaging" for its potential and limitations in order to utilize and truly benefit from this novel technique.
http://www.brain.riken.go.jp/english/b_rear/b5_lob/a_miyawaki.html
P3 11:30-12:00, October 9 Main HallBiological large scale integrationStephen QuakeDept of Bioengineering and (by courtesy) Applied Physics, Stanford University and Howard Hughes Medical InstituteContacts: [email protected]
The integrated circuit revolution changed our lives by automating computational tasks on a grand scale. My group has been asking whether a similar revolution could be enabled by automating biological tasks. To that end, we have developed a method of fabricating very small plumbing devices – chips with small channels and valves that manipulate fluids containing biological molecules and cells, instead of the more familiar chips with wires and transistors that manipulate electrons. Using this technology, we have fabricated chips that have thousands of valves in an area of one square inch. We are using these chips in applications ranging from bioreactors to structural genomics to systems biology. However, there is also a substantial amount of basic physics to explore with these systems – the properties of fluids change dramatically as the working volume is scaled from milliliters to nanoliters!
http://med.stanford.edu/profiles/Stephen_Quake/
Plenary Talk AbstractsSession Abstracts
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P4 12:00-12:30, October 9 Main HallEvolvability and hierarchy in rewired bacterial gene networksLuis Serrano1,2, Mark Isalan*1, Caroline Lemerle2, Konstantinos Michalodimitrakis2, Barbara Di Ventura2, Pedro Beltrao2, Carsten Horn2 and Emanuele Raineri2
1. EMBL-CRG Systems Biology Programme, Centre for Genomic Regulation, Spain2. EMBL, Germany*Contacts: [email protected]
Bacterial gene networks are highly plastic, allowing radical reconnections at the summit of the gene network hierarchy, fuelling evolvability.Sequencing of genetic material from several organisms has revealed that duplication and drift of existing genes has primarily molded the contents of a given genome. Though the effect of knocking out or over-expressing a particular gene has been studied in many organisms, no study has systematically explored the effect of adding new links in a biological network. To explore network plasticity, we constructed 598 recombinations of promoters (including regulatory regions) with different transcription or s-factors in Escherichia coli, over the genetic background of the wild-type. We found that ~95% of reconnected networks are tolerated by the bacterial cell and very few give different growth profiles. Expression levels correlate with the position of the factor in the wild-type network hierarchy. Most importantly, we find that certain combinations consistently survive over the wild-type under various selection pressures. This suggests that new links in the network could readily confer a fitness advantage to individuals in a population and hence may fuel evolution.
http://www-db.embl.de/jss/EmblGroupsHD/per_397.html
P5 9:30-10:00, October 10 Main HallDealing with the complexity of a ‘simple’ eukaryotic cell.Stephen G. OliverFaculty of Life Sciences, The University of Manchester, U.K.Contacts: [email protected]
Systems biology aims at taking a more synthetic or holistic approach to deciphering the workings of living organisms. Although the ultimate aim is to construct mathematical models of complete cells or organisms that have both explanatory and predictive power, we are some way from achieving such global syntheses and we need a principled way of reducing the complexity of the problem. Accordingly, we require a top-down strategy to provide an initial coarse-grained model of the cell, and a bottom-up strategy in which individual sub-systems are modeled.Metabolic Control Analysis (MCA) is a conceptual and mathematical formalism that models the relative contributions of individual effectors in a pathway to both the flux through the pathway and the concentrations of individual intermediates within it. To exploit MCA in an initial top-down systems analysis of the eukaryotic cell, two categories of experiments are required. In category 1 experiments, flux is changed and the impact on the levels of the direct and indirect products of gene action is measured. We have measured the impact of changing the flux on the transcriptome, proteome, and metabolome of Saccharomyces cerevisiae. In this whole-cell analysis, flux equates to growth rate. In category 2 experiments, the levels of individual gene products are altered, and the impact on the flux is measured. We have used competition analyses between the complete set of heterozygous yeast deletion mutants to reveal genes encoding proteins with high flux control coefficients. For the bottom-up approach, the initial problem is one of systems identification. While a lot of time is currently spent debating the question “What is Systems Biology?”, why (in an organism where we know so much about its biochemistry, physiology, and cell biology as S. cerevisiae) should it be a problem to identify the biological sub-systems that must be fully characterised and built into a comprehensive model of the eukaryotic cell? This problem arises because we have previously studied these biological systems in isolation and in a rigorously reductionist fashion. Now, we must study them as parts of an integrated whole. The problem is that our current view of, say, a metabolic or signal transduction pathway is often two-dimensional (rather than four-dimensional) and is frequently poorly integrated, if at all, with other cellular pathways. Thus our view of the network of metabolic pathways may not be the same as the yeast’s. In order to gain a “yeast’s eye view”, we have coupled flux balance analysis with both metabolomics and genetics. Although the initial aim of these approaches is the identification of the ‘natural’ metabolic systems of yeast, the principles involved should be more widely applicable to the problem of biological systems identification.
http://www.ls.manchester.ac.uk/people/profile/index.asp?tb=0
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I S1a SYSTEMS BIOLOGY FOR MEDICINE 14:00-16:00, October 9
Systems Biology for Drug Discovery Main HallS1a-1 From molecular events to clinical outcome: computational systems biology in the pharmaceutical
industry Klaus Prank GlaxoSmithKline
S1a-2 Harnessing systems biology using chemical synergies Joseph Lehár Computational Biology, CombinatoRx Inc, Cambridge MA, Bioinformatics, Boston University Contacts: [email protected]
Combination drugs can overcome compensatory mechanisms or evolved resistance by attacking disease on several fronts, and also provide a new window on biological systems. We present simulations and experiments that show the relationship between chemical synergies and target connectivity, as well as preliminary results from combination screens of targeted agents in yeast and tumor cell lines.Despite the success of discovery efforts focused on specific targets, many drugs are less effective than expected [Sams-Dodd 2005], due to mechanistic complexity [Hartwell 2001] or evolved resistance. Network simulations [Csermely 2005] and clinical oncology [Kaelin 2005] suggest that disease is more controllable through multi-target approaches, and indeed combinations are the norm for cancer and many infectious diseases. CombinatoRx is systematically screening combinations of approved drugs in cellular disease models [Borisy 2003], to find synergies that can be optimized towards novel combination drugs.We show that chemical combinations can also yield connectivity information through their response surface shapes. Pathway simulations with pairs of inhibitors produce distinct responses depending on how the targets are connected. The predicted shapes are reproduced in a yeast experiment, with further support from screens using human cells. While analogous to genetic interactions [Tong 2003], chemical synergies provide complementary and more detailed information for network models about connections between their protein targets. Chemicals can also be efficiently screened in disease models that are not amenable to genetic studies. We also present preliminary results from screens testing combinations of ~100 chemical probes with known targets using yeast and tumor cell lines. The experiments are designed to improve our understanding of yeast networks, and to identify new multi-target mechanisms with therapeutic potential for cancer.
http://users.rcn.com/lehar
S1a-3 Application of systems biology for pharmaceutical drug development Jeff Trimmer Entelos Inc.
S1a-4 Systems biology in drug discovery and development: impact and challenges Didier Scherrer AstraZeneca
S1a-5 Technological breakthrough for cell-based target discovery Masato Miyake CytoPathfinder, Inc. Contacts: [email protected]
Strategy to identify new and right targets at early stage of drug discovery has long been discussed to improve the R&D productivity. Genome-wide target screening and target combination finding are growing as new waves of cell-based target discovery on the background of emerged antibodies, aptamers, and nucleic acid medicines. The experimental scale of the cell-based screening is getting larger year by year for successful target discovery. Therefore, high-throughput screening and data management & integration technologies are rapidly growing. On the other sides, technologies to select right targets are studied in cell biology. Various technologies such as stem cell differentiation, cell separation, immortalization, xenografts, etc. are used to establish in vitro models (cells and markers) which correlate to clinical data. However the culture scale of reliable in vitro model is still small in general. The experimental scale gap between new target discovery and right target discovery may be pointed out as technological innovation needs. Here, we introduce Transfection microarray (TMA), which is a microarray for highly paralleled cell transfection. By using TMA, large-scale functional screening of cDNAs / siRNAs is operated in the small culture. We may show the TMA-based strategy to identify new and right targets at early stage of drug R&D.
http://www.cytopathfinder.com
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I S2a SYSTEMS BIOLOGY FOR MEDICINE 10:30-12:30, October 10
Cardiovascular Systems Biology Main HallS2a-1 Cardiac systems biology Andrew McCulloch1, Jacob Feala1, Sarah Flaim1, Roy Kerckhoffs1, Giovanni Paternostro2, Jeffrey Saucerman3
1Department of Bioengineering, University of California, San Diego, La Jolla, CA, 2The Burnham Institute, La Jolla, CA, 3Department of Biomedical Engineering, University of Virginia, Charlottesville, VA
Computational models of the heart can be integrative in several important ways. First, they permit information integration of genome scale data sets that would otherwise be difficult to interpret and understand. We illustrate this in the analysis of high-throughput phenotypic and metabonomic data on cardiac function in the fruitfly drosophila melanogaster. We use drosophila as a model organism for studying cardiac aging and hypoxia tolerance, and integrating these data with constrain-based metabolic models built in large part with data from the Kyoto Encyclopedia of Genes and Genomes (KEGG). Systems models of cardiac myocytes achieve functional integration, by predicting how the functions of individual network components combine to give rise to physiological functions. We illustrate this with our recent models of β-adrenergic regulation of myocyte excitation-contraction coupling. Multi-scale computational models aim to achieve structural integration across physical scales of biomedical organization from molecule to organize. We illustrate this with examples from our recent research on arrhythmia mechanisms in genetic disease and the effects of external interventions such as pacing and pericardiectomy on ventricular-vascular coupling in vivo.
http://cmrg.ucsd.edu
S2a-2 Kyoto model, a comprehensive cardiac cell model Akinori Noma, Satoshi Matsuoka and Nobuaki Sarai Cell/Biodynamics Simulation Project Kyoto University, Department of Physiology, Faculty of Medicine Kyoto University, Japan Contacts: [email protected]
The magnitude and time course of developed tension is regulated by multiple functional units, such as [Ca2+]i, molecular machinery
of contraction, membrane excitation, ion homeostasis within the cell, excitation-contraction coupling, neural regulation, cell volume regulation and energy metabolism in cardiac myocytes. So far, a huge amount of experimental findings on each issue has been accumulated, and it is possible to develop a comprehensive cardiac cell model to analyze the interactions of many molecular functional units underlying the regulation of the cardiac contraction. Starting from the models of cardiac membrane excitation (1), we developed a comprehensive cell model, Kyoto Model (2). Kyoto model can respond to various experimental interventions in a reversible manner. Increasing [Ca2+]
o results in a positive inotropy accompanied with the slight shortening of the action potential
duration. Decreasing [Na+]o increases the force of contraction through the accumulation of Ca2+ within the sarcoplasmic reticulum
by modulating the Na/Ca exchange. Varying [K+]o affects both the action potential shape and the resting membrane potential. The
force of contraction increases with decreasing [K+]o. The Ca2+ stored within the sarcoplasmic reticulum (2~4 mM) is released by
the activation of the RyR channel through the influx of Ca2+ via L-type Ca2+ channels. [Ca2+]i is determined by the intracellular Ca2+
buffer as well as the binding to troponin C. The contraction model is based on the Negroni and Lascano (2001), but is improved for the positive cooperativity for Ca2+-mediated activation by combining with the model of Robinson et al (2002). The ATP homeostasis is established between the consumption by the myofilament, Na/K pump and SERCA and the production by mitochondria. Removing oxygen results in shortening of the action potential and loss of contraction. Quantitative dynamic computer models, which integrate a variety of molecular functions into a cell model, provide a powerful tool to create and test working hypotheses. Our new modeling tool, the simBio package (freely available from http://www.sim-bio.org/) is used for constructing cell models such as cardiac cells, epithelial cells and pancreatic β cells. The simBio package is written in Java, uses XML and solves ordinary differential equations.1) DiFrancesco, D., Noble, D., 1985. Philos. Trans. R. Soc. Lond. B Biol. Sci. 307:353-398.2) Matsuoka S., Sarai N., Jo H., and Noma A. 2004 Prog. Biophys. Mol. Biol. 85:279-299.3) Negroni, J. A., Lascano, E.C. 1999. J.Mol.Cell.Cardiol. 31: 1509-1526.4) Robinson JM., Wang Y., Kerrick GL., Kawai R., and Cheung HC. 2002 J. Mol. Biol. 322:1065-1088.http://www.card.med.kyoto-u.ac.jp
S2a-3 Cardiomyopathy in mice and men Jonathan Seidman Harvard Medical School
Hypertrophic cardiomyopathy (HCM), caused by missense mutations in sarcomere protein genes, increases left ventricular wall thickness, susceptibility to cardiac arrhythmias and sudden cardiac death. Cardiac tissue from affected individuals demonstrate fibrosis, myocyte disarray and myocyte hypertrophy. Disorganized cell-cell contact (myocyte disarray) and cardiac fibrosis, prototypic but protean features of HCM histopathology, are suggested as potential triggers for ventricular arrhythmias that lead to sudden death. We have studied the epidemiology of left ventricular hypertrophy and have demonstrated that rare sarcomere protein gene mutations account for more than 50% of unexplained in young and middle aged, while other causes may account for most hypertrophy in the elderly.The mechanisms by which sarcomere protein gene mutations lead to unexplained hypertrophy are being investigated in mouse models of this disease. Rigorous assessment of whether these factors increase arrhythmia vulnerability in humans is difficult due to limited
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myocardial tissue access and confounding variables including genetically heterogeneous HCM mutations, background genotypes and lifestyles. We report electrophysiological studies and comprehensive myocardial histopathologic analyses of mice engineered to carry an HCM mutation. Genetically inbred HCM mice had remarkably inhomogeneous histopathology and susceptibility to arrhythmias. Among inbred HCM mice, neither the extent nor distribution of myocyte disarray or cardiac fibrosis correlated with abnormalities in ex vivo signal conduction properties or in vivo electrophysiological properties. In contrast, increased ventricular hypertrophy significantly increased arrhythmia susceptibility. These data indicate that somatic responses to a sarcomere gene mutation account for variable HCM histopathology and demonstrate that myocyte hypertrophy more than fibrosis or disarray correlates with arrhythmic risk. Independent somatic triggers appear to stimulate fibrosis, and myocyte disarray. A shared factor activates cardiac hypertrophy and arrhythmias. Presumably each of these separate factors activates a distinct pathway that stimulates different responses to sarcomere protein gene mutations.
http://genetics.med.harvard.edu/~seidman/
S2a-4 Direct observation of transcription in the human cell using tiling array Tatsuhiko Kodama The University of Tokyo
Sequential gene expression upon stimulation is a key cellular mechanism for adaptation, and temporal analysis of transcriptional activation by TNFa-nuclear factor kappa B, nuclear receptors and p53 indicate that oscillating activation may be an important mechanism to generate a temporal cascade. Transcription of pre-mRNA in the human cell is coupled with its processing and selective degradation. Observation of this complex process is hampered by an interruption of coding sequence by a large non-coding intorns. Oligonucleotide tiling array covering whole genome sequence has been developed to obtain higher resolution of gene expression,. As compared with exon RNA, intron RNA is degraded rapidly during splicing, and may be useful tool to monitor the rate of transcriptional activation. Here we report that first wave of oscillating expression of intron RNA and its processing can be monitored using tiling array with high temporal resolution (7.5min). We selected 100 genes induced by TNFa and designed tiling array monitoring pre-mRNAs of these gene loci. First wave of oscillating expression was monitored in 4 large gene loci (>100kb) and average speed of transcriptional elongation was 3.2kb/min, which is faster than previously reported value without measureing the oscillation (1.2-24kb/min). Temporal analysis of transcription using tiling arrays will be a useful tool analyzing the transcription and processing.
http://www.lsbm.org
I S2d SYSTEMS BIOLOGY FOR MEDICINE 14:00-16:30, October 10
Systems Immunology Main HallS2d-1 Evolution and divergence of herpesviral protein interaction networks Even Fossum*1, Armin Baiker*1, Caroline C. Friedel2, Silpa Suthram3, Seesandra V. Rajagopala4, Björn Titz4, Tina Schmidt5, Theo Kraus1, Sourav Bandyopadhyay3, Dietlinde Rose1, Mareike Uhlmann1, Christine Zeretzke1,
Yu-An Dong2, Hélène Boulet1, Susanne M. Bailer5,Ulrich Koszinowski1, Trey Ideker6, Peter Uetz4, Ralf Zimmer2
and Jürgen Haas1
1Max-von-Pettenkofer Institut, LMU München, 2Institut für Informatik, LMU München, 3Program in Bioinformatics, University of California San Diego, 4Institut für Genetik, Forschungszentrum Karlsruhe , 5Institut für Medizinische Biochemie und Molekularbiologie, Universität des Saarlandes, Homburg, 6Department of Bioengineering, University of California San Diego
Contacts: [email protected]
Herpesviruses are a family of large DNA viruses widely spread in vertebrates which cause a variety of different diseases in animals and man. We performed a comprehensive yeast-two-hybrid analysis of intraviral protein interactions in five different species of the herpesvirus family: Herpes simplex virus 1 (HSV-1), Varicella zoster virus (VZV), murine Cytomegalovirus (mCMV), Epstein-Barr virus (EBV) and Kaposi’s sarcoma associated herpesvirus (KSHV) revealing 1,252 interactions including 231 interactions between 41 core ortholog proteins. Whereas previous studies compared species that had been analysed in different laboratories by various methods, we explored 5 different species using exactly the same protocols. Nevertheless, at first glance there was little overlap between the networks of the five herpesvirus species, similar to previous Y2H datasets of different cellular networks. The general network topology was similar in all herpesviral networks: the degree distribution differed from cellular networks (if a power law distribution is approximated the power coefficient is considerably lower in comparison to cellular networks) and showed no high local clustering as in small-world networks1. Moreover, herpesviral networks could not be subdivided into distinct functional submodules or complexes, which appears to be an inherent characteristic of large cellular networks such as that of yeast and human. Co-immunoprecipitation experiments indicated that the majority of interactions is conserved between core orthologs and demonstrated that protein function can be conserved without sequence homology. In contrast, the network outside the common core is either species- or subfamily-specific, reflecting distinct functional properties of these proteins. Whereas the five species were equidistant based on their core interaction networks, the analysis of the complete viral networks yielded a phylogeny that was consistent with the known evolutionary relationships between the alpha, beta, and gamma subfamilies. Our study provides evidence that protein interactions and network structures constitute adaptive evolutionary traits and can thus be used to assign phylogenetic relationships.
http://www.baygene.de/pro-engl-3_1a.htm
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S2d-2 Pathway biology approach to the interferon system Peter Ghazal University of Edinburgh Medical School
Interferons (IFNs) play a pivotal role in innate and adaptive immunity against infection. Here, we present a systematized interpretation and analysis of the IFN pathway based on a research synthesis review of 257 nodes in the network. The relationships of the components were graphically notated as a consensus logic interaction diagram. Topological characterisation of the constructed pathway showed network features consistent with a scale-free connectivity and systems robustness with predicted flexibility for a number of different states. A genetic network of 56 genes and 100 edges from the consensus diagram was used for analysis of gene expression data obtained by profiling primary mouse macrophages treated with IFNγ and/or infected with murine cytomegalovirus. Statistical and simulation analyses showed the expression changes mapped to discrete and specific sub-systems of the IFN pathway, indicative of pro-inflammatory and anti-viral functions. Notably, IFNγ co-stimulation of infected cells results in the dominance of IFNγ over the viral specific sub-network. These results reveal for the first time discrete states of sub-system activity of the IFN pathway and represent a systematic methodology for constructing and exploiting biological pathways in general.
S2d-3 The center for inflammation and regenerative medicine: a service model Gilles Clermont The University of Pittsburgh Contacts: [email protected]
The University of Pittsburgh Medical Center is a large tertiary care center hosting more than 130 intensive care unit beds, is the largest solid organ transplant, and hosts the McGowan Institute dedicated to regenerative medicine. Systems modeling of inflammation, the crucial pathophysiologic process determining outcome in the critically ill patient, is a prime focus of interest of a team including clinicians, biologists, mathematicians, engineers and computer scientists. This interdisciplinary team has created the Center for Inflammation and Regenerative Medicine, which seeks to (1) offer transdisplinary expertise to academic and corporate researchers interested in the analysis and modeling of complex datasets, (2) train a new generation of scientists in translational systems biology and (3) promote scientific diffusion of the relevance of an integrative approach to patient care and the development of therapies.
www.mirm.pitt.edu/cirm
www.scai-med.org www.pittsburghcomplexity.net www.iccai.org
S2d-4 To kill or not to kill - decision making in natural killer cells Roland Eils1,3, Sven Mesecke1, Doris Urlaub2, Hauke Busch1, Carsten Watzl2
1Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany; 2Institute for Immunology, University of Heidelberg, Germany; 3Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, Germany
Contacts: [email protected]
The immune system is essential in the protection of the host against a variety of infectious agents and the growth of transformed cells. Natural Killer (NK) cells are at the junction of the innate and the adaptive immune response and are important in the fight against viral infections and cancer. The effector functions of NK cells are controlled by a balance of positive and negative signals that are transmitted via various kinds of surface receptors. Inhibitory receptors guarantee the tolerance of NK cells towards target cells with normal MHC class I expression. Loss of this expression, e.g. during viral infection or transformation, reduces the inhibitory signal, and enables stimulatory surface receptors to shift the balance towards activation and subsequent killing of a locally attached target cell. To date our understanding about the integration of positive and negative signals and the decision making process inside NK cells remains poor. Here, we propose a mechanism by which NK cells first integrate antagonising signals and then compute a reliable killing decision. Predictions derived from this mechanistic model are tested experimentally and will be compared with established knowledge. This proposed mechanism of NK cell regulation enables a novel insight into the decision making process during lymphocyte activation. It can serve as basis for any future manipulation of NK cell function to enhance the anti-tumour activity of these important immune cells.
http://www.dkfz.de/tbi
S2d-5 Stem cells and pain: linking immunity to regeneration Marie Csete Emory/GaTech Human Embryonic Stem Cell Core Contacts: [email protected]
Pain is experienced by all people, yet is poorly understood and often poorly treated. In particular many traumatic or degenerative disease processes (for which stem cell therapies are being studied) are complicated by pain. In this way, pain is part of normal regeneration, yet the role of stem cells in treating pain has not been explored. Pain can be broadly divided into nociceptive
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(appropriate to the stimulus) and neuropathic (inappropriate severe and long-lasting) types. We used an animal model of neuropathic pain, chronic constriction injury of the rat sciatic nerve, to study the potential of stem cells for pain therapy. Our data show that infusion of bone marrow mononuclear cells containing a mixed stem cell population after the injury, results in reversal of pain behaviors 10 days later, whereas untreated control rats remain in pain. Several possible mechanisms for pain reversal by bone marrow transplant will be discussed including modulation of immune cell infiltrates, neurotrophic factor signaling (particularly erythropoietin and GDNF), vasodilatation, elaboration of heat shock proteins, and regeneration of Schwann and vascular cells. This work suggests that stem cells modulate pain signals as part of their regenerative roles, and serve as a link to the nervous system after injury.
http://userwww.service.emory.edu/~mcsete
I S3a SYSTEMS BIOLOGY FOR MEDICINE 9:15-10:30, October 11
Systems Biology of Diabetes (Novo Nordisk-sponsored) Main HallS3a-1 Understanding diabetes pathogenesis: the need for systems biology Pierre De Meyts Receptor Systems Biology Laboratory, Hagedorn Research Institute, Gentofte, Denmark Contacts: [email protected]
The two major forms of diabetes mellitus, type 1 and type 2 diabetes, are both complex diseases of poorly understood pathogenesis. The poor understanding of molecular mechanisms underlying pathogenesis results in a penury of effective drug therapies. Type 1 diabetes results from progressive beta cell destruction by incompletely defined autoimmune processes. Insulin treatment is an absolute requirement to prevent death from ketoacidosis. Type 2 diabetes is a complex disease which is reaching epidemic proportions due a combination of lifestyle factors that favor obesity, and genetic and environmental factors. The pathogenesis of type 2 diabetes involves alterations in insulin production and secretion by the pancreatic beta cells, as well as disturbances in the target cells sensitivity to insulin action. Reductionist approaches have failed to unravel the complex interactions between transcriptional networks that regulate beta cell development and differentiated function, and the signal transduction mechanisms in both beta cells and insulin target tissues, the combined disturbance of which results in impaired metabolic homeostasis. A systems biology approach is clearly warranted.
S3a-2 A systems biology approach to type 1 diabetes Allan E. Karlsen1,2, Jørn Nerup2 & Flemming Pociot2
1Insulin, Incretin and Islet Biology, Novo Nordisk A/S, 2Steno Diabetes Center, Denmark Contacts: [email protected]
Type 1 diabetes mellitus (T1D) is the result of an autoimmune associated destruction of the beta-cells in the islets of Langerhans in the pancreas. The pathogenesis of T1D is accompanied by infiltration of the islets with auto-reactive lymphocytes and macrophages (insulitis), releasing a cocktail of cytokines of which especially interleukin-1β is specifically toxic to the beta-cells in the islets.We have combined transcriptome and proteome analysis of different in vitro and in vivo models of T1D to elucidate the mechanisms behind cytokine and immune mediated beta-cell destruction.The results have identified a number of proteins, that when over-expressed in beta-cells influence their response to cytokines. Combining this information with data from our genetic studies in a systems biology approach supports the hypothesis that spontaneous and cytokine induced beta-cell destruction is caused by complex, intracellular protein – protein or protein/DNA interactions, ”controlled” at the level of expression by common alleles (polymorphisms) of normal genes in unfavourable combinations. Thus, a battle between protective and deleterious effects in the beta-cells determines the outcome. Knowledge about the underlying mechanisms may provide novel targets for future pharmacological and/or genetic intervention in the beta-cell destructive processes in diabetes.
http://www.novonordisk.com
S3a-3 The transcriptome as a window into pathogenesis of type 1 diabetes Nathan Goodman, Burak Kutlu Institute for Systems Biology [email protected]
We have generated a comprehensive atlas of genes expressed in beta cells, islets, and related cell types and lines by combining data from MPSS analysis and array studies. We find around 9800 genes expressed consistently in human islets regardless of individual variation. Slightly more genes are expressed in exocrine tissue, 11200, duct cells have around 4000, and rat beta cells and insulin-producing cell lines have around 7500. Due to technical difficulties, it is impossible to isolate human beta cells, but based on computational analysis, we have determined a core list of 2025 and 860 genes that are enriched in human islets and beta cells, respectively. We are also studying the dynamics of cytokine-induced beta cell destruction by microarray and qPCR analysis. Results from arrays show 1057 genes are differentially expressed over a period of 96h IL1+IFN exposure. Chemokines, NF-kB and JAK-STAT signaling pathways are dramatically activated. Our approach mainly relies on integrating and comparing observations from different species
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and publicly available pathway and interaction data. Comparison with similar experiments in rodents points reveals many similarities, however with delayed behavior in human cells. The time series will hopefully help us draw casual relationships between the activated pathways and beta cell death.
http://T1DBase.org
I S3d SYSTEMS BIOLOGY FOR MEDICINE 11:00-12:30, October 11
Cancer Systems Biology Main HallS3d-1 Design Principles of the JAK-STAT Signaling Pathway Ursula Klingmueller Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ)
Growth and differentiation processes are regulated by complex intracellular signaling networks. In many cancer cells signaling through the JAK-STAT or the SMAD signaling pathways are altered. To identify general principles how these pathways influence cellular decisions and to predict targets for intervention we are combining quantitative data generation with mathematical modeling. We applied quantitative immunoblotting to monitor the interleukin (IL)-6 induced activation of gp130, JAK1 and STAT3 in primary hepatocytes. The time-resolved experimental data could only be fitted at sufficient quality by a mathematical model capturing the possibility that STAT3 cycles between the nucleus and the cytoplasm. Although it has been demonstrated that SMAD2 cycles between the cytoplasm and the nucleus it was not possible to fit time resolved data for transforming growth factor (TGFbeta) induced SMAD2 phosphorylation in in primary hepatocytes by a simple cycling model. We had to include a negative feedback loop and experimentally verified a critical role for the oncoprotein SnoN. Thus, by dynamic pathway modeling rapid nuclear-cytoplasmic cycling could be identified as a general building principle of signaling cascades that make use of latent transcription factors and rapidly mediate signal transmission from the cell surface to the nucleus.
www.dkfz.de/de/systembiologie/index.html
S3d-2 Predicting the outcome of chemotherapy through pathway modelling Charles Auffray CNRS and Pierre & Marie Curie University – Villejuif, France Contacts: [email protected]
The molecular mechanisms underlying innate tumor drug resistance to cancer therapy remain poorly understood, as molecular studies have focused on drug-selected tumor cell lines or individual candidate genes using samples derived from patients already treated with drugs. Transcriptional profiles of clinical samples collected from colorectal patients prior to their exposure to a combined chemotherapy were established using microarrays. Vigilant experimental design, power simulations and robust statistics allowed successful discrimination, for the first time prior to drug exposure, of subsequently diagnosed chemo-sensitive and resistant patients, based on the expression profile of 679 genes. Functional annotation, ontology enrichment analysis and pathway modelling using CellDesigner provided a unique representation of the cellular states underlying drug responses. It forms a solid foundation for a system-level analysis of the molecular interaction networks involved, and for the design of by-pass chemotherapy schemes allowing critical therapeutic intervention. In addition, through multivariate analysis and cross validation, powerful predictors of the response to chemotherapy were developed.Graudens et al. Deciphering cellular states of innate tumor drug responses. (2006) Genome Biology 7:R19
http://genomebiology.com/2006/7/3/R19
S3d-3 From simulation to therapy: a systems biology approach to oncogene detection Avijit Ghosh Drexel University Contacts: [email protected]
Activation of the Extracellular signal Regulated Kinases (ERK1/2; p42/p44 MAPK) is one of the most extensively studied signaling pathways, not least because it occurs downstream of oncogenic RAS. We take advantage of the wealth of experimental data available on the canonical RAS/ RAF/ MEK/ ERK pathway of Bhalla et. al. to test the utility of a newly developed nonlinear analysis algorithm designed to predict likelihood of cellular transformation. By using ERK phosphorylation as an "output signal", the method analyzes experimentally determined kinetic data and predicts putative oncogenes and tumor suppressor gene products impacting the RAS/ MAPK module using a purely theoretical approach. This analysis identifies several modifiers of ERK/ MAPK activation described previously. In addition, several novel enzymes are identified which are not previously described to affect ERK/ MAPK phosphorylation. We have extended this method to study disparate pair mutations in enzyme/protein interactions and in expression levels in signal transduction pathways and have applied it to the MAPK signaling pathway to study how synergistic or cooperative mutations in signaling networks act together to cause malignant transformation.The set of in silico transformed cells designed in this manner have been subject to a series of virtual drugs designated by a binding
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affinity kd and concentration. A map of best targets within the pathway can be quantitated and furthermore ranked. Among the highly
ranked targets are several well known in the literature such as the Ras inhibitors. Several novel targets are also highly ranked. In addition, the analysis points to the use of Calcium blockers, not currently used in cancer therapy, as a possible avenue for therapeutic intervention.
II S1b SYSTEMS BIOLOGY OF BASIC BIOLOGICAL SYSTEMS 14:00-16:00, October 9
Cyclic and Dynamic Behaviours 5FS1b-1 A generic model of cell cycle regulation in eukaryotes John J. Tyson, Attila Csikasz-Nagy, Katherine C. Chen, and Bela Novak Department of Biological Sciences, Virginia Polytechnic Institute & State University, USA, and Department of Agricultural
Chemical Technology, Budapest University of Technology & Economics, Hungary Contacts: [email protected]
The protein interaction network regulating DNA synthesis and mitosis seems to be universal among eukaryotic cells. The idiosyncrasies of cell cycle regulation in particular organisms are attributable to specific settings of the rate constants in the dynamical network, and these settings are determined ultimately by the genetic makeup of an organism. Alternative parameter settings are known for fission yeast, budding yeast, early embryos of frog and fruit fly, and for mammalian cells in culture. Generic properties of the model are revealed by one-parameter bifurcation diagrams, which show (1) how cell growth drives progression through the cell cycle, (2) how cell size homeostasis may be achieved (3) how cell cycle checkpoints operate, and (4) how mutations alter the way cells grow and divide. Two-parameter bifurcation diagrams compactly summarize the dependence of cell phenotype on gene dosage. This theoretical framework reveals both the universality and particularity of cell cycle regulation and facilitates construction, in modular fashion, of increasingly complex models of the networks controlling cell growth and division.Ref. Csikasz-Nagy, Battogtokh, Chen, Novak & Tyson (2006) Biophys J 90:4361-79This research is supported, in part, by the Defense Advanced Research Project Agency (USA), the James S. McDonnell Foundation (USA), and COMBIO (EU).
http://mpf.biol.vt.edu/
S1b-2 Probing structure and dynamics of cell cycle in budding yeast Lilia Alberghina#, Matteo Barberis# *, Marco Vanoni #, Edda Klipp* #Dept. of Biotechnology and Biosciences - University of Milano-Bicocca - Milano, Italy, *Max-Planck Institute for Molecular
Genetics - Berlin Center for Genome based Bioinformatics (BCB) - Berlin, Germany Contacts: [email protected]
The construction of a novel mathematical model of the G1 to S transition is reported. It accounts both for literature findings and for our recent results (1,2). The model was implemented by a set of ordinary differential equations and analyzed by simulation. We investigate the dynamics of the G1 to S transition by simulation in several genetic and nutritional set ups and in response to different signalling pathways. The model was found highly consistent with experimental data. The main control of the G1 to S transition is given by the requirement for a critical cell size (Ps) to enter S phase. The model has been shown to be able to correctly estimate Ps in various growth conditions. Sensitivity analysis of Ps indicate that it is an emergent property of the network, dependent also from growth rate. This fact supports a new interpretation on the reported role of ribosome biogenesis in controlling Ps. 1. L. Alberghina, R.L. Rossi, L. Querin, V. Wanke, and M. Vanoni “A cell sizer network involving Cln3 and Far1 controls entrance
into S phase in the mitotic cycle of budding yeast” – J. Cell Biol. 167, 433-443 (2004)2. R.L. Rossi, V. Zinzalla, A. Mastriani, M. Vanoni and L. Alberghina “Subcellular localization of the cyclin dependent kinase
inhibitor Sic1 is modulated by the carbon source in budding yeast” – Report - Cell Cycle 4, 1798-1807 (2005)
http://www.btbs.unimib.it/indexuk.htm (Keywords: Research-groups-containing: cell cycle)http://www.unimib.it
S1b-3 Circadian systems of cyanobacheria Takao Kondo Division of Biological Science, Graduate School of Science, Nagoya University and CREST/SORST, JST, Japan Contacts: [email protected]
Cyanobacteria are the simplest organisms that exhibit circadian rhythms. In the cyanobacterium, Synechococcus elongatus PCC 7942, three genes (kaiA, kaiB and kaiC) were identified to code essential components of the circadian clock. As we found robust circadian cycling of KaiC phosphorylation even without kaiBC mRNA accumulation, we attempted to reconstitute the oscillation of KaiC phosphorylation in vitro. By incubating KaiC with KaiA, KaiB and ATP, we found the self-sustainable circadian oscillation of KaiC phosphorylation. The in vitro oscillation of KaiC phosphorylation persisted for at least three cycles and the period was compensated against temperature change. Furthermore, changes in circadian period observed in vivo in various KaiC mutant strains were consistent with those measured in vitro when the incubations were carried out with the respective mutant KaiC proteins. These results demonstrate that the oscillation of KaiC phosphorylation is the primary pacemaker of the cyanobacterial circadian clock.We analyzed the in vitro KaiC phosphorylation cycle from four aspects as follows; 1) interaction of KaiA and KaiB to KaiC,
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2) interactions of two phosphorylation site, 3) energetics of the phosphorylation cycle of KaiC and 4) interactions among KaiC hexamers. From these analyses, we will propose a circadian programs of three proteins system for robust and tunable oscillations that tick biological time in the living cell.
http://www.bio.nagoya-u.ac.jp/seminar/b1.html (in Japanese)http://www.bio.nagoya-u.ac.jp/english/index.html (in English)
S1b-4 Analysis and synthesis of mammalian circadian clocks Hiroki R. Ueda Laboratory for Systems Biology, Center for Developmental Biology, RIKEN Contacts: [email protected]
The logic of complex and dynamic biological networks is difficult to elucidate without (1) comprehensive identification of network structure, (2) prediction and validation based on quantitative measurement and perturbation of network behavior, and (3) design and implementation of biological networks driven by the same logic as the original network. Mammalian circadian clock system is such a system consisting of complexly integrated regulatory loops and displaying the various dynamic behaviors including 1) endogenous oscillation with about 24-hour period, 2) entrainment to the external environmental changes (temperature and light cycle), 3) temperature compensation over the wide range of temperature, and 4) synchronization of multiple cellular clocks against the inevitable molecular noise. To elucidate complex structure and dynamic behavior of mammalian circadian clock, we comprehensively identify the transcriptional regulatory circuits composed of 20 transcription factors, and three type of DNA elements including “morning” element (Bmal1/Clock Binding element, E-box/E’-box), “day” element (DBP/E4BP4 binding element, D-box) and “night” element (RevErbA/ROR binding element, RREs). The following quantitative measurement and perturbation of clock circuits revealed that E-box/E'-box regulation represents a topological and functional vulnerability in mammalian circadian clocks, and also found the interesting property of peripheral circadian clocks. In this conference, we will also report a current progress in the synthesis of transcriptional circuits underlying mammalian clock and discuss the logic governing this complex and dynamic biological networks.References1. Ueda, H.R. et al. A transcription factor response element for gene expression during circadian night. Nature 418, 534-539 (2002).2. Ueda, H.R. et al. System-level identification of transcription circuit underlying mammalian circadian clocks. Nat. Genet. 37,
187-192 (2005).3. Sato T K, et al. Feedback repression is required for mammalian circadian clock function. Nat Genet. 38, 312-9 (2006).
http://www.cdb.riken.jp/jp/02_research/0202_creative20.html
S1b-5 Multi-loop architecture in clock circuits Andrew J. Millar University of Edinburgh
II S2b SYSTEMS BIOLOGY OF BASIC BIOLOGICAL SYSTEMS 10:30-12:30, October 10
Yeast Systems Biology Sub Hall 1S2b-1 Dynamic modeling of stress response of yeast cells Edda Klipp Max Planck Institute for Molecular Genetics, Berlin, Germany Contacts: [email protected]
Investigation of cellular systems is more and more supported by computational methods like bioinformatics and mathematical modeling, which is an important aspect of Systems Biology. A frequently used method is the description of reaction systems by sets of ordinary differential equations. The structure of the equations is established based on the knowledge about the network structure, i.e. about the relevant pathways and protein-protein interactions, while the parameters are determined from experimental observations, preferentially time course measurements.Using the power of such models, we investigate stress response processes in the yeast Saccharomyces cerevisiae. The adaptation of the cells to environmental changes like nutrient supply, pheromone stimulation or osmotic stress is mediated by signaling pathways that eventually regulate the expression of many genes. The products of such genes, in turn, regulate the metabolism or the cell cycle progression in order to compensate for or adapt to the external stimuli. The predictions of the models agree well with experimental results obtained under different stress conditions or using certain mutants. Simulations reveal properties of the signaling process and enlighten the roles of different components in the adaptation process. The cross talk between different networks and the regulation of cycle progression by signal transduction pathways will be discussed.The presented examples show that mathematical models are helpful to formulate experimental knowledge in a testable form, to explain hitherto unsolved phenomena, and to even predict the outcome of new experiments.
http://www.molgen.mpg.de/~ag_klipp
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S2b-2 Quantitative physiology of a cellular information sensing and relaying system Roger Brent The Molecular Sciences Institute, Berkeley, California, USA
I will review some of recent findings about the yeast pheromone response system from the Alpha project. Many of these findings are at least somewhat surprising. Some seem important, may be fundamental, in the sense that they may apply across eukaryotic biology for systems of this basic type.For signal dynamics (Yu et al., 2006), these include the fact that signal propagation is slow, taking minutes to reach the nucleus, that a each measurement point the signal shows a consistent pattern of rise, overshoot, correction, and decline toward a stable value, that overshoot correction depends on negative feedback, that the negative feedback(s) do not bring about densensitization (adaptation), and that we can experimentally decouple signal propagation time from signal amplitude. For equilibrium system output (in prep), findings include that this system does not undergo desensitization (adaptation) over longer times, that is not an amplifier, and that it is not a switch. Rather, the system goes to great lengths, across many steps, to transmit accurate information about extracellular signal concentration, as measured by the percent receptor occupied. Put another way, one of the functions of the system is to keep information in the signal, in this case information about measured pheromone concentration, from being degraded during the many stages of its transmission. This behavior is not a trivial consequence of the known reactions in the system but in one case we have established that proper behavior again involves a negative feedback. Using protein mass spectrometry, we have also undertaken a comprehensive search for feedbacks within the system. We have so far identified circa 100 candidate sites, and have shown that some are functional.The picture in 2006 is thus of progress gained from of patient multidisciplinary development and experimentation on a tightly defined model system in a model organism. By pursuing this course, and by maintaining a resolutely agnostic stance as to how the system might operate, we have discovered a number of basic attributes of this function. Our point of understanding seems roughly equivalent to the degree of understanding of nerve impulse transmission in the 1930s, with two major differences. First, simple concepts from information theory seem applicable to this system, and we are particularly excited that work to date has given us unexpected insight into the signal’s semantic content. Second, the pheromone response system operates within a genetically tractable organism for which genetic analysis is already yielding insight. This combination of disciplinary approaches to the study of a simple prototype system should continue to yield insights and may help define one thing that 21st century systems biology can be.http://www.molsci.org/
S2b-3 Interrogation of cellular networks Mike Tyers Samuel Lunenfeld Research Institute, University of Toronto, Toronto, Canada Contacts: [email protected]
Systematic approaches to chart biological networks include global analyses of gene expression, deletion phenotypes, genetic interactions and protein interactions. We have used these approaches to investigate the long-standing problem of cell size homeostasis in budding yeast. Before commitment to division in late G1 phase, cells must achieve a minimum critical cell size, as dynamically regulated by nutrient conditions. To uncover new pathways that coordinate growth and division, we have determined the cell size phenome using population-level size selection and barcode microarray analysis. Hundreds of small (whiskey or whi) and large (lge) mutants have been recovered and are currently being assembled into networks by systematic size epistasis and proteomic analysis.A crucial property of biological networks is compensation in gene function (buffering), as often revealed by genetic interactions. Systematic interrogation of the genetic landscape will therefore require simultaneous and precisely controlled perturbation of multiple network nodes, a task most readily accomplished with small molecule probes. To this end, we have begun to assemble a collection of small molecules that exhibit genotype-specific toxicity, as scored against many dozens of deletion mutants that affect various aspects of cell biology. An initial chemical-genetic interaction matrix, a corresponding chemical-chemical interaction matrix and possible implications for drug discovery will be presented.
http://www.mshri.on.ca/tyers/
S2b-4 Sources and control of cell to cell variation in the response of yeast to mating pheromone Alejandro Colman-Lerner, Rich Yu, Andrew Gordon, Tina Chin, C. Gustavo Pesce and Roger Brent The Molecular Sciences Institute, Berkeley, California, USA
We studied the quantitative behavior of a prototypical eukaryotic signal transduction system, the pheromone response pathway in yeast. We used fluorescent proteins, in transcriptional reporters and in fusions to pathway components expressed from native chromosomal promoters, to measure signal trasmission through the pathway in single cells. In this talk, I will focus on how faithfully this system relays information. We studied 1) how precisely pheromone dose information is “seen” at different steps down signal propagation in population of cells and 2) on the sources and control of variability system output in single cells. We found that at most points we measured, system output maps precisely onto the proportion of receptors that are bound by pheromone and that this behavior requires the operation of negative feedbacks. We also found large cell to cell variation in system output. Only a small proportion of total cell-to-cell variation is caused by ‘gene expression noise’. Instead, variation is dominated by differences in the capacity of individual cells to transmit signals through the pathway (‘pathway capacity’) and to express genes into proteins (‘expression capacity’). Our results indicate that various aspects of system’s quantitative behavior, including the degree of cell to cell variation, are under genetic regulation. Taken together, our results highlight the importance of a quantitative and dynamic measurments for the understanding of information carrying systems.
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II S2c SYSTEMS BIOLOGY OF BASIC BIOLOGICAL SYSTEMS 14:00-16:30, October 10
Metabolomics and Bioprocess Sub Hall 1S2c-1 Bottom-up reconstruction of the human metabolic network based on Build-35 and bibliomic data B. Palsson, N. Hurlen, S. Becker, N. Jamshidi, M. Mo, I. Thiele Department of Bioengineering, UCSD, La Jolla, CA
A genome-scale metabolic network for H. sapiens has been constructed based on the annotated build-35 of the human genome sequence and a comprehensive evaluation of the published literature on human metabolism over the past 50 years. The reconstruction accounts for 1496 ORFs, and the metabolic network has 2766 metabolites and 3311 reactions. The network can be used to; 1) assess where our knowledge is weak or missing, 2) analyze HT data sets, and 3) perform in silico analysis of network properties. Examples of all three applications will be given.
http://gcrg.ucsd.edu/personnel/palsson.htm
S2c-2 Systems level analysis and engineering of industrial bacteria Sang Yup Lee Dept. Chemical and Biomolecular Eng., Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea Contacts: [email protected]
Recent advances in omics research and modeling and simulation tools are enabling systems-level understanding of cellular behaviors, and consequently systematic engineering of the organisms to achieve desired goals. We have been developing various mathematical and analytical tools. One of the important technologies we are employing for strain development is metabolic flux analysis, which allows quantitative analysis of all intracellular fluxes based on certain constraints cells must obey under the given conditions. Metabolic flux analyses have been carried out under various genetically and environmentally perturbed conditions using genome scale in silico models. In this talk, the approaches taken in my group using genome-scale metabolic flux analysis in developing various biotechnological processes. In particular, I will focus on metabolic pathway engineering of Escherichia coli and other microorganisms towards enhanced production of desired products. Combination of in silico analysis and actual metabolic engineering allowed efficient creation of strains having improved performance. Detailed procedure and results will be presented. Also, general strategies for the improvement of strain based on the systems level analysis, especially how to find gene deletion and amplification targets for strain engineering, will be presented. [This work was supported by the Korean Systems Biology Research Grant from the MOST.]
http://mbel.kaist.ac.kr
S2c-3 Metabolome analysis and synthetic biology Masaru Tomita Institute for Advanced Biosciences, Keio University, Human Metabolome Technologies, Inc. Contacts: [email protected]
We have developed a metabolome analysis method based on capillary electrophoresis time-of-flight mass spectrometry (CE/TOFMS). This technology has been applied to numerous fields such as medical diagnosis (blood, urine, tissue), food production (farm products, fermentation), environmental biology (soil microbes), and systems biology of model organisms (E.coli and other bacteria) at our institute. We have recently discovered a biomarker of acetaminophen-induced hepatotoxicity, ophthalmate being a sensitive biomarker of glutathione depletion (Soga 2006 J. Biol. Chem.).The metabolome technology has made “multi-omics” analysis possible. We systematically obtained multi-omics data sets for Escherichia coli BW25113 and its single gene deletion mutants. Our data covers the metabolome (CE-TOFMS), proteome (western blot, shotgun proteomics, and 2D-DIGE), fluxome (GC-MS and NMR) and transcriptome (real time RT-PCR and DNA microarray).Using the collected multi-omics data, a simulation model of central carbon metabolism was constructed and the dynamic responses of the model after pulse addition of glucose were compared with experimental results.Finally, I will describe our ongoing research on genome engineering with the ultimate goal of designing and synthesize useful microorganisms based on computer models.
http://www.iab.keio.ac.jp
S2c-4 A systems biology approach to identify and therapeutically exploit the weakness of the robust tumour metabolism
Marta Cascante1*, S. Marin1, G. Alcarraz1, P. Vizan1, A. Ramos1, S. Diaz1, P. de Atauri1, J.J. Centelles1, P. W-N. Lee2, V. Selivanov1
1Dept. Bioquímica i Biol. Molec., CeRQT-Parc Científic Barcelona (PCB), Associated Unit to CSIC, University of Barcelona, Barcelona,C./ Martí i Franqués 1, 08028 Barcelona, Spain, 2Harbor-UCLA Research and Education Institute, University of California, Los Angeles School of Medicine, USA.
Contacts: *Corresponding author E-mail: [email protected]
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Metabolic profile is the end point of the signaling events, where changes caused by diseases may be reflected and so it could be of key importance in correlating genotype with altered cellular phenotypes.A package in C++ has been developed for the dynamic tracer-based Mass Spectrometry (MS) or NMR isotopomer data analysis, which is connected with underlying enzyme kinetics. A core module of isotopomer distribution could be linked with various tissue-specific kinetic models, constructed for glucose metabolic network. This tool is applied to analyze metabolic adaptations in cancer cells and hepatocytes based in both enzyme kinetic information and tracer-based metabolomic data. From this “in silico” model, simultaneous estimation of metabolic fluxes, involved in the different glycolytic/gluconeogenic hepatic futile cycles, have been performed under different glycolytic and gluconeogenic substrates present in the medium. This analysis showed the importance of metabolic flux redistribution through futile cycles in maintaining cellular homeostasis. These examples demonstrate advantages of our new method which is not restricted by steady state and makes use of the enzyme kinetic information.This work is a first step in the construction of “in silico” metabolic network flux simulators in different cell types that can be very useful to design new therapies in multifactorial chronic diseases as cancer or diabetes as well as to predict drug side effects.
http://www.bq.ub.es/bioqint/arecerca.html
II S3b SYSTEMS BIOLOGY OF BASIC BIOLOGICAL SYSTEMS 9:15-10:30, October 11
Developmental Systems Biology Sub Hall 1S3b-1 C. elegans early embryogenesis: global, local and evolutionary views Fabio Piano Center for Comparative Functional Genomics and Department of Biology, New York University Contacts: [email protected].
Once fertilized, animal embryos must follow a series of events that give rise to different cell identities raising important fundamental questions in development. We are using C. elegans early embryogenesis (EE) as a model for approaching metazoan development at a systems level. In recent years C. elegans has become a prime model for powerful high-throughput functional genomics approaches, including global RNAi-based analyses followed by time-lapse microscopy. These approaches are particularly useful for studying developmental processes since development can be regarded as driven by the complex dynamic interactions of thousands of genes and their products. Hence, functional genomics techniques that give insight into gene function on a global level have opened the door for decoding gene interaction networks that control development. Since many components of developmental networks are conserved in evolution, specific insights into the genome-wide architecture of developmental networks in C. elegans are likely to be important for understanding molecular networks driving developmental decisions in other metazoans, including humans. Yet key evolutionary network changes are likely to underpin evolution of development. Our approaches to tackle these problems will be discussed.
S3b-2 Interactions among the pigment cells of zebrafish give rise to turing pattern Shigeru Kondo Nagoya University, Japan Contacts: [email protected]
The question of how complex animal body patterns arise from seemingly disorganized or formless initial structures represents an intriguing challenge not only to biologists but also to mathematicians, physicists and chemists. In 1952, the British mathematician Alan Turing proposed a simple mathematical equation capable of generating a wide range of patterns commonly found in the natural world, such as stripes, spots and reticulations. This model, known as the reaction-diffusion model, mathematically demonstrates that the interaction between a local activator and a long-range inhibitor can give rise to various periodic structures in response to differences in their individual diffusion rates. Although it was clear to have the potential capability to solve the fundamental problem of embryology, the difficulty of proving in an experiment had obstructed the proof of this epoch-making theory for a long time.Animal skin patterns are ideal subjects to study the molecular basis of the Turing mechanism. They are visible from outside, and it is clear that they form without any prepattern because most skin patterns usually are not similar to the inside structures. We discovered in 1995 that the skin pattern of a certain tropical fish changed continuously so that a Turing model might predict, and it became proof that the principle of Turing was actually working in a living thing. By using zebrafish as a new experimental system, we are trying to clarify the molecular network that constructs the putative Turing system.This research is funded by Riken(CDB), Grant in Aid “Gakujutu-Sousei”, and “Genome” from MEXT.
http://www.bio.nagoya-u.ac.jp/~z3/index.html
S3b-3 Quantitative analysis of C. elegans embryogenesis Shuichi Onami RIKEN Genomic Sciences Center, Japan Contacts: [email protected]
An embryo is a temporally and spatially dynamic system made up of many components. Quantitative analysis is essential for understanding such a large-scale dynamic system, in which actual behavior of the systems under various conditions is measured, mathematical models of the systems are created based on the measured behavior, the created models are refined by comparing
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actual behavior of the systems and simulated behavior of the models, and then the refinement of the model is repeated. To find basic principles of animal development, I am studying C. elegans embryogenesis using quantitative analysis. In this talk, I will present our quantitative cell division pattern analysis of RNAi embryos. In this analysis, position of nuclei in RNAi embryos are four-dimensionally measured using an image processing-based automated system and functions of genes are predicted from statistical comparisons of cell division patterns of these embryos. I will then present our quantitative analysis on molecular mechanisms that determine arrangement of cells in the embryo. I will discuss how computer simulations and image-processing-based in vivo measurements revealed the mechanism for male pronuclear migration and that for the symmetric/asymmetric positioning of nucleus in one-cell embryos. Finally, I will present recent progress of our research.
http://www.so.bio.keio.ac.jp, http://www.gsc.riken.jp
II S3e SYSTEMS BIOLOGY OF BASIC BIOLOGICAL SYSTEMS 11:00-12:30, October 11
Systems Neurobiology Sub Hall 1S3e-1 Understanding molecular complexity at the neuronal synapse August B Smit and Ka Wan Li Dept. Molecular & Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam,
The Netherlands Contacts: [email protected]
Synapses are the central elements of communication between brain cells. The unsurpassed capacity of the brain to store and retrieve information, to make associations and to adapt to a changing environment are all considered to arise primarily from molecular adjustments in synapses. Synaptic mal-adaptations are known to cause or contribute to disease. Many drugs currently prescribed for brain disorders have known synaptic targets, however, the indirect effects on the synaptic protein network are poorly understood. Understanding the effects of drugs, or perturbations in general, on the complete synaptic protein/gene network is highly relevant both for a better understanding of synapse function and the identification of candidate proteins for future drug development. Therefore, it is crucial to understand the functional organization of the synaptic proteins network. Based on novel quantitative proteomics data, we work towards the construction of computational models, which explain how a complex protein network drives synaptic functions, and which predict its adaptive capacities in response to environmental cues, such as behavioral challenges and pharmacological interventions. Specific objectives are to provide targets for synaptic modulation and to dissect disease phenotypes by identifying crucial nodes and connectivity of the network. http://www.cncr.nl/mcn/index.html
S3e-2 Modelling structure and function of the post-synaptic proteome J Douglas Armstrong1, Andrew J Pocklington1 & Seth GN Grant2
1School of Informatics, Institute for Adaptive and Neural Computation, University of Edinburgh, 2Wellcome Trust Sanger Institute, Cambridge
Contacts: [email protected]
Proteomic study of the mammalian synapse has generated an extensive list of molecular components, revealing it as one of the most complex biological systems. While fundamental to information processing, behaviour and cognitive disorders, the molecular architecture of signalling in the synapse and its relation to higher-level function is now beginning to emerge. We present a model of the synaptic proteome that captures its structural organisation. Each component is annotated with information describing its molecular features/domains, evolutionary orthologues across 19 species, measurements of gene/protein expression in brain regions and functional annotation from yeast, fly, mouse and human. The model reveals a highly integrated and modular structure. Modules, defined by molecular interactions, not only share common network properties but also functional annotation, regional expression patterns and evolutionary origins. The picture that emerges is of a set of input modules (e.g. receptor complexes) that are closely linked to higher order cognition (and disorders), of more recent evolutionary origin and with high regional variation in the brain. These then link through more central processing modules to a series of output modules (e.g. gene regulatory complexes) that are more closely related to vital functions, ancient evolutionary origin and little variability across the brain.
www.inf.ed.ac.uk/~jda
S3e-3 Systems analysis of spike-timing dependent synaptic plasticity Shinya Kuroda1, Hidetoshi Urakubo1, and Robert C. Froemke2
1CREST, Japan Science and Technology Agency, Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Japan, 2Department of Otolaryngology, University of California, San Francisco, USA
Contacts: [email protected]
Spike timing-dependent synaptic plasticity (STDP), which depends on the relative timing of pre- and postsynaptic spiking, is thought to play an important role in neural development and information storage. However, mechanism of spike-timing detection in STDP
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remains unclear. To understand the mechanism of spike-timing detection in STDP, we developed a computational model of STDP, and found that long-term potentiation (LTP), but not long-term depression (LTD), could be reproduced, indicating an existence of an unknown mechanism for spike-timing detection in STDP. We searched a requirement for spike-timing detection in LTD, and predicted an allosteric kinetics of NMDARs. We experimentally validated the prediction of allosteric kinetics of NMDARs based on the NMDARs-mediated EPSPs. Furthermore, the allosteric kinetics of NMDARs was valid over more complex spike-timing dependent synaptic plasticity in experiments. Thus, our results indicate that a simple allosteric kinetics of NMDARs can code complex spike-timing information into synaptic plasticity. In this talk, I will discuss the possible role of the allosteric kinetics of NMDARs in coding of complex spike-timing information into STDP, which may restructure neural circuits and embed experiences into the brain.
http://www.kurodalab.org
II S3h SYSTEMS BIOLOGY OF BASIC BIOLOGICAL SYSTEMS 14:00-16:30, October 11
Signal Transduction Sub Hall 1S3h-1 Cell-signaling dynamics in time and space Boris N. Kholodenko Thomas Jefferson University
We employ computational and experimental approaches to reveal kinetic and molecular factors that control the temporal dynamics of the EGFR signaling network, including transient versus sustained activation patterns, discontinuous bistable dynamics and oscillations. Quantitative analysis of signal transduction is confronted by a combinatorial explosion in the number of feasible molecular species presenting different states of signaling networks that include receptors and scaffolds with multiple binding domains. We show that a mechanistic description of a highly combinatorial network may be drastically reduced using a “domain-oriented”, macro-modeling framework. Using this approach, we explored the role of the scaffold protein GAB1 in the control of mitogenic (Ras/MAPK) and survival (PI3K/Akt) signaling. The results demonstrate that the essential function of GAB1 is to enhance PI3K/Akt activation and extend the duration of Ras/MAPK signaling. The spatial separation of kinases and phosphatases in MAPK cascades may cause precipitous spatial gradients of phosphorylated kinases with high concentration near the cell surface and low in the perinuclear area. The results suggest that there are additional (besides diffusion) mechanisms that facilitate signaling to distant targets. They may involve endocytosis, scaffolding and active transport of signaling complexes by molecular motors. We show how traveling waves of phosphorylated kinases spread the signals over long distances. In addition to mechanistic modeling, an integrative, modular approach to inferring the structure of cellular signaling and gene networks is proposed. We demonstrate how dynamic connections leading to a particular module (e.g., an individual gene/protein or a cluster) can be retrieved from experimentally measured network responses to perturbations influencing other modules. References. Kholodenko, B.N. (2006) Cell-signalling dynamics in time and space. Nat Rev Mol Cell Biol, 7, 165-176.Sontag, E., Kiyatkin, A. and Kholodenko, B.N. (2004) Inferring dynamic architecture of cellular networks using time series of gene expression, protein and metabolite data. Bioinformatics, 20, 1877-1886.
http://www.cellnetworks.org
S3h-2 Emerging principles of living systems Hans V. Westerhoff 1,2, Frank Bruggeman1,2, Barbara Bakker2 and Jacky L. Snoep1,2,3
1Manchester Center for Integrative Systems Biology, The University of Manchester, UK, EU, 2BioCenter Amsterdam, Vrije Universiteit Amsterdam, NL, EU and 3Department of Biochemistry, University of Stellenbosch, South Africa
Contacts: [email protected]
Much of the primary function of living cells is in chemical and physical processes, such as the generation of amino acids for protein synthesis or the contraction of actomyosin. These primary processes are carried out by metabolic and other pathways of substantial length, which are activated by signal transduction and gene-expression pathways. One issue is how the dynamics of any of these pathways and the flux through any of these processes is controlled by the various molecular processes. This control turns out to be a system property that cannot be assessed from the study of individual steps of the pathway alone.It is an important characteristic of living systems that the individual reaction rates in these pathways need to be regulated so as to stay in tune with each other whilst they change strongly with changing functional requirements. This regulation is effected through gene expression but also through metabolic regulation and is again a systems property rather than a property of the individual processes that are being regulated.This presentation will show that both control and regulation are indeed system properties and that both are subject to a number of general laws or principles. These laws relate to robustness (lack of control), fragility, homeostasis, adaptation ad differentiation. We shall discuss how recognition of some of these principles may help understand important aspects of multifactorial disease and lead to new strategies for drug design. http://www.mcisb.org/http://www.bio.vu.nl/hwconf/
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S3h-3 Ligand-dependent cell fate control of ErbB signaling network in breast cancer cells Mariko Hatakeyama Cellular Systems Biology Team, RIKEN Genomic Sciences Center Contacts: [email protected]
Over-expression and mutation of ErbB receptors are implicated with various kinds of human cancers. On the other hand, ErbB receptor ligands, epidermal growth factor (EGF) and heregulin (HRG) induce transient and sustained extracellular signal-regulated kinase (ERK) and protein kinase B/Akt activities in human MCF-7 breast cancer cells, of which distinct kinetics result in cellular proliferation and differentiation, respectively. Comprehensive analysis of ErbB signaling network is necessary to understand the mechanism of cell fate control and cancer development. In our study, we quantitatively analyzed time-course events of the intracellular signaling and transcription that are initiated by the EGF and HRG. Our results indicated that ligand-induced intracellular signaling and early transcription was first regulated in ligand dose-dependent manner. However, those early transcripts crosstalk with intracellular signaling and then convert dose-dependent signals to binary response that may determine cell fate. We will discuss about mechanistic properties of ErbB receptors and its contribution for controlling cellular network based on the result given by mathematical modeling. 1. Naka, et al. Compensation effect of MAPK cascade on formation of Phospho-protein gradient. BioSystems 83, 2-3,
167-177, 2006.2. Suenaga, et al. Novel mechanism of interaction of p85 subunit of PI3K and ErbB3 receptor-derived phosphotyrosyl
peptides. J. Biol. Chem. 280, 1321-1326, 2005.3. Kimura, et al. Inference of S-system models of genetic networks using a cooperative coevolutionary algorithm.
Bioinformatics 21, 1154-1163, 2005.4. Hatakeyama, et al. Transformation potency of ErbB heterodimer signaling is determined by B-Raf kinase. Oncogene 23,
5023-5031, 2004.5. Suenaga, et al. Tyr317 phosphorylation increases Shc structural rigidity and reduces coupling of domain motions remote
from the phosphorylation site as revealed by molecular dynamics simulations. J. Biol. Chem. 279, 4657-4662, 2004.6. Hatakeyama, et al. A computational model on the modulation of MAPK and Akt pathways in heregulin induced ErbB
signaling. Biochem J., 373, 451-463, 2003. 7. Suenaga, et al. Molecular dynamics, fee Energy and SPR analyses of the interactions between SH2 domain of growth factor
receptor binding protein 2 and ErbB phosphotyrosyl peptides. Biochemistry (U.S), 42, 5195-5200, 2003. http://csb.gsc.riken.jp/
S3h-4 Rules for modeling signal-transduction systems William S. Hlavacek Center for Nonlinear Studies, Los Alamos National Laboratory, U.S.A. Contacts: [email protected]
The behavior of a signal-transduction system depends on the dynamics of protein interactions. The site-specific details of these interactions can be represented using formal rules, which can be visualized using graphs. A set of rules can be processed to automatically generate a dynamical model that accounts comprehensively for the protein complexes implied by the interactions encoded in the rules. The number of possible complexes is often large, which limits conventional approaches to model specification. After summarizing the motivation for rule-based modeling, I will introduce the method, including recent improvements that should facilitate high-throughput modeling and simulations of large-scale networks, and then illustrate how a rule-based approach is being used to model aspects of epidermal growth factor and antigen-recognition receptor signaling. Finally, I will point to future challenges and the promise of an extensible standardized modeling language suited for the complexities of cellular signaling.William S. Hlavacek, James R. Faeder, Michael L. Blinov, R. G. Posner, M. Hucka, W. Fontana (2006) Rules for modeling signal-transduction systems. Sci. STKE 2006, re6. http://www.t10.lanl.gov/wish/
S3h-5 Reaction cycles in the spatial and temporal organization of cell signaling Philippe Bastiaens EMBL Heidelberg, Germany
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III S2e FRONTS IN SYSTEMS BIOLOGY 10:30-12:30, October 10
Network Biology Sub Hall 2S2e-1 Interactome networks Marc Vidal Center for Cancer Systems Biology (CCSB), and Department of Cancer Biology, Dana-Farber Cancer Institute, Department of
Genetics, Harvard Medical School Contacts: [email protected]
For over half a century it has been conjectured that macromolecules form complex networks of functionally interacting components, and that the molecular mechanisms underlying most biological processes correspond to particular steady states adopted by such cellular networks. However, until recently, systems-level theoretical conjectures remained largely unappreciated, mainly because of lack of supporting experimental data.To generate the information necessary to eventually address how complex cellular networks relate to biology, we initiated, at the scale of the whole proteome, an integrated approach for modeling protein-protein interaction or “interactome” networks. Our main questions are: How are interactome networks organized at the scale of the whole cell? How can we uncover local and global features underlying this organization, and how are interactome networks modified in human disease, such as cancer? DFCI Center for Cancer Systems Biology (CCSB)http://ccsb.dfci.harvard.edu/home.htmlVidal Labhttp://vidal.dfci.harvard.edu/
S2e-2 Protein network comparative genomics Trey Ideker University of California San Diego Contacts: [email protected]
With the appearance of large networks of protein-protein and protein-DNA interactions as a new type of biological measurement, methods are needed for constructing cellular pathway models using interaction data as the central framework. The key idea is that, by comparing the molecular interaction network with other biological data sets, it will be possible to organize the network into modules representing the repertoire of distinct functional processes in the cell. Three distinct types of network comparisons will be discussed, including those to identify:(1) Protein interaction networks that are conserved across species(2) Networks in control of gene expression changes(3) Networks correlating with systematic phenotypes and synthetic lethalsUsing these computational modeling and query tools, we are constructing network models to explain the physiological response of yeast to DNA damaging agents.Relevant articles and links:Yeang, C.H., Mak, H.C., McCuine, S., Workman, C., Jaakkola, T., and Ideker, T. Validation and refinement of gene regulatory pathways on a network of physical interactions. Genome Biology 6(7): R62 (2005).Kelley, R. and Ideker, T. Systematic interpretation of genetic interactions using protein networks. Nature Biotechnology 23(5):561-566 (2005).Sharan, R., Suthram, S., Kelley, R. M., Kuhn, T., McCuine, S., Uetz, P., Sittler, T., Karp, R. M., and Ideker, T. Conserved patterns of protein interaction in multiple species. Proc Natl Acad Sci U S A. 8:102(6): 1974-79 (2005).Suthram, S., Sittler, T., and Ideker, T. The Plasmodium network diverges from those of other species. Nature 437: (November 3, 2005).
http://www.pathblast.orghttp://www.cytoscape.orgAcknowledgements: We gratefully acknowledge funding through NIH/NIGMS grant GM070743-01; NSF grant CCF-0425926; Unilever, PLC, and the Packard Foundation.
S2e-3 Genome network project in Japan Yoshihide Hayashizaki Genome Exploration Research Group, Riken Genomic Sciences Center, Riken Yokohama Institute, Japan Contacts: [email protected]
Analysis of the Fantom-3/GenomeNetwork transcriptome dataset, including 158,807 cDNAs, 11.5 million CAGE tags and 2.4 million GSC tags, suggests that mammalian genomes express an unprecedented number of independent transcripts, of which about half are grouped in Transcriptional Unit (TU) containing non-coding RNAs, while a considerable fraction of these was shown to be non-coding RNA variant of TU containing protein coding mRNAs. In this very large transcript collection, we found extensive transcription overlap identifying a very large number of novel RNAs sense-antisense (S/AS) potential transcript pairs, to which a large number of transcribed repeats and repeat containing RNA has to be added. These S/AS show significant coexpression and are regulated in
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various tissues, organs and cells in our analysis. Experimental evidence shows that RNAs constituting S/AS pairs regulate each other concentration, through RNA-based gene regulation mechanisms such as RNAi intermediates.The FANTOM full-length cDNAs are the collection of the elements and the integrated database provides us the tool to understand the molecular system connecting gene to phenotype. Our next goal is focused on constructing the system to accelerate the analysis of the network of transcription. For this purpose, the deep CAGE technology, the technology to analyze physical binding of transcription factors and DNA, such as Chip on CHIP, and matrix RNAi were integrated into a pipeline of analysis. In this talk the future system to analyze genome network will be discussed.
http://www.gsc.riken.go.jp/eng/output/topics/genome.html
S2e-4 Single molecule imaging of motor proteins in living cells - deciphering physical networks of molecular motions
Hideo Higuchi and Tomonobu M Watanabe Biomedical Engineering Research Organization, Tohoku University, Japan
Motor proteins, e.g., myosin, kinesin and dynein, are involved in membrane transport in a cell. Single-molecule measurements in an in vitro assay provide us great deal of information of motor mechanism. However, physiological conditions in the cell are much different from those in vitro. Here, we developed novel techniques to observe the elementary steps of the movement of motor proteins in living cells. To record the movement of motor proteins in cells with high spatio-temporal resolution, membrane Receptor (HER2) was labeled with stable and intense Quantum dots via antiHER2. They were endocytosed into a breast cancer cell in which HER2 was overexpressed. We observed the movements of the transported vesicle of antiHER2-QD in three dimensions using a new microscopic system. AntiHER2-QD was transported along an actin filament by myosin VI, and toward the nucleus by dynein on microtubules. The position of movement was analyzed with 2 nm and 0.3 ms resolutions. The movement along the membrane consisted of 29 and 16 nm steps. The movements toward and away from the nucleus consisted of successive 8 nm steps. This movement will be generated by kinesin, also composed of sequential 8 nm steps. Thus, the techniques we developed were new and useful tools for investigation of molecular functions of proteins.
http://www.cir.tohoku.ac.jp/higuchi-p/NanoSystem/index.htmhttp://web.tubero.tohoku.ac.jp/~nim/
III S3c FRONTS IN SYSTEMS BIOLOGY 9:15-10:30, October 11
Complex Systems Biology Sub Hall 2S3c-1 Interaction balance coordination as organizing principle in complex systems biology Mihajlo Mesarovic, Sree N.Sreenath and Girish Balakrishnan Complex Systems Biology Center, EECS, Case Western Reserve University Contacts: [email protected]
Complexity and sophistication of behavior of eukaryotes depend directly on their genome regulatory functions. Evidence indicates that evolution of eukaryotes is accompanied with increase in genetic resources allocated to regulatory functions. In human more than 90% of the genetic materials are protein non-coding, including introns -considered as junk genes-but is identified as performing vital regulatory functions leaving only 1.5% for exon-active genes. Progress in understanding complexity in systems biology will depend on understanding eukaryote’s regulatory functions.Obstacles to progress are conceptual and representational. Conceptually engineering concepts like feedbacks - negative and positive - are dominant regulatory motifs in systems biology. They are insufficient to understand organized complexity of eukaryotes. Organizational sciences and in particular mathematical multilevel hierarchical systems theory provide a wealth of new motifs for understanding in systems biology. Two case studies will be presented:• Explanation of angiogenesis as an exemplification of Interaction Balance Coordination Principle (IBCP) not only in cancers growth but also in metastasis (non-local distant action) as well in neural growth. • Modular coordination in JAK-STAT in myeloproliferative diseases.Representationaly, the focus in systems biology should not be restricted to quantification. Non-numerical branches of mathematics are more appropriate since biological phenomena cannot be represented with the precision of classical physics. Result of, mathematical general systems theory will be presented proving an exceedingly broad applicability of IBCP.New direction in systems biology research is needed for a search for coordination motifs as well as experimental validation of IBCP and other newly discovered motifs.
http://eecs.case.edu/people/faculty/mdm5
S3c-2 Coordination of gene expression by RNA operons Jack D. Keene Molecular Genetics & Microbiology, Duke University Medical Center, Durham, N.C. USA
The organization of genes along the genomes of higher eukaryotes does not correlate well with the functions of their encoded proteins as these genomes do not contain DNA operons like bacteria. For example, eukaryotic genes that are clustered in “expression
2929
neighborhoods” may be co-expressed but they do not appear to be functionally related to one another. Studies have suggested that eukaryotic transcription is leaky, sometimes stochastic, and probably not as precisely coordinated as previously thought. However, since the question of how eukaryotic gene expression is coordinated is essentially unknown, it has been assumed that dispersed genes are coordinated by temporal activation of their promoters. The Posttranscriptional RNA Operon model offers a mechanism of coordinated expression for higher eukaryotes that is based on the organization of functionally-related eukaryotic mRNAs within messenger ribonucleoprotein complexes (mRNPs). RNA-binding proteins (RBPs) and microRNAs both interact with discrete groups (classes or modules) of mRNAs that can be regulated together to provide collective functional outcomes and coordinated gene expression networks. These RNA operons or regulons can coordinate and couple mRNA decay, mRNA translation, splicing, export or localization of functionally related genes. I will discuss combinatorial interactions of RBPs and microRNAs that regulate posttranscriptional RNA operons.
http://mgm.duke.edu/faculty/keene/index.htm
S3c-3 Applications of complex systems biology to the study of neural systems Kenneth A. Loparo EECS Department, Case Western Reserve University Contacts: [email protected]
In this talk we will discuss the role of “complexity” in the study of the dynamics of neural systems and how the analysis of complex physiological time series is related to health and disease. Of particular interest is the dynamical process of neural plasticity in developing organisms. In this context, the “triple helix” of nature-nurture-niche plays a critical role in the neurodevelopmental process. Developmental sleep physiology recognizes this interplay and can quantify this interaction through a computational description of the process of “ontogenetic adaptation”. Understanding how remodeling and restructuring of the neural circuits is affected by the interplay between genetics and environment can have a significant impact on a variety of diverse fields including genetics, behavior, developmental psychology, neurobiology, and medicine. Our approach is to develop a computational phenotype that can quantify the process of neurodevelopment and provide a deeper understanding of the role of sleep in the maturational process in developing organisms. Our computational work fills an important gap in integrative neurosciences by identifying biomarkers for neurodevelopment between the molecular and behavioral/cognitive level that can provide additional insight into the neurobiology and dynamical processes of maturation of brain networks in developing organisms. Using computational neurophysiological techniques, including dynamic analyses of temporal features and patterns that are associated with the sleep process, we are able to capture the dynamic interactions among multiple behaviors that comprise the sleep process. Applying these analyses of sleep as phenotypic markers of brain organization and maturation provides a more complete picture of how adaptation and remodeling relates to physiologic function and development.
http://www.case.edu
III S3f FRONTS IN SYSTEMS BIOLOGY 11:00-12:30, October 11
Control and System Theory for Systems Biology Sub Hall 2S3f-1 Robustness analysis of biological networks using sensitivity measures Francis J. Doyle III Dept. of Chemical Engineering, and Biomolecular Science & Engineering, University of California, Santa Barbara, USA Contacts: [email protected]
A property of particular interest in systems biology is the robustness of a biophysical network: the ability to maintain some target level of behavior or performance in the presence of uncertainty and/or perturbations. In biological systems, these disturbances can be environmental (heat, pH, etc.) or intrinsic to the organism (changes in kinetic parameters). While preliminary results are available for simple (low-dimensional, deterministic) biological systems, general tools for analyzing these tradeoffs are the subject of active research.In this talk we introduce tools from systems theory that elucidate design principles in these complex architectures through the analysis of robust and fragile regions of the network. The problems used to illustrate the issue are drawn from circadian rhythm gene networks, hence the tools are extended to deal with oscillatory systems. Examples are presented for Drosophila, Mouse, and Arabidopsis networks. Recent to address discrete stochastic models are also covered. Finally, we highlight some recent results that analyze robustness properties at the tissue level, where intercellular coupling appears to be responsible for the generation of robust rhythms.
http://doyle.chemengr.ucsb.edu
S3f-2 Feedback control regulation of cell division Pablo A. Iglesias The Johns Hopkins University Contacts: [email protected]
During cell division, cells must accurately duplicate and segregate their genetic material before rearranging their morphology so as to produce two daughter cells of equal size. To achieve this, mitosis proceeds as a well-ordered sequence of biochemical events
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involving the temporal and spatial distribution of a wide variety of proteins, regulated by with numerous checkpoints that rely on active feedback loops. In contrast, cytokinesis, the last step in the mechanical separation of the two daughter cells, is typically viewed as an open-loop process, despite the fact that aberrant cytokinesis can lead to tumorigenesis. In this talk we demonstrate that feedback loops are also employed during cytokinesis. Specifically, we will show the presence of mitotic-specific feedback pathways that regulate the location of actin motor and crosslinking proteins vital to cell division. This feedback loop is activated by mechanical perturbations that affect cellular shape. Our results will demonstrate how the study of cellular division can benefit from a systems-level approach.
http://www.ece.jhu.edu/~pi/
S3f-3 The architecture of cellular regulation John Doyle California Institute of Technology Contacts: [email protected]
This talk focuses on architectural and organizational principles of cellular regulation, building on insights about the fundamental nature of complex biological and technological networks drawn from three converging research themes. 1) With molecular biology’s detailed description of components and growing attention to systems biology the organizational principles of biological networks are becoming increasingly apparent (www.sbml.org). 2) Advanced technology’s complexity is now approaching biology’s. While the components differ, there is striking convergence at the network level of architecture and the role of layering, protocols, and feedback control in structuring complex multiscale modularity. New theories of the Internet and related networking technologies have led to test and deployment of new protocols for high performance networking (www.hot.caltech.edu, netlab.caltech.edu). 3) A new mathematical framework for the study of complex networks suggests that this apparent network-level evolutionary convergence within/between biology/technology is not accidental, but follows necessarily from the universal system requirements to be efficient, adaptive, evolvable, and robust to perturbations in their environment and component parts. [1] H. El-Samad, H. Kurata , J.C. Doyle , C.A. Gross, and M. Khammash, 2005, Surviving Heat Shock: Control Strategies for
Robustness and Performance, PNAS 102(8): FEB 22, 2005[2] Jin C, Wei D, Low SH, Bunn J, Choe HD, Doyle JC,et al, FAST TCP: From theory to experiments IEEE NETWORK 19
(1): 4-11 JAN-FEB 2005[3] Doyle et al, (2005), The “Robust Yet Fragile” Nature of the Internet, PNAS 102 (41), October 11, 2005 [4] MA Moritz, ME Morais, LA Summerell, JM Carlson, J Doyle (2005) Wildfires, complexity, and highly optimized tolerance,
PNAS, 102 (50) December 13, 2005; ,[5] H El-Samad , A Papachristodoulou, S Prajna, J Doyle, and M Khammash (2006), Advanced Methods and Algorithms for
Biological Networks Analysis, PROCEEDINGS OF THE IEEE, 94 (4): 832-853 APR 2006[6] Kurata, H El-Samad, R Iwasaki, H Ohtake, JC Doyle, et al. (2006) Module-based analysis of robustness tradeoffs in the
heat shock response system. PLoS Comput Biol 2(7): July 2006[7] M Chiang, SH Low, AR Calderbank, JC. Doyle (2006) Layering As Optimization Decomposition, PROCEEDINGS OF
THE IEEE, to appear
http://www.cds.caltech.edu/sostools/http://www.cds.caltech.edu/~doyle/
III S3g FRONTS IN SYSTEMS BIOLOGY 14:00-16:30, October 11
Synthetic Biology Main HallS3g-1 Languages and grammars for programming in DNA Drew Endy MIT Biological Engineering, Massachusetts Institute of Technology Contacts: [email protected]
Biology is going through a fundamental transition, from preexisting, natural, and evolving systems to synthetic, engineered, and disposable systems. Here, we’ll review how the adoption of past engineering lessons such as standardization and abstraction are beginning to make the process of engineering biology simpler, cheaper, and more reliable. We’ll also explore how and why engineers are beginning to redesign simple genomes from scratch. From these technical foundations we’ll discuss recent and imaginable future progress on the engineering of living organisms to process information, construct materials, produce chemicals, provide energy and food, and help maintain or enhance human health and our environment. The talk will end with a brief discussion for what needs to happen next.
http://mit.edu/endy/
S3g-2 Applications in systems and synthetic biology Adam Arkin University of California, Berkeley
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S3g-3 Impact of a whole genome cloning on systems biology Mitsuhiro Itaya Institute for Advanced Biosciences, Keio University Contacts: [email protected]
Most DNA cloning vectors cannot handle a large number of genes at one time. We have developed a method to transfer whole genomes from one bacterial species into another (1). The BGM cloning vector derived from the 4.2-Mb genome of Bacillus subtilis bacterium was suitable for target DNA, the 3.5-Mb genome of the nonpathogenic, unicellular photosynthetic bacterium Synechocystis. The resultant bacterium putatively named as CyanoBacillus, with a composite genome 7.7 Mb in size, grew only in the B. subtilis culture medium in which the cloning procedures were carried out. Technical breakthroughs unveiled for the first time biological significance such as exclusiveness of the second RNA operon genes (rrn), and structural requirement of symmetry on bacterial chromosome in vivo.(1) Itaya, M., Tsuge, K. Koizumi, M., and Fujita, K. Combining two genomes in one Cell: Stable cloning of the Synechosystis PCC6803 genome in the Bacillus subtilis 168 genome. Proc. Natl. Acad. Sci., U. S. A., 102, 15971-15976 (2005).
http://www.iab.keio.ac.jp/ja/jprofile_mitsuhiro_itaya.html
S3g-4 Adaptive response of a gene network to environmental changes by fittness-induced attractor selection Tetsuya Yomo Department of Bioinformatics Engineering, Graduate School of Information Science and Technology, Graduate School of
Frontier Biosciences and Complex Systems Biology Project, ERATO, JST, Osaka University Contacts: [email protected]
Cells switch between various stable genetic programs (attractors) to accommodate environmental conditions. Signal transduction machineries efficiently convey environmental changes to gene expression. However, since the number of environmental conditions is larger than that of commensurate cellular programs, not every condition, notably those that are rarely encountered, have led to the evolution of a cognate signal transduction pathway. Here we show that in the absence of signal transduction, switching to the appropriate attractor state expressing the genes that afford adaptation to the external condition can occur. In a synthetic bistable gene switch in Escherichia coli in which mutually inhibitory operons govern the expression of two genes required in two alternative nutritional environments, cells reliably selected the “adaptive attractor” driven by gene expression noise. A mathematical model suggests that the non-adaptive attractor state is avoided because the lower cellular activity suppresses mRNA metabolism, leading to larger fluctuations in gene expression which renders the non-adaptive state less stable. Although attractor selection is not as efficient as signal transduction via a dedicated cascade, it is simple and robust and may represent the general primordial mechanism for adaptive responses that preceded the evolution of signaling cascades for the frequently encountered environmental changes.
http://www-symbio.ist.osaka-u.ac.jp/sbe.html
S3g-5 Programmable bacterial catalysts Vítor Martins dos Santos, Miguel Godinho de Almeida, Jacek Puchalka, Amit Khachane, Kenneth Timmis German Research Centre for Biotechnology (GBF), Division of Microbiology, Braunschweig, Germany Contacts: [email protected]
We will report on the preliminary results of a transnational, recently begun project that aims at constructing a functioning, streamlined bacterial cell devoid of most of its genome and endowed with a series of highly coordinated, newly assembled genetic circuits for the biotransformation of a range of chloroaromatics into high added value compounds and that include circuits for synchronized behaviour, noise minimisation and/or low-temperature biocatalysis and, in addition, amenable to directed, accelerated evolution so that the function of each or some of the individual circuits can be optimised. This will be tested for the production of high added value compounds from chloroaromatics in bioreactors. By achieving such constructs as a proof-of-principle, it is aimed at establishing a solid, rational framework for the engineering of cells performing effectively and efficiently specific functions of biotechnological and medical interest. This encompasses the production of series of different, versatile circuits and the corresponding components that can be used as building blocks in circuit engineering. The proposed workflow intertwines mathematical modelling with wet-lab experimental work as an integral module at every stage.
www.helmholtz-hzi.de
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III S3i FRONTS IN SYSTEMS BIOLOGY 14:00-16:30, October 11
Novel computational environments for systems biology Sub Hall 2S3i-1 Linking text with knowledge - challenges in text mining for biology Junichi Tsujii Department of Computer Science, Faculty of Information Science and Technology, The University of Tokyo, The University of
Manchester and National Centre for Text Mining (NaCTeM), Manchester Interdisciplinary Biocentre Contacts: [email protected], [email protected]
While there are a few Text Mining tools on market, they hardly satisfy actual requirements of biologists. Simple application of data mining techniques to text does not work. Since language and text have their own inherent structures, it is essential for TM tools to be able to recognize and exploit their structures to reveal information encoded in them. However, the major difficulties in treating information encoded in language are caused by the nature of the mapping between surface linguistic forms and information conveyed by them. It is hugely ambiguous. Furthermore, the same information can be conveyed by using many different surface forms. Before more ambitious goals such as discovering new, hidden knowledge, we have to resolve these essential properties of the mapping between language and information.Although techniques have been developed in natural language processing (NLP) research to resolve the difficulties, they were considered, until very recently, non-deployable for large scale text mining. However, due to recent technological development in corpus-based NLP techniques, many of NLP techniques have become robust and efficient enough for large scale text mining applications. The progresses in the filed have been enormous, which will open up many possible applications of NLP-based Text Mining in the near future.
http://www-tsujii.is.s.u-tokyo.ac.jp/
S3i-2 Going with the flow: distributed computing for systems biology using Taverna Carole Goble The School of Computer Science, The University of Manchester, UK Contacts: [email protected]
Linking together the many hundreds of publicly available or privately generated data sets and analytical tools into discovery pipelines is a key necessity for Systems Biology, but also a costly and frustrating business. Workflows offer a flexible and systematic approach for representing and executing these in silico experimental protocols. The Taverna workbench, a product of the myGrid project (http://www.mygrid.org.uk), is an open source workflow system that enables the scientists themselves to design, build and run workflows that control the flow of data between web-enabled and local Java resources. It has been designed primarily for the Life Sciences, and developed with a great deal of support and practical feedback from bioinformaticians. Taverna is very popular. It is used for gene alerting, sequence annotation, proteomics, functional genomics, chemoinformatics, systems biology and protein structure prediction applications, amongst others. The background and philosophy behind Taverna will be presented, highlighting how it complements a data warehouse approach. A number of real examples of its use in Systems Biology will be presented. The need for further tools and better data publishing practices will be highlighted, as will reflections on the changes to scientific practice observed when biologists adopt a Taverna approach to scientific discovery.
http://www.cs.man.ac.uk/~carole
S3i-3 The DREAM project: establishing a community-based gold standard for systems biology Andrea Califano Columbia University Medical Center
S3i-4 The systems biology markup language (SBML): where it's been and where it's going Michael Hucka California Institute of Technology Contacts: [email protected]
A cornerstone of systems biology is the use of computational modeling, by which hypotheses can be cast into a quantitative form that can be tested systematically. The use of computational modeling by biologists promises to pave the way for more rigorous analyses of biological functions, and ultimately will lead to new and better treatments for disease.A crucial enabler for more widespread use of computational modeling in biology is reaching agreement on how to represent, store, and communicate models between software tools. The Systems Biology Markup Language (SBML) project is an effort to create a machine-readable format for representing computational models in biology. By supporting SBML as an input and output format, different software tools can operate on the same representation of a model, removing chances for errors in translation and assuring a common starting point for analyses and simulations. SBML has become the most successful effort in this direction so far, with over 100 software systems supporting it today.In this presentation, I will discuss the current state of SBML, including recent developments such as this year's finalization of Version
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2 of SBML Level 2. I will also survey some of the software tools that support SBML, and related projects that have arisen to support more effective use of computational models. Lastly, I will discuss expected future developments in SBML.
http://sbml.orghttp://bnmc.caltech.edu
S3i-5 MIRIAM and BioModels DB: curation and exchange of quantitative models Nicolas Le Novere EMBL-EBI, Hinxton, United Kingdom Contacts: [email protected]
With Computational Systems Biology now being "mainstream" life science, the generation and use of quantitative models is no longer a lonely exercise reserved to the unchallenged specialist. On the contrary, those models have to be verified and, if possible, reused. Beside the effort of developing common syntaxes, the community of modellers and tool developers recently focused on the semantics of models. MIRIAM is a standard that describes the conditions which a biological model should meet to be correctly understood and reused. The guidelines address the problem of the correspondance of the model with its reference description, the details of the creation process and the annotation of all model components. An effective way of increasing the exchange of models compliant with MIRIAM is to store them in a relational database. BioModels Database is a resource that stores curated versions of peer-reviewed models. After careful verification of the syntax and semantics of a model, including its simulation, a thorough annotation procedure ensures that the model will be retrieved quickly and its components easily identified. Models can be retrieved in various formats. It is expected that those efforts will increase the average quality of published quantitative models, and make those models a standard piece of each biologist's toolbox.
http://www.ebi.ac.uk/~lenov/
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ihar
a
BC22
S
yste
m-l
evel
per
turb
atio
n an
alys
is o
f m
amm
alia
n ci
rcad
ian
cloc
kTe
tsuy
a J.
Kob
ayas
hi, H
idek
i Uka
i, R
ikuh
iro
G. Y
amad
a, M
aki U
kai-
Tade
num
a, T
akao
K
ondo
, Hir
oki R
. Ued
a
BC23
P
redi
ctin
g re
gula
tion
of
the
phos
phor
ylat
ion
cycl
e of
Kai
C c
lock
pro
tein
usi
ng
mat
hem
atic
al m
odel
sH
isak
o Ta
kiga
wa-
Imam
ura,
Ats
ushi
Moc
hizu
ki
BC24
Fo
rwar
d an
d in
vers
e bi
furc
atio
n an
alys
is o
f a
synt
heti
c ge
ne r
egul
ator
y ne
twor
k
(the
rep
ress
ilat
or)
Stef
an M
uell
er, J
ames
Lu
BC25
M
odel
ing
the
G1/
S p
hase
tran
siti
on d
urin
g liv
er r
egen
erat
ion
A. B
eed,
S. L
egew
ie, P
. Wes
tern
ark,
H. H
erze
l
BC26
T
he e
ffec
t of
tran
scri
ptio
nal d
elay
s in
cyc
lic
bioc
hem
ical
Ger
man
A. E
ncis
o
BC27
G
enom
e-w
ide
iden
tifi
cati
on o
f m
orni
ng e
lem
ent r
egul
ator
s by
hig
h-th
roug
hput
cel
l-ba
sed
scre
enin
gH
iros
hi F
ujis
him
a, T
akey
a K
asuk
awa,
Hid
eki U
kai,
Ryo
taku
Kit
o, H
irok
i R. U
eda
BC28
S
yste
m-l
evel
iden
tifi
cati
on o
f ro
bust
and
sen
sitiv
e ge
ne e
xpre
ssio
nTa
keya
Kas
ukaw
a, T
etsu
ya J
. Kob
ayas
hi, R
ikuh
iro
G. Y
amad
a, J
ohn
B. H
ogen
esch
, H
irok
i R. U
eda
35
BC29
C
ell-
base
d sc
reen
ing
for
stab
ilit
y re
gula
tors
of
mam
mal
ian
cloc
k pr
otei
nsR
yota
ku K
ito,
Hir
oshi
Fuj
ishi
ma,
Hid
eki U
kai,
Yoic
hi M
inam
i, H
irok
i R. U
eda
BC30
K
inet
ic m
odel
ing
of g
ene
expr
essi
on. S
tudy
of
ace
oper
on g
enet
ic r
egul
atio
n in
E
sche
rich
ia c
oli c
ells
Kir
ill P
esko
v, O
leg
Dem
in
Yea
st S
yste
ms
Bio
logy
BY01
D
etec
ting
cel
l cyc
le r
egul
ated
gen
es o
f S.
pom
be b
y us
ing
nMD
S w
itho
ut s
inus
oida
l fi
ttin
gY-
H. T
aguc
hi
BY02
In
tegr
ativ
e st
rate
gy f
or c
onst
ruct
ing
a la
rge-
scal
e ce
ll c
ycle
mod
el in
sil
ico
Yuya
Fuk
ano,
Shu
nsuk
e Ya
mam
ichi
, Hir
oyuk
i Kur
ata
BY03
In
ferr
ing
phys
ical
mod
els
of p
rote
in-D
NA
bin
ding
fro
m h
igh-
thro
ughp
ut d
ata
Just
in B
. Kin
ney,
Gas
per
Tka
cik,
Cur
tis
G. C
alla
n, J
r.
BY04
P
rote
in-p
rote
in in
flue
nce
netw
orks
in S
acch
arom
yces
cer
evis
iae
Kar
thik
Ram
an, N
agas
uma
Cha
ndra
BY05
E
ngin
eeri
ng r
edox
bal
ance
in S
acch
arom
yces
cer
evis
iae
to r
educ
e ov
erfl
ow m
etab
olis
mG
outh
am V
emur
i, J
ens
Nie
lsen
, Lis
beth
Ols
son
BY06
D
iffe
rent
ial e
volu
tiona
ry c
onse
rvat
ion
of m
otif
mod
es in
the
yeas
t pro
tein
inte
ract
ion
netw
ork
Wen
-Shy
ong
Tzou
, Wei
-Po
Lee
BY07
A
naly
sis
of r
egul
ator
y ne
twor
ks o
f th
e m
itot
ic e
xit s
yste
m in
Sac
char
omyc
es c
erev
isia
eW
ee K
heng
Yio
, Utt
am S
uran
a, B
alta
zar
Agu
da
BY08
Q
uant
ifica
tion
of
uppe
r li
mit
Cdc
pro
tein
s do
sage
in S
. cer
evis
iae.
Yuki
Shi
miz
u-Yo
shid
a, H
isao
Mor
iya,
Hir
oaki
Kit
ano
BY09
O
rgan
izat
ion
of th
e ye
ast m
etap
hase
spi
ndle
Eug
enio
Mar
co, J
onas
F. D
orn,
Khu
loud
Jaq
aman
, Gre
gory
S. J
elso
n, G
aude
nz
Dan
user
, Pet
er K
. Sor
ger
BY11
D
ynam
ics
and
regu
lati
on o
f th
e he
tero
trim
eric
G-p
rote
in c
ycle
Tau-
Mu
Yi,
Hir
omas
a Ta
naka
, Tra
vis
Moo
re
BY12
In
vest
igat
ion
of f
erm
enta
tion
cha
ract
eris
tics
of
the
drug
res
ista
nce
gene
QD
R3
in S
. ce
revi
siae
Duy
gu D
ikic
iogl
u, P
inar
Pir
, Z. I
lsen
Ons
an, K
utlu
O. U
lgen
, Bet
ul K
irda
r,
Stev
e G
. Oli
ver
BY13
Y
east
sys
tem
s bi
olog
y ne
twor
kR
ober
ta M
usta
cchi
, Jen
s N
iels
en
BY14
C
ompu
tati
onal
ana
lysi
s of
rel
evan
t asp
ects
of
the
G1
to S
tran
siti
on m
odel
in b
uddi
ng
yeas
tM
atte
o B
arbe
ris,
Edd
a K
lipp
, Mar
co V
anon
i, L
ilia
Alb
ergh
ina
BY15
A
sys
tem
s bi
olog
y st
udy
of th
e ki
neti
cs o
f Sa
ccha
rom
yces
cer
evis
iae
resp
onse
to
oxid
ativ
e st
ress
indu
ced
by c
umen
e hy
drop
erox
ide
Lee
pika
Tul
i, A
na M
arti
ns, W
ei S
ha, P
edro
Men
des,
Vla
dim
ir S
hula
ev
Met
abol
omic
s an
d B
iopr
oces
s
BM01
In
sil
ico
anal
ysis
of
syst
emat
ic r
espo
nse
to th
e ch
ange
of
enzy
me
conc
entr
atio
n ba
sed
on
glyc
olys
is b
ioch
emic
al n
etw
ork
of S
acch
arom
yces
cer
evis
iae
Xue
lian
Yan
g, M
ing
Yan,
Lin
Xu,
Dec
hong
Kon
g, C
hang
qing
Liu
, Pin
gkai
Ouy
ang
BM02
S
imul
atio
n an
d an
alys
is o
f et
hano
l con
cent
rati
on r
espo
nse
to e
nzym
e am
ount
cha
nges
in
S. c
erev
isia
e gl
ycol
ysis
pat
hway
mod
elD
echo
ng K
ong,
Xue
lian
Yan
g, M
ing
Yan,
Cha
ngqi
ng L
iu, L
in X
u
BM03
C
onta
ct-d
epen
dent
indu
ctio
n of
per
sist
ence
Mic
hael
S. K
oeri
s, M
icha
el A
. Koh
ansk
i, K
yle
R. A
llis
on, G
abor
Bal
azsi
, Bor
is H
ayet
e,
Jam
es J
. Col
lins
BM04
S
yste
m a
naly
sis
and
expe
rim
enta
l val
idat
ion
of g
luco
se u
ptak
e ra
te b
y ph
osph
otra
nsfe
rase
sy
stem
in E
sche
rich
ia c
oli
Yous
uke
Nis
hio,
Yos
hihi
ro U
suda
, Kaz
uhik
o M
atsu
i, H
iroy
uki K
urat
a
BM05
C
alci
um-d
epen
dent
act
ivat
ion
and
mem
bran
e as
soci
atio
n of
the
nont
radi
tion
al m
aize
li
poxy
gena
se in
tran
sgen
ic r
ice
plan
tsO
ksoo
Han
, Kyo
ung
won
Cho
, Sun
gkuk
Jan
g
BM06
E
ffica
cy e
valu
atio
n of
gin
seno
side
Rb1
in b
rain
tiss
ue o
f m
ice
expo
sed
to im
mob
iliz
atio
n st
ress
usi
ng G
C/M
S b
ased
on
met
abol
omic
sB
ong
Chu
l Chu
ng, S
ang
Hee
Lee
, Sun
Yeo
u K
im, E
unjo
o H
Lee
BM08
A
naly
sis
of p
hyto
alex
ins
by h
igh
perf
orm
ance
liqu
id c
hrom
atog
raph
y-m
ass
spec
trom
etry
(H
PL
C-M
S)
foll
owin
g in
duct
ion
in D
atur
a m
etel
Els
adig
A. E
ltay
eb, F
atm
a A
l Bar
wan
i, B
asm
a A
l Sal
hi, T
. Kha
n
BM09
H
ypox
ic r
espo
nse
of h
uman
red
blo
od c
ell m
etab
olis
m a
sses
sed
by m
etab
olom
ics
and
sim
ulat
ion
Aya
ko K
inos
hita
, Mak
oto
Suem
atsu
, Yoi
chi N
akay
ama,
Tom
oyos
hi S
oga,
M
asar
u To
mit
a
BM10
M
etab
olom
e pr
ofili
ng o
f E
. col
i by
capi
llar
y el
ectr
opho
resi
s us
ing
nove
l tec
hniq
ues
of
mul
ti-w
avel
engt
h sp
ectr
al a
naly
sis
and
data
min
ing
Ars
en B
atag
ov, F
rank
Bag
anz
BM11
M
odel
ling
suc
rose
acc
umul
atio
n in
mat
urin
g su
garc
ane
Laf
ras
Uys
, Joh
ann
M. R
ohw
er
BM12
In
sili
co a
naly
sis
of th
e ca
uses
of
hete
roge
neou
s ge
ne e
xpre
ssio
ns in
live
r am
mon
ia
met
abol
ism
Yasu
hiro
Nai
to, H
iros
hi O
no, H
irom
u N
akaj
ima,
Mas
aru
Tom
ita
36
BM13
D
ynam
ic m
odel
ing
of E
sche
rich
ia c
oli c
entr
al c
arbo
n m
etab
olis
m b
ased
on
mul
ti-o
mic
s da
taN
obuy
oshi
Ish
ii, T
omoy
a B
aba,
Tom
oyos
hi S
oga,
Aki
o K
anai
, Ken
ji N
akah
igas
hi,
Mar
tin
Rob
ert,
Taka
shi T
ogas
hi, T
akas
hi H
iras
awa,
Mik
i Nab
a, K
enta
Hir
ai,
Am
inul
Hoq
ue, Y
uji K
akaz
u, K
aori
Sug
awar
a, S
aori
Iga
rash
i, Sa
tosh
i Har
ada,
Tak
eshi
M
asud
a, N
aoyu
ki S
ugiy
ama,
Kat
suyu
ki Y
ugi,
Kaz
uhar
u A
raka
wa,
Nay
uta
Iwat
a,
Yosh
ihir
o To
ya, T
suyo
shi I
was
aki,
Yoic
hi N
akay
ama,
Aki
ko H
agiy
a, M
asat
aka
Yosh
ino,
Ta
kaak
i Nis
hiok
a, K
azuy
uki S
him
izu,
Hir
otad
a M
ori,
Mas
aru
Tom
ita
BM14
A
com
puta
tion
al m
odel
of
card
iac
mit
ocho
ndri
a: s
imul
atio
n st
udie
s of
Ca2
+-d
epen
dent
re
gula
tion
and
sub
stra
te d
epen
denc
y of
mit
ocho
ndri
al e
nerg
y m
etab
olis
mR
yuta
Sai
to, N
obua
ki S
arai
, Sat
oshi
Mat
suok
a, A
kino
ri N
oma
BM15
M
etab
olic
net
wor
ks: c
onne
ctiv
ity
mat
rix-
base
d is
otop
omer
ana
lysi
s on
Mat
lab/
Oct
ave
Jun
Oht
a
BM16
In
sil
ico
geno
me
scal
e m
odel
ing
of P
seud
omon
as p
utid
a K
T24
40Se
ung
Bum
Soh
n, T
ae Y
ong
Kim
, San
g Yu
p L
ee
BM17
C
utD
B −
a d
atab
ase
of p
rote
olyt
ic e
vent
sYo
shin
obu
Igar
ashi
, Ale
xey
Ero
shki
n, S
vetl
ana
Gra
mat
ikov
a, K
osi G
ram
atik
off,
Jeff
rey
W. S
mit
h, A
dam
God
zik,
And
rei O
ster
man
BM18
M
etaA
naly
zer:
a s
oftw
are
tool
for
ana
lyzi
ng G
C-M
S d
ata
Inho
Par
k, K
iYou
ng L
ee, K
iryo
ng H
a, D
oheo
n L
ee, K
wan
g H
. Lee
BM19
P
redi
ctio
n of
sul
fur
stre
ss r
espo
nses
in A
rabi
dops
is th
alia
naR
yoko
Mor
ioka
, Shi
gehi
ko K
anay
a, M
itsu
ru Y
ano,
Mas
ami Y
. Hir
ai, K
azuk
i Sai
to
BM20
H
igh-
thro
ughp
ut p
rote
omic
iden
tifica
tion
of th
erm
al s
tabl
e pr
otei
ns f
rom
ther
mop
hilic
ba
cter
iaSh
ir-L
y H
uang
, Zha
ng-y
an H
uang
, Yu-
Jing
Zhu
ang,
Yu-
Lin
g Su
BM21
S
erum
met
abol
omic
pro
fili
ng to
stu
dy h
orm
one
acti
ons:
the
case
of
horm
onal
reg
ulat
ion
of g
ende
r di
ffer
ence
sL
ouis
a C
heun
g, H
ans
Sten
lund
, Pet
ra T
olle
t-E
gnel
l, T
hom
as M
orit
z,
Am
ilca
r F
lore
s-M
oral
es
Dev
elop
men
tal S
yste
ms
Bio
logy
BD01
G
row
th-b
ased
mor
phog
enes
is o
f ve
rteb
rate
lim
b bu
dYo
shih
iro
Mor
ishi
ta, Y
oh I
was
a
BD02
Pa
tter
n fo
rmat
ion
of p
lant
leaf
ven
atio
nH
iron
ori F
ujit
a, A
tsus
hi M
ochi
zuki
BD03
M
athe
mat
ical
mod
elin
g fo
r pa
tter
n fo
rmat
ion
of d
endr
ite
Kao
ru S
ugim
ura,
Tad
ashi
Uem
ura,
Ats
ushi
Moc
hizu
ki
BD04
T
he m
echa
nism
of
cell
dif
fere
ntat
ion
in B
acil
lus
subt
ilis
Dag
mar
Ibe
r, J
oann
a C
lark
son,
Mic
hael
D. Y
udki
n, I
ain
D. C
ampb
ell
BD05
M
odel
ing
and
sim
ulat
ion
of c
ardi
omyo
cyte
dev
elop
men
tH
itom
i Ito
h, Y
asuh
iro
Nai
to, M
asar
u To
mit
a
BD06
Id
enti
fica
tion
of
a ge
neti
c m
odifi
er o
f co
ngen
ital
hea
rt d
efec
t in
Type
IIA
pro
coll
agen
de
fici
ent m
utan
t mic
e su
gges
ts a
dyn
amic
reg
ulat
ory
syst
em in
car
diac
dev
elop
men
tP
aul L
. F. T
ang,
Ala
n Y.
B. T
ang,
Kat
hryn
S. E
. Che
ah, Y
ou-q
iang
Son
g
BD07
G
enom
e ba
sed-
met
abol
ic n
etw
ork
of M
annh
eim
ia s
ucci
nici
prod
ucen
s us
ing
upda
ted
geno
me
anno
tati
onTa
e Yo
ng K
im, J
in S
ik K
im, H
yun
Uk
Kim
, Jon
g M
yeon
g Pa
rk, H
yoha
k So
ng,
Sang
Yup
Lee
BD08
L
ogic
al m
odel
of
the
regu
lato
ry n
etw
ork
defi
ning
the
dors
al-v
entr
al b
ound
ary
of
th
e dr
osop
hila
win
g im
agin
al d
isc
Ait
or G
onza
lez,
Cla
udin
e C
haou
iya,
Den
is T
hief
fry
BD09
M
odel
ing
embr
yoni
c de
velo
pmen
t in
Dro
soph
ila
by e
volu
tion
ary
lear
ning
of
dyna
mic
al
syst
emSo
o-Ji
n K
im, J
e-K
eun
Rhe
e, J
in-W
u N
am, J
e-G
un J
oung
, Byo
ung-
Tak
Zha
ng
BD10
A
rtifi
cial
ant
s de
posi
t phe
rom
one
to s
earc
h fo
r re
gula
tory
DN
A e
lem
ents
Yunl
ong
Liu
, Hir
oki Y
okot
a
BD11
S
impl
ified
mod
els
of g
row
th f
or c
ells
and
tiss
ues
Eri
c M
jols
ness
, Ser
gey
Nik
olae
v, P
rzem
ek P
rusi
nkie
wic
z, A
lex
Sado
vsky
, S. F
adee
v,
Nik
olay
Kol
chan
ov
BD12
Fa
ctor
s di
ffer
enti
atin
g ce
ll f
ates
in a
pro
neur
al c
lust
erC
hao-
Pin
g (C
herr
i) H
su
BD13
A
mod
el f
or d
ynam
ic p
osit
ioni
ng o
f ce
ntro
som
es in
C. e
lega
ns e
mbr
yo b
ased
on
imag
e pr
oces
sing
ana
lyse
sA
kats
uki K
imur
a, S
huic
hi O
nam
i
BD14
S
imul
atin
g ev
olut
ion
and
deve
lopm
ent i
n an
imal
bod
y pl
anK
oich
i Fuj
imot
o, S
huji
Ish
ihar
a, K
unih
iko
Kan
eko
BD15
P
redi
ctio
n of
cel
lula
r be
havi
or d
urin
g ce
ll-s
orti
ng a
nd la
yer
form
atio
n of
cer
ebra
l cor
tex
by a
n in
sil
ico
cell
mod
elTa
kuya
Mae
da, I
tsuk
i Aji
oka,
Kaz
unor
i Nak
ajim
a
BD16
3D
Mon
te C
arlo
sto
chas
tic
sim
ulat
ion
of b
acte
rial
div
isio
n si
te p
lace
men
t on
a gr
aphi
cs
proc
essi
ng u
nit i
s si
gnifi
cant
ly f
aste
r th
an c
onve
ntio
nal C
PU
impl
emen
tati
onSa
tya
Nan
da V
el A
rjun
an, A
nton
Kra
tz, M
asar
u To
mit
a
BD18
G
ener
atio
n of
rob
ust l
eft-
righ
t asy
mm
etry
in th
e m
ouse
em
bryo
req
uire
s a
self
-en
hanc
emen
t and
late
ral-
inhi
biti
on s
yste
mTe
tsuy
a N
akam
ura,
Nao
ki M
ine,
Ets
ushi
Nak
aguc
hi, A
tsus
hi M
ochi
zuki
, M
asam
ichi
Yam
amot
o, K
enta
Yas
hiro
, Chi
kara
Men
o, H
iros
hi H
amad
a
BD19
A
n au
xin
tran
spor
t mod
el f
or r
egul
atio
n of
pla
nt o
rgan
init
iati
onH
enri
k Jo
nsso
n, M
arcu
s H
eisl
er, B
ruce
E. S
hapi
ro, E
llio
t M. M
eyer
owit
z, E
ric
Mjo
lsne
ss
BD20
D
egra
dati
on o
f co
ir p
ith
by th
e cy
anob
acte
rium
Osc
illa
tori
a sp
. and
its
valu
e ad
ded
prod
ucts
Seth
uram
an P
rabh
a, B
alai
ah A
nand
hraj
, Vis
wad
evan
Vis
waj
ith,
Pal
aniv
el V
aral
aksh
mih
, P
icha
imut
hu A
brah
am C
hris
toph
er, P
erum
al M
alli
ga
37
BD21
U
se o
f eu
geno
l as
seed
-bor
ne f
ungi
con
trol
ler
in p
akch
oi(b
rass
ica
chin
ensi
s L
.) f
or s
eed
coat
ing
tech
nolo
gyN
uchn
apa
Kot
abin
, Non
glak
Sai
thep
, Ara
ya J
atis
atie
nr, C
haiw
at J
atis
atie
nr
BD22
Q
uant
itat
ive
phen
otyp
ic a
naly
sis
of C
. ele
gans
em
bryo
sK
oji K
yoda
, Shu
ichi
Ona
mi
Syst
ems
Neu
robi
olog
y
BN01
S
yste
mic
mod
el f
or th
e C
a2+
sig
nall
ing
in th
e ne
uron
al c
ell
Cri
stin
a -
Mar
ia D
abu
BN02
Id
enti
fyin
g m
olec
ular
pat
hway
s un
derl
ying
syn
apti
c fu
ncti
on a
nd d
isea
seA
ndre
w J
. Poc
klin
gton
, Set
h G
. N. G
rant
, J. D
ougl
as A
rmst
rong
BN03
S
imul
atio
n of
che
mot
acti
c ne
twor
ks in
nem
atod
e C
. ele
gans
: is
ther
e an
y ch
ange
on
netw
orks
by
expo
sure
to io
nizi
ng r
adia
tion
?M
ichi
yo S
uzuk
i, T
etsu
ya S
akas
hita
, Tos
hio
Tsuj
i, K
ana
Fuk
amot
o, N
obuy
uki H
amad
a,
Yasu
hiko
Kob
ayas
hi
BN04
P
redi
ctio
n an
d va
lida
tion
of
a ti
min
g-de
tect
ion
mec
hani
sm f
or s
pike
tim
ing-
depe
nden
t pl
asti
city
Hid
etos
hi U
raku
bo, R
ober
t C. F
roem
ke, S
hiny
a K
urod
a
BN05
R
eali
stic
mod
els
of th
e N
MD
A r
ecep
tor
com
plex
Mel
anie
Ste
fan,
Nic
olas
Le
Nov
ere
BN06
A
kin
etic
mod
el o
f co
rtic
o-st
riat
al s
ynap
tic
plas
tici
tyTa
kash
i Nak
ano,
Tom
okaz
u D
oi, J
unic
hiro
Yos
him
oto,
Ken
ji D
oya
BN07
T
he h
eter
ogen
eity
of
astr
ocyt
ic c
alci
um r
espo
nses
may
be
regu
late
d by
con
cent
rati
on o
f in
trac
ellu
lar
enzy
mes
Isao
Got
o, K
iyoh
isa
Nat
sum
e
BN08
D
AR
PP
-32,
a c
ompl
ex in
tegr
ator
of
dopa
min
e an
d gl
utam
ate
sign
alli
ngE
ric
Fer
nand
ez, R
enau
d Sc
hiap
pa, J
ean-
Ant
oine
Gir
ault
, Nic
olas
Le
Nov
ere
Sign
al T
rans
duct
ion
BS01
H
ypot
hesi
s te
stin
g an
d m
odel
dis
crim
inat
ion
in y
east
osm
osen
sing
Joer
g Sc
habe
r, B
odil
Nor
dlan
der,
Dag
mar
a M
edra
la, S
tefa
n H
ohm
ann,
Edd
a K
lipp
BS03
Fi
ne tu
ning
of
Mdm
2-M
dmX
-p53
reg
ulat
ory
netw
ork
dyna
mic
s by
a r
eser
voir
com
plex
Sohy
oung
Kim
, Mir
it I
. Ala
djem
, Geo
ffery
B. M
cFad
den,
Kur
t W. K
ohn
BS04
A
naly
sis
of C
heA
-Che
Yp
affi
nity
and
ada
ptat
ion
erro
r in
bac
teri
al c
hem
otax
isYu
ri M
atsu
zaki
, Shi
nich
i Kik
uchi
, Mas
aru
Tom
ita
BS05
D
ynam
ic m
odel
ing
of th
e gp
130-
JAK
1-S
TAT
3 si
gnal
ing
path
way
in p
rim
ary
hepa
tocy
tes
Seba
stia
n B
ohl,
Tho
mas
Mai
wal
d, T
hom
as F
rahm
, Jen
s Ti
mm
er, U
rsul
a K
ling
mue
ller
BS06
L
ocal
mod
el f
or n
eutr
ophi
l gra
dien
t sen
sing
and
pol
ariz
atio
nM
atth
ew O
nsum
, Chr
isto
pher
V. R
ao
BS07
T
he y
east
map
Mar
cus
Kra
ntz,
Ste
fan
Hoh
man
n, H
iroa
ki K
itan
o
BS08
M
odel
ling
the
yeas
t MA
P-K
inas
e ne
twor
kC
arl-
Fre
drik
Tig
er, M
arcu
s K
rant
z, S
tefa
n H
ohm
ann,
Hir
oaki
Kit
ano
BS09
M
onit
orin
g M
AP
K o
smo-
sign
alin
g in
indi
vidu
al y
east
cel
lsD
ale
Muz
zey,
Car
los
A. G
omez
-Uri
be, J
erom
e T.
Met
teta
l, A
lexa
nder
van
Oud
enaa
rden
BS10
E
xper
imen
tal a
naly
sis
and
quan
tita
tive
mod
elin
g of
inte
ract
ions
bet
wee
n se
roto
nin
rece
ptor
sig
nali
ng p
athw
ays
Chi
ung-
wen
Cha
ng, R
avi I
yeng
ar, H
arel
Wei
nste
in
BS11
H
MG
B1
asso
ciat
ed in
trac
ellu
lar
netw
ork
Xia
o P
eng,
Kam
-Len
Dan
iel L
ee, C
hi-H
ung
Tzan
g, Q
i Zha
ng, M
eng-
Su Y
ang
BS12
M
odel
-bas
ed r
eal-
tim
e an
alys
is a
nd in
sil
ico
para
met
er id
enti
fica
tion
of
Jak/
STA
T s
igna
l tr
ansd
ucti
on in
sin
gle
cell
sM
arti
n M
onni
gman
n, D
irk
Eng
el, A
ndre
as H
errm
ann,
Mic
hael
Vog
t,
Pet
er C
. Hei
nric
h, G
erha
rd M
uell
er-N
ewen
BS13
Ly
soph
osph
atid
ylch
olin
e st
imul
ates
incr
ease
d le
vel o
f tr
ansc
ript
of
proi
nflam
mat
ory
gene
s in
mac
roph
ages
Jann
e O
estv
ang,
Han
s-R
icha
rdt B
ratt
bakk
, Sju
r H
useb
y, M
ette
Lan
gaas
, A
stri
d L
aegr
eid,
Ber
it J
ohan
sen
BS14
A
t the
inte
rfac
e of
exp
erim
ent a
nd th
eory
: cen
tral
mec
hani
sms
of T
ype
1 T-
cell
diff
eren
tiatio
nE
dda
Schu
lz, A
ndre
as R
adbr
uch,
Tho
mas
Hoe
fer
BS15
S
yste
ms
biol
ogy
of g
astr
oint
esti
nal t
umou
r bi
olog
y -
stud
ies
of g
astr
in m
edia
ted
regu
lati
on o
f ge
ne e
xpre
ssio
nTo
nje
S. S
teig
edal
, Tor
unn
Bru
land
, Ber
it D
oset
h E
itre
m, E
ndre
And
erss
en,
Liv
Tho
mm
esen
, Ast
rid
Lae
grei
d
BS16
G
loba
l gen
e ex
pres
sion
in H
EK
293
cel
ls w
ith
cont
roll
able
IC
ER
I o
r IIγ
over
expr
essi
onK
rist
ine
Mis
und,
Sun
niva
Hoe
l, T
orun
n B
rula
nd, E
ndre
And
erss
en, A
stri
d L
aegr
eid,
L
iv T
hom
mes
en
BS17
M
odel
ling
of n
egat
ive
feed
back
loop
s re
gula
ting
the
JAK
2/ST
AT
5 si
gnal
tran
sduc
tion
path
way
Juli
e B
achm
ann,
Chr
isti
an F
leck
, Tho
mas
Mai
wal
d, J
ulio
Ver
a G
onza
lez,
O
laf W
olke
nhau
er, J
ens
Tim
mer
, Urs
ula
Kli
ngm
uell
er
BS18
A
lter
ed d
ynam
ic b
ehav
ior
of th
e JA
K2/
STA
T5
sign
alin
g pa
thw
ay b
y S
TAT
5 ov
erex
pres
sion
And
rea
C. P
feife
r, C
hris
tian
Fle
ck, J
ens
Tim
mer
, Urs
ula
Kli
ngm
uell
er
BS19
C
ompu
tati
onal
mod
elin
g of
the
MC
F-7
Erb
B s
igna
ling
net
wor
k an
d an
alys
is o
f li
gand
-de
pend
ent r
espo
nses
Mar
c R
. Bir
twis
tle,
Mar
iko
Hat
akey
ama,
Nor
iko
Yum
oto,
Bab
atun
de A
. Ogu
nnai
ke,
Jan
B. H
oek,
Bor
is N
. Kho
lode
nko
BS20
Fo
rmal
des
crip
tion
of
NF
- κB
pat
hway
, its
rol
e in
apo
ptos
is, c
arci
noge
nesi
s, in
flam
mat
ion
and
way
s of
its
inac
tivat
ion
for
pred
icti
on o
f ne
w ta
rget
s fo
r an
ti-c
ance
r an
d an
ti-
infl
amm
ator
y th
erap
yR
usla
n N
. Sha
ripo
v, A
lla
F. K
olpa
kova
, Fed
or A
. Kol
pako
v
38
BS21
S
caff
old
prot
eins
con
fer
dive
rse
regu
lato
ry p
rope
rtie
s to
pro
tein
kin
ase
casc
ades
Jaso
n L
ocas
ale,
And
rey
Shaw
, Aru
p C
hakr
abor
ty
BS22
O
ptim
al in
form
atio
n pr
oces
sing
in s
mal
l sto
chas
tic
bioc
hem
ical
net
wor
ksIl
ya N
emen
man
, Man
uel J
Mid
dend
orf,
Eta
y Z
iv, C
hris
H W
iggi
ns
BS23
R
espo
nse
of a
rob
ust s
igna
ling
net
wor
k ag
ains
t tar
gete
d pe
rtur
bati
ons
Dhi
raj K
umar
, Shi
lpi J
ayas
wal
, Kan
ury
VS
Rao
BS24
M
AP
K s
igna
ling
net
wor
k pr
oper
ties
giv
ing
rise
to s
peci
fic
cell
ular
fat
e de
cisi
ons
Silv
ia S
anto
s, P
hili
ppe
Bas
tiae
ns
BS25
P
reci
se a
dapt
atio
n in
bac
teri
al c
hem
otax
is th
roug
h "a
ssis
tanc
e ne
ighb
orho
ods"
Rob
ert E
ndre
s, N
ed W
ingr
een
BS26
H
olis
tic
anal
ysis
of
epid
erm
al g
row
th f
acto
r re
cept
or s
igna
ling
pat
hway
Sali
ha D
urm
us, K
. Yal
cin
Arg
a, K
utlu
O. U
lgen
BS27
G
ene
expr
essi
on d
ata
to d
eter
min
e si
gnal
ing
path
way
s fo
r cu
tane
ous
chem
ical
irri
tati
onJa
mes
N. M
cDou
gal
BS28
F
GF
sig
nali
ng n
etw
ork
mod
el in
clud
ing
mul
tipl
e ce
llul
ar c
ompa
rtm
ents
Tats
unor
i Nis
him
ura,
Mas
aru
Tate
no
BS29
E
luci
dati
on o
f th
e hi
dden
dyn
amic
fea
ture
s in
the
ER
K p
athw
ayD
ongs
an K
im, K
wan
g-H
yun
Cho
BS30
E
ndoc
ytos
is a
nd s
igna
ling
: com
peti
tion
of
Rab
pro
tein
s fo
r m
aint
enan
ce a
nd c
atas
trop
he
of s
ubce
llul
ar c
ompa
rtm
ents
Per
la D
el C
onte
-Zer
ial,
Lut
z B
rusc
h, C
laud
io C
olli
net,
Joc
hen
Rin
k,
Yann
is K
alai
dzid
is, A
ndre
as D
euts
ch, M
arin
o Z
eria
l
BS31
E
luci
dati
ng th
e fr
eque
ncy-
deco
ding
mec
hani
sm f
or d
iffe
rent
ial g
onad
otro
pic
subu
nit
gene
exp
ress
ion
Stef
an L
im, Y
u-K
ai T
he, S
ihui
Wan
g, G
unar
etna
m R
ajag
opal
, Phi
lipp
a M
elam
ed
BS32
S
tabi
lity
and
kin
etic
s of
the
TG
F-b
eta
path
way
Pon
tus
Mel
ke, H
enri
k Jo
nsso
n, E
vang
elia
Par
dali
, Pet
er te
n D
ijke
, Car
sten
Pet
erso
n
BS35
U
nder
stan
ding
the
prin
cipl
es o
f th
e co
mpu
tati
onal
pro
cess
per
form
ed b
y is
ofor
ms
in
MA
P k
inas
e ca
scad
eC
elli
na C
ohen
-Sai
don,
Ari
el C
ohen
, Ale
xand
er S
igal
, Nat
alie
Per
zov,
Tam
ar D
anon
, U
ri A
lon
BS36
A
mod
elin
g te
chni
que
base
d on
tran
sfer
fun
ctio
n fo
r bi
olog
ical
sys
tem
s an
d it
s ap
plic
atio
n to
MA
PK
sig
nal t
rans
duct
ion
Taka
shi N
akak
uki,
Nor
iko
Yum
oto,
Tak
ashi
Nak
a, M
arik
o H
atak
eyam
a
BS37
Q
uant
itat
ive
anal
ysis
of
dose
- an
d ti
me-
depe
nden
t ear
ly tr
ansc
ript
ion
cont
roll
ed b
y R
TK
-m
edia
ted
sign
al tr
ansd
ucti
on p
athw
ays
Take
shi N
agas
him
a, H
idet
oshi
Shi
mod
aira
, Kao
ri I
de, T
akas
hi N
akak
uki,
Yu
kita
ka T
ani,
Mar
iko
Hat
akey
ama
BS38
B
iopa
th -
a n
ew a
ppro
ach
to f
orm
al d
escr
ipti
on a
nd s
imul
atio
n of
com
plex
bio
logi
cal
syst
ems
and
proc
esse
sF
edor
Kol
pako
v, R
usla
n Sh
arip
ov, E
kate
rina
Kal
ashn
ikov
a, E
lena
Che
rem
ushk
ina
BS39
T
hres
hold
s in
tran
sien
t dyn
amic
s of
sig
nal t
rans
duct
ion
path
way
sK
atja
Rat
eits
chak
, Ola
f Wol
kenh
auer
BS40
A
com
puta
tion
al m
odel
of T
ype
I in
terf
eron
rec
epto
r si
gnal
ing
path
way
Ivan
Mar
tine
z-F
orer
o, J
aim
e Ir
anzo
, Jor
ge E
lorz
a, P
ablo
Vil
losl
ada
Syst
ems
Bio
logy
for
Med
icin
eSy
stem
s B
iolo
gy f
or D
rug
Dis
cove
ry
MR0
1 A
com
puta
tion
al d
rug
targ
et a
nd d
rug
scre
enin
g pi
peli
neX
ingh
ua S
hi, F
ang
fang
Xia
, Ric
k St
even
s
MR0
2 D
rug
disc
over
y in
sm
all m
olec
ule
met
abol
ic s
pace
Cor
ey A
dam
s, M
ike
Kei
ser,
Pat
rici
a B
abbi
tt, B
rian
Sho
iche
t
MR0
3 F
low
cyt
omet
ric
anal
ysis
and
cyt
otox
icit
y as
say
of e
xtra
cts
of A
stro
dauc
us P
ersi
cus
in
com
pari
son
to D
oxor
ubic
in in
hum
an b
reas
t can
cer T
47D
cel
lsE
brah
im A
zizi
, Moh
amm
adho
ssei
n A
bdol
moh
amm
adi,
Sha
mil
eh F
oula
ddel
, G
hola
mre
za A
min
, Abb
as S
hafie
e
MR0
4 G
enet
ic s
ynth
etic
leth
alit
y sc
reen
ing
by s
hRN
A-m
edia
ted
RN
A in
terf
eren
ce to
olYu
lia
Ein
av, R
euve
n A
gam
i, D
an C
anaa
ni
MR0
5 In
sil
ico
anal
ysis
of
vibr
io v
ulni
ficus
CM
CP
6 m
etab
olis
m f
or th
e fa
cili
tate
d dr
ug ta
rget
ing
Hyu
n U
k K
im, T
ae Y
ong
Kim
, Kw
angj
oon
Jeon
g, S
oo Y
oung
Kim
, Joo
n H
aeng
Rhe
e,
Sang
Yup
Lee
MR0
7 O
ne e
nzym
e ca
n gi
ve b
oth
enan
tiom
ers
Yosu
ke T
erao
, Ken
ji M
iyam
oto,
Hir
omic
hi O
hta
MR0
8 G
enom
e-w
ide
biol
ogic
al r
espo
nse
fing
erpr
inti
ng (
Bio
ReF
) of
trad
itio
nal C
hine
se
med
icin
e fo
rmul
a IS
F-1
rev
eals
a p
oten
tial
rol
e of
hem
e ox
ygen
ase-
1 pa
thw
ay in
the
anti
oxid
ant t
hera
pyJi
anhu
i Ron
g, C
ynth
ie Y
im-H
ing
Che
ung,
Jia
ngan
g Sh
en, P
aul K
won
g-H
ang
Tam
, A
llan
Sik
-Yin
Lau
Car
diov
ascu
lar
Syst
ems
Bio
logy
MV0
1 Id
enti
fica
tion
and
inte
grat
ive
anal
ysis
of
nove
l gen
es w
ith
card
iac
expr
essi
on in
mou
seIn
ju P
ark,
Hoy
ong
Lee
, Tae
wan
Kim
, Do
Han
Kim
, Chu
nghe
e C
ho
MV0
2 D
ynam
ical
ana
lysi
s of
bet
a-ad
rene
rgic
sig
nali
ng p
athw
ays
in c
ardi
ac m
yocy
tes
Sung
-You
ng S
hin,
Won
-Sun
g B
ae, T
ae-H
wan
Kim
, San
g-M
ok C
hoo,
Kw
ang-
Hyu
n C
ho
MV0
3 M
easu
rem
ent o
f ca
lcin
euri
n ac
tivit
y in
HL
-1 c
ell l
ine
by c
apil
lary
ele
ctro
phor
esis
Shei
kh M
d. E
naye
tul B
abar
, Eun
Joo
Son
g, Y
oung
Soo
k Yo
o
MV0
4 A
com
pute
r m
odel
of
beta
1-ad
rene
rgic
sig
nali
ng c
asca
de in
car
diac
myo
cyte
Mas
anor
i Kuz
umot
o, S
atos
hi M
atsu
oka,
Aki
nori
Nom
a
MV0
5 Im
pact
of
a no
n-ge
nom
ic p
athw
ay o
n Q
T in
terv
als
shor
teni
ng b
y te
stos
tero
ne: M
echa
nism
of
sex
-rel
ated
dif
fere
nce
in f
atal
arr
hyth
mia
sJu
nko
Kur
okaw
a, C
hang
-Xi B
ai, T
etsu
shi F
uruk
awa
39
MV0
6 A
nut
rige
nom
ics
appr
oach
to d
efine
a “
life
styl
e al
gori
thm
” to
be
used
in c
hron
ic d
isea
se
prev
enti
on, d
iagn
osis
and
ther
apy.
Inge
rid
Arb
o, H
ans-
Ric
hard
Bra
ttba
kk, S
iv A
agaa
rd, A
nn K
rist
in D
e So
ysa,
In
ge L
inds
eth,
Fed
on L
indb
erg,
Met
te L
anga
as, E
ndre
And
erss
en, B
ard
Kul
seng
, B
erit
Joh
anse
n
MV0
7 M
athe
mat
ical
mod
els
of li
popr
otei
n m
etab
olis
mB
rend
an O
'Mal
ley,
J. P
anov
ska,
M T
inda
ll, L
. War
e, L
Pic
kers
gill
, J K
ing
MV0
8 G
enet
ic a
naly
sis
of th
e ca
lciu
m s
igna
lsom
e in
hea
rt a
nd id
enti
fica
tion
of
mol
ecul
ar h
ubs
invo
lved
in h
eart
fai
lure
Josh
ua S
ung
Woo
Yan
g, Y
ong
Il Y
oum
, In-
Sun
Chu
MV0
9 P
rote
in in
tera
ctio
n ne
twor
k in
E-C
cou
plin
gG
il B
u K
ang,
Jun
Hyu
ck L
ee, M
un-K
youn
g K
im, S
ung
Hyu
n K
im, S
oo H
yun
Eom
MV1
0 C
ompe
nsat
ory
chan
ges
in th
e ac
tivit
y of
gen
etic
net
wor
k of
cal
cium
sig
nall
ing
com
pone
nts
in r
espo
nse
to d
rug-
indu
ced
pert
urba
tion
s of
cal
cium
hom
eost
asis
Youn
g Il
Yeo
m, S
o C
hon
Han
, Jos
hua
Sung
Woo
Yan
g, S
eong
-Min
Par
k, I
n Su
n C
hu
MV1
1 A
nti-
prol
ifer
ativ
e ef
fect
s of
rat
aor
tic
smoo
th m
uscl
e ce
lls
by b
erap
rost
, a P
GI2
ana
logu
e,
thro
ugh
the
indu
ctio
n of
PPA
R-d
elta
and
its
dow
nstr
eam
eff
ecto
r of
iNO
SSh
u-H
ui J
uan,
Ja-
Lin
g L
ee, H
eng
Lin
MV1
2 P
rote
omic
and
met
abol
omic
ana
lysi
s of
HL
-1 c
ardi
omyo
cyte
sE
un J
oo S
ong,
Byu
ng H
wa
Jung
, Bon
g C
hul C
hung
, You
ng S
ook
Yoo
MV1
3 A
con
stru
ctio
n of
larg
e-sc
ale
prot
ein-
prot
ein
inte
ract
ion
netw
ork
of c
alci
um s
igna
ling
pa
thw
ay in
myo
card
ial m
uscl
e sy
stem
and
its
vali
dati
on b
y us
ing
mas
s sp
ectr
omet
ry
base
d hi
gh th
roug
hput
pro
teom
e an
alys
is te
chni
ques
Hye
jin
Song
, Hye
kyun
g K
won
, Zee
-Yon
g P
ark
MV1
4 In
tegr
ated
app
roac
h fo
r si
mul
atio
n of
phy
siol
ogic
al, b
iom
echa
nica
l, an
d m
olec
ular
-ge
neti
cal a
spec
ts o
f ar
teri
al h
yper
tens
ioin
Fedo
r A
. Kol
pako
v, R
usla
n N
. Sha
ripo
v, E
lina
A. B
iber
dorf
, Yur
iy L
. Tra
khin
in,
Mik
hail
V. P
uzan
ov, A
lexa
nder
V. K
oshu
kov,
Ale
xand
er M
. Blo
khin
, Ark
adiy
L. M
arke
l, L
udm
ila
N. I
vano
va
MV1
5 A
ntih
yper
tens
ive
and
endo
thel
inpr
otec
tive
effi
cien
cy o
f at
orva
stat
in a
nd n
ebiv
olol
co
mbi
nati
on in
pat
ient
s w
ith
esse
ntia
l hyp
erte
nsio
nYu
liya
Sha
posh
niko
va
MV1
6 T
heor
etic
al a
naly
sis
of o
xyge
n tr
ansp
ort a
nd N
O d
iffu
sion
insi
de m
icro
vasc
ulat
ure
Ken
ta Y
ashi
ma,
Kot
aro
Oka
MV1
7 H
CN
et: a
n in
tegr
ated
dat
abas
e of
hea
rt a
nd c
alci
um f
unct
iona
l net
wor
ks f
or s
yste
ms
biol
ogy
Seon
g-H
wan
Rho
, Seo
ng-E
ui H
ong,
Do
Han
Kim
MV1
8 E
luci
dati
on o
f a
pote
ntia
l fra
nk-s
tarl
ing
mec
hani
sm th
roug
h m
odel
ing
and
sim
ulat
ion
Nat
alie
S. S
chne
ider
, Tak
ao S
him
ayos
hi, A
kira
Am
ano,
Tet
suya
Mat
suda
MV1
9 C
hara
cter
isti
cs o
f lo
cal a
nd f
ocal
Ca2
+ s
igna
ling
in c
ardi
omyo
cyte
cel
l lin
e H
L-1
Yuhu
a L
i, M
in-J
eong
Son
, Sun
woo
Lee
, Le
Thi
Thu
, Do
Han
Kim
, Jou
ng R
eal A
hn,
Sun-
Hee
Woo
MV2
0 C
ompu
tati
onal
app
roac
hes
for
regu
lati
on o
f L
-typ
e ca
lciu
m c
hann
el b
y ph
osph
oryl
atio
n in
car
diac
myo
cyte
sM
asay
uki T
akah
ashi
, Ken
ta Y
ashi
ma,
Koh
ji H
otta
, Kot
aro
Oka
MV2
1 A
ntii
sche
mic
effi
cien
cy o
f at
orva
stat
in in
the
pati
ents
wit
h is
chem
ic h
eart
dis
ease
sYu
liya
Sha
posh
niko
va, V
era
Shko
lnik
Syst
ems
Imm
unol
ogy
MI0
1 S
truc
tura
l ana
lysi
s of
the
T-ce
ll-r
ecep
tor-
indu
ced
sign
alin
g ne
twor
kJu
lio
Saez
-Rod
rigu
ez, L
uca
Sim
eoni
, Jon
atha
n L
indq
uist
, Reb
ecca
Hem
enw
ay,
Urs
ula
Bom
mha
rdt,
Bor
ge A
rndt
, Utz
-Uw
e H
aus,
Rob
ert W
eism
ante
l,
Ern
st D
iete
r G
ille
s, S
teff
en K
lam
t, B
urkh
art S
chra
ven
MI0
2 M
odel
ing
chan
ges
in I
kB a
nd N
F-k
B a
ctiv
atio
n in
mac
roph
ages
trea
ted
wit
h di
chlo
ropr
opio
nani
line
John
B. B
arne
tt, I
rina
V. U
styu
gova
, Dav
id K
link
e, K
athl
een
Bru
ndag
e, T
hom
as M
. Har
ty
MI0
3 M
icro
arra
y an
alys
is c
hara
cter
izes
gen
e re
gula
tion
in h
uman
ast
rocy
tes
follo
win
g D
NA
da
mag
eJu
n-ic
hi S
atoh
, Hir
oko
Tabu
noki
MI0
4 C
hara
cter
izat
ion
of th
e cl
eava
ge o
f si
gnal
pep
tide
at t
he C
-ter
min
us o
f he
pati
tis
C v
irus
co
re p
rote
in b
y si
gnal
pep
tide
pep
tida
seH
sin-
Chi
eh M
a, Y
i-Yu
ng K
u, Y
i-C
hing
Hsi
eh, S
hih-
Yen
Lo
MI0
5 In
ter-
indi
vidu
al p
rote
omic
pro
fili
ng o
f bl
ood
mon
ocyt
es r
evea
ls b
iolo
gica
l ins
ight
sH
aife
ng W
u, P
hili
p D
iaz,
Min
g Ji
n
MI0
6 M
odel
ing
the
infl
uenc
e of
dia
bati
c gl
ucos
e co
ncen
trat
ion
on n
eutr
ophi
l act
ivat
ion
Urs
ula
Kum
mer
, Jen
s C
hris
tian
Bra
sen
MI0
7 E
luci
dati
ng th
e m
olec
ular
reg
ulat
ion
of g
anod
erm
a lu
cidu
m p
olys
acch
arid
es in
hum
an
mon
ocyt
ic c
ells
: fro
m g
ene
expr
essi
on to
net
wor
k co
nstr
ucti
onH
sueh
-Fen
Jua
n, K
un-C
hieh
Che
ng, H
suan
-Che
ng H
uang
, Che
rn-H
an O
u,
Jenn
-Han
Che
n, W
en-B
in Y
ang,
Shu
i-Te
in C
hen,
Chi
-Hue
y W
ong
MI0
8 C
oexp
ress
ion
netw
orks
for
mac
roph
ages
init
iate
d by
two
mem
bers
of
the
TN
F li
gand
su
perf
amily
.R
ajee
v A
uror
a, J
enni
fer
Kie
sel,
Ran
gesh
Kun
nava
kam
, You
sef A
bu-A
mer
MI0
9 Pr
even
tion
of f
etal
loss
due
to s
yste
mic
infla
mm
atio
n an
d an
ti-ph
osph
olip
id a
ntib
odie
s by
D
6Ye
ny M
arti
nez
de la
Tor
re, C
hiar
a B
urac
chi,
Ele
na M
. Bor
roni
, Raf
fael
la B
onec
chi,
M
anue
la N
ebul
oni,
Fra
nces
co T
edes
co, S
ergi
o A
. Lir
a, A
nnun
ciat
a V
ecch
i,
Mas
sim
o L
ocat
i, A
lber
to M
anto
vani
MI1
0 A
gen
etic
sw
itch
in h
uman
cel
ls e
luci
date
d by
"sy
stem
s vi
rolo
gy"
Mar
ia W
erne
r, J
ieZ
hi Z
ou, J
enny
Alm
qvis
t, I
ngem
ar E
rnbe
rg, E
rik
Aur
ell
40
Syst
ems
Bio
logy
of
Dia
bete
s (N
ovo
Nor
disk
-spo
nsor
ed)
MD0
1 T
he id
enti
fica
tion
of
new
nov
el b
iom
arke
rs o
f di
seas
e an
d to
xici
ty u
sing
UP
LC
/MS
e an
d ad
vanc
ed m
ulti
Rob
ert P
lum
b, J
erem
oy N
icho
lson
, Ian
Wil
son,
Pau
l Rai
nvil
le
MD0
2 H
∞ c
ontr
olle
r de
sign
for
glu
cose
-ins
ulin
sys
tem
s: a
BM
I op
tim
izat
ion
appr
oach
Che
ng-L
iang
Che
n, H
ong-
Wen
Tsa
i
MD0
3 Q
uali
tativ
e, in
tegr
ated
mod
elin
g of
lipi
d m
etab
olis
m in
hep
atoc
ytes
Ovi
diu
Rad
ules
cu, A
nne
Sieg
el, M
iche
l Le
Bor
gne,
Phi
lipp
e V
eber
, Eli
sabe
th P
ecou
, Sa
ndri
ne L
agar
rigu
e, P
asca
l Mar
tin
MD0
4 St
udy
of d
epen
denc
y of
syn
chro
niza
tion
of b
eta-
cells
insu
lin s
ecre
tion
on s
ize
of la
nger
hans
is
lets
Ari
osto
Siq
ueir
a Si
lva,
Jos
e A
ndre
s Yun
es
MD0
5 D
iabe
tes
man
agem
ent s
yste
m b
ased
on
syst
ems
biol
ogy
aim
ed a
t off
erin
g a
ther
apeu
tic
stra
tegy
for
eac
h pa
tien
tM
asay
oshi
Sei
ke, T
akeo
Sai
tou,
Yas
uhir
o K
ouch
i, K
aoru
Asa
no, T
akes
hi O
hara
, Ya
suhi
ro N
aito
, Hir
omu
Nak
ajim
a
MD0
6 Id
enti
fica
tion
of
the
spec
ific
geno
mic
and
pro
teom
ic m
arke
rs in
Str
epto
zoto
cin-
indu
ced
diab
etic
rat
pan
crea
s in
res
pons
e to
fun
gal p
olys
acch
arid
e tr
eatm
ents
Sang
Woo
Kim
, Hye
Jin
Hw
ang,
Jun
g Yo
ung
Oh,
Eun
Jae
Cho
, Yu
Mi B
aek,
Jo
ng W
on Y
un
MD0
7 T
ime-
depe
nden
t pla
sma
prot
ein
chan
ges
in s
trep
tozo
toci
n-in
duce
d di
abet
ic r
ats
in
resp
onse
to f
unga
l pol
ysac
char
ide
trea
tmen
tsSa
ng W
oo K
im, H
ye J
in H
wan
g, E
un J
ae C
ho, J
ung
Youn
g O
h, Y
u M
i Bae
k,
Jong
Won
Yun
MD0
8 G
ene
expr
essi
on p
rofi
ling
in s
trep
tozo
toci
n-in
duce
d di
abet
ic r
at li
ver
and
kidn
ey in
re
spon
se to
fun
gal p
olys
acch
arid
e th
erap
yH
ye J
in H
wan
g, S
ang
Woo
Kim
, Eun
Jae
Cho
, Jun
g Yo
ung
Oh,
Yu
Mi B
aek,
Jo
ng W
on Y
un
MD0
9 D
iffe
rent
ial e
xpre
ssio
n of
the
kidn
ey p
rote
ins
in s
trep
tozo
toci
n-in
duce
d di
abet
ic r
ats
befo
re a
nd a
fter
adm
inis
trat
ion
of f
unga
l pol
ysac
char
ides
Hye
Jin
Hw
ang,
San
g W
oo K
im, E
un J
ae C
ho, J
ung
Youn
g O
h, Y
u M
i Bae
k,
Jong
Won
Yun
Can
cer
Syst
ems
Bio
logy
MC0
1 M
odel
ing
of th
e es
trog
en r
ecep
tor-
regu
late
d pr
otei
n ne
twor
k in
bre
ast c
ance
rO
zgur
Sah
in, F
lori
an H
ahne
, Tim
Bei
ssba
rth,
Ann
emar
ie P
oust
ka, S
tefa
n W
iem
ann,
D
orit
Arl
t
MC0
2 O
n th
e ro
le o
f bi
omec
hani
cs in
the
grow
th o
f m
ulti
cell
ular
sph
eroi
dsD
irk
Dra
sdo,
Ste
fan
Hoe
hme
MC0
3 S
tudy
of
earl
y tu
mou
r de
velo
pmen
t and
its
glyc
olyt
ic p
rope
rtie
sA
rios
to S
ique
ira
Silv
a, J
ose
And
res Y
unes
MC0
4 A
ppli
cati
ons
of s
ensi
tivit
y an
alys
is f
or d
rug
disc
over
y an
d de
velo
pmen
t in
the
Erb
B
rece
ptor
net
wor
kB
rian
Har
ms,
All
en L
ee, R
icar
do P
axso
n, U
lrik
Nie
lsen
, Bir
git S
choe
berl
MC0
5 D
elin
eati
ng b
reas
t can
cer
gene
exp
ress
ion
syst
ems
by R
NA
inte
rfer
ence
and
glo
bal
mic
roar
ray
anal
ysis
in h
uman
tum
or c
ells
Hol
ger
Sult
man
n, M
ark
Fell
man
n, A
ndre
as B
unes
s, M
arku
s R
usch
haup
t, A
chim
Tre
sch,
Ti
m B
eiss
bart
h, R
upre
cht K
uner
, Ann
emar
ie P
oust
ka
MC0
6 S
yste
ms-
leve
l mec
hani
sms
of tu
mor
igen
esis
Pil
ar H
erna
ndez
, Jai
me
Hue
rta-
Cep
as, D
avid
Mon
tane
r, Fa
tim
a A
l-Sh
ahro
ur, J
oan
Vall
s,
Lai
a G
omez
, Gab
riel
Cap
ella
, Joa
quin
Dop
azo,
Miq
uel A
ngel
Puj
ana
MC0
7 Sy
stem
atic
dis
cove
ry o
f ca
ndid
ate
gene
tic in
tera
ctio
ns le
adin
g to
bre
ast c
ance
r su
scep
tibili
tyM
ikke
l Zah
le O
este
rgaa
rd, J
onat
han
Tyre
r, B
ruce
AJ
Pond
er, D
ougl
as F
Eas
ton,
F
rede
rick
Rot
h, P
aul D
P P
haro
ah
MC0
8 M
eta-
anal
ysis
of
brea
st c
ance
r m
icro
arra
y da
ta: r
elia
ble
iden
tifi
cati
on o
f up
- an
d do
wn-
regu
late
d ge
nes
Yuri
y V.
Kon
drak
hin,
Vla
dim
ir V
. Por
oiko
v, R
usla
n N
. Sha
ripo
v, A
lexa
nder
E. K
el,
Fedo
r A
. Kol
pako
v
MC0
9 C
yclo
net -
an
inte
grat
ed d
atab
ase
on c
ell c
ycle
reg
ulat
ion
and
carc
inog
enes
isFe
dor
Kol
pako
v, V
ladi
mir
Por
oiko
v, R
usla
n Sh
arip
ov, L
ucia
no M
ilan
esi,
Ale
xand
er K
el
MC1
0 M
etab
olic
cha
nges
dur
ing
carc
inog
enes
is: p
oten
tial
impa
ct o
n in
vasi
vene
ssK
iera
n Sm
allb
one,
Rob
ert A
. Gat
enby
, Rob
ert J
. Gil
lies
, Dav
id J
. Gav
agha
n,
Phi
lip
K. M
aini
MC1
1 Te
mpo
ral g
ene
expr
essi
on p
rofi
ling
app
lied
to th
e hy
poxi
c re
spon
seR
enau
d Se
igne
uric
, Mau
d St
arm
ans,
Mic
hael
Mag
agni
n, N
atal
Van
Rie
l, B
rad
Wou
ters
, P
hili
ppe
Lam
bin
MC1
2 M
AP-
kina
se s
igna
ling
in e
ryth
roid
pro
geni
tor
cells
elu
cida
ted
by a
dyn
amic
pat
hway
mod
elM
arce
l Sch
illi
ng, T
hom
as M
aiw
ald,
Jen
s Ti
mm
er, U
rsul
a K
ling
mue
ller
MC1
3 M
icro
RN
A e
xpre
ssio
n pr
ofili
ng o
f he
pato
cell
ular
car
cino
ma
usin
g m
icro
arra
yH
isak
azu
Iwam
a, T
suto
mu
Mas
aki,
Shi
geki
Kur
iyam
a
Fro
nts
in S
yste
ms
Bio
logy
Net
wor
k B
iolo
gy
FN01
E
volu
tion
ary
cons
erva
tion
of
dyna
mic
pro
tein
-pro
tein
inte
ract
ion
netw
orks
Che
n-hs
iung
Cha
n, S
heng
-An
Lee
, Che
ng-Y
an K
ao
FN02
C
orre
lati
on a
nd r
espo
nse
of a
sto
chas
tic
gene
sw
itch
Yuri
e O
kabe
, Yuu
Yag
i, M
asak
i Sas
ai
FN03
D
esig
n pr
inci
ples
in E
. col
i tra
nscr
ipti
on n
etw
ork
reve
aled
by
usin
g a
com
preh
ensi
ve
libr
ary
of fl
uore
scen
t tra
nscr
ipti
onal
rep
orte
rsA
lon
Zas
lave
r, A
nat B
ren,
Mic
hal R
onen
, Sha
lev
Itzk
ovit
z, I
lya
Kik
oin,
Sea
gull
Sha
vit,
W
olfr
am L
iebe
rmei
ster
, Mik
e Su
rett
e, U
ri A
lon
41
FN04
N
etw
ork
iden
tifi
cati
on f
or th
e G
1 to
S tr
ansi
tion
in m
amm
alia
n ce
lls
Luc
iano
Mil
anes
i, Fe
rdin
ando
Chi
arad
onna
, Rob
erta
Alfi
eri,
Dan
iela
Gag
lio,
M
arco
Van
oni,
Lil
ia A
lber
ghin
a
FN05
L
ogic
of
tran
scri
ptio
nal c
ircu
its
unde
rlyi
ng m
amm
alia
n ci
rcad
ian
cloc
ksM
aki U
kai-
Tade
num
a, H
irok
i R. U
eda
FN06
N
etw
ork
cond
itio
ns f
or in
stab
ilit
ies
in b
ioch
emic
al m
odel
sM
aya
Min
chev
a
FN08
A
ste
pwis
e st
ruct
ural
equ
atio
n m
odel
ing
algo
rith
m to
pre
dict
gen
etic
net
wor
ksG
race
Shw
u-R
ong
Shie
h, C
hing
-Yun
Yu,
Chu
ng-M
ing
Che
n, J
uili
ng H
uang
, W
oei-
Fuh
Wan
g
FN09
Pa
tter
n re
cogn
itio
n m
etho
d fo
r in
ferr
ing
of g
enet
ic n
etw
orks
Gra
ce S
hwu-
Ron
g Sh
ieh,
Che
ng-L
ong
Chu
ang,
Chu
ng-M
ing
Che
ng
FN10
A
hyb
rid
sim
ulat
ion
fram
ewor
k fo
r ge
nom
e sc
ale
stud
y of
mol
ecul
ar d
ynam
ics
in
Esc
heri
chia
col
iSa
mik
Gho
sh, P
reet
am G
hosh
, Kal
yan
Bas
u, S
ajal
K. D
as
FN11
R
econ
stru
ctio
n of
the
hum
an m
etab
olic
net
wor
k an
d it
s re
lati
on w
ith
hum
an d
isea
seH
ong
wu
Ma,
Ana
toly
Sor
okin
, Ale
x Se
lkov
, Evg
eni S
elko
v, S
haki
r A
li,
Ale
xand
er M
azei
n, S
aow
alak
Kal
apan
ulak
, Ole
g D
emin
, Igo
r G
orya
nin
FN12
Fi
ndin
g pe
rtur
bati
on-s
peci
fic
regu
lati
on p
athw
ays
by in
tegr
atin
g ge
neti
c re
gula
tory
and
m
etab
olic
pat
hway
Ho
Jung
Nam
, Hyo
jin
Kan
g, S
ejun
Lee
, Doh
eon
Lee
FN13
H
ighl
y co
rrel
ated
gro
ups
of m
ulti
ple
gene
s an
d/or
met
abol
ites
in A
rabi
dops
is th
alia
na
dete
cted
by
grap
h cl
uste
ring
(D
PC
lus)
Ats
ushi
Fuk
ushi
ma,
Md.
Alt
af-U
l-A
min
, Ken
Kur
okaw
a, S
hige
hiko
Kan
aya,
M
asam
i Yok
ota
Hir
ai, K
azuk
i Sai
to
FN14
T
rans
crip
tion
al r
egul
atio
n of
the
abio
tic
stre
ss r
espo
nse
in A
rabi
dops
isD
anie
l Mac
Lea
n, N
oah
Whi
tman
, Chr
is W
ilks
, Seu
ng Y
on R
hee
FN15
P
heno
typi
c co
mpl
exit
y du
ring
C. e
lega
ns e
arly
em
bryo
gene
sis
and
syst
emat
ic
imte
rpre
tati
on o
f pl
eiot
ropy
wit
h pr
otei
n in
tera
ctio
n ne
twor
ksL
ihua
Zou
, Bri
an R
oss,
Jun
Liu
, Hui
Ge
FN16
S
toch
asti
c m
odel
of
a bi
olog
ical
clo
ckH
ites
h M
istr
y
FN17
M
etho
ds f
or th
e st
ruct
ural
and
fun
ctio
nal a
naly
sis
of s
igna
ling
net
wor
ksSt
effe
n K
lam
t, J
ulio
Sae
z-R
odri
guez
, Ern
st D
iete
r G
ille
s
FN18
T
he E
dinb
urgh
pat
hway
edi
tor:
a n
ovel
app
roac
h to
cre
atin
g an
d an
nota
ting
com
plex
bi
olog
ical
net
wor
ksA
nato
ly S
orok
in, A
lex
Selk
ov, S
haki
r A
li, S
tuar
t Moo
die,
Igo
r G
orya
nin
FN19
A
lgeb
raic
met
hod
for
the
anal
ysis
of
sign
alin
g cr
osst
alk
Yosh
iya
Mat
suba
ra, S
hini
chi K
ikuc
hi, M
asah
iro
Sugi
mot
o, K
otar
o O
ka, M
asar
u To
mit
a
FN20
M
axim
um e
ntro
py a
ppro
ach
to n
etw
ork
reco
nstr
ucti
onG
aspe
r T
kaci
k, E
lad
Schn
eidm
an, W
illi
am B
iale
k
FN21
P
rinc
iple
s of
mic
roR
NA
reg
ulat
ion
of a
hum
an c
ellu
lar
sign
alin
g ne
twor
kQ
ingh
ua C
ui, Z
henb
ao Y
u, E
nric
o P
uris
ima,
Edw
in W
ang
FN22
S
ignA
lign
: a to
ol f
or a
naly
sing
sig
nali
ng p
athw
ays
Srid
har
Har
ihar
aput
ran,
Tho
ralf
Toe
pel
FN23
S
et-u
p of
the
nati
onal
net
wor
k fo
r sy
stem
s bi
olog
y in
Ger
man
yU
te H
eisn
er
FN24
S
etti
ng th
e fr
amew
ork
for
larg
e sc
ale
syst
em b
iolo
gy: t
he in
tegr
atio
n of
hum
an p
rote
in
inte
ract
ome
Mat
thia
s E
. Fut
schi
k, G
auta
m C
haur
asia
, Eri
ch W
anke
r, H
ansp
eter
Her
zel
FN25
A
sys
tem
bio
logy
app
roac
h to
the
imm
une
syst
em n
etw
ork
reve
als
func
tion
al d
iffe
renc
es
in h
ealt
h an
d m
ulti
ple
scle
rosi
sP
ablo
Vil
losl
ada,
Ric
ardo
Pal
acio
s, J
oaqu
in G
oni,
Nie
ves
Vel
ez, J
orge
Sep
ulcr
e
FN26
M
odel
ing
the
extr
acel
lula
r an
d ce
ll-s
urfa
ce e
nvir
onm
ent i
mpa
ctin
g W
nt s
igna
ling
Ann
a G
eorg
ieva
, Sat
ish
Tade
pall
i, B
rian
Sto
ll
FN27
M
athe
mat
ical
mod
elli
ng o
f th
e ro
le o
f H
IF-1
in tu
mou
r gr
owth
Ale
xand
er G
. Fle
tche
r, S.
Jon
atha
n C
hapm
an, C
hris
toph
er J
. W. B
rew
ard
FN28
G
raph
theo
ry a
nd n
etw
orks
in b
iolo
gyO
live
r M
ason
, Mar
k V
erw
oerd
FN29
To
war
ds a
pro
teom
e sc
ale
map
of
the
hum
an in
tera
ctom
e ne
twor
kJe
an-F
ranc
ois
Rua
l, K
avit
ha V
enka
tesa
n, T
ong
Hao
, Tom
oko
Hir
ozan
e-K
ishi
kaw
a,
Am
elie
Dri
cot,
Nin
g L
i, G
abri
el B
erri
z, F
ranc
is G
ibbo
ns, M
atij
a D
reze
,N
ono
Ayi
vi-G
uede
hous
sou,
Nie
ls K
litg
ord,
Chr
isto
phe
Sim
on, M
ike
Box
em,
Stua
rt M
ilst
ein,
Jen
nife
r R
osen
berg
, Deb
ra S
. Gol
dber
g, L
an Z
hang
, Sh
aryl
Won
g, G
iova
nni F
rank
lin,
Sim
ing
Li,
Joa
nna
Alb
ala,
Jan
ghoo
Lim
, C
arle
ne F
raug
hton
, Est
elle
Lla
mos
as, S
ebih
a C
evik
, Cam
ille
Bex
, Phi
lipp
e L
ames
ch,
Rob
ert S
. Sik
orsk
i, J
ean
Van
denh
aute
, Hud
a Z
oghb
i, A
lex
Smol
yar,
Ste
phan
ie B
osak
, R
eyna
ldo
Sequ
erra
, Lyn
n D
ouce
tte-
Stam
m, M
icha
el E
. Cus
ick,
Dav
id E
. Hil
l,
Fre
deri
ck P
. Rot
h, M
arc
Vid
al
FN30
L
ag-a
ppen
ded
PC
A: a
new
met
hod
for
infe
rrin
g th
e ca
usal
rel
atio
nshi
p be
twee
n ge
nes
from
tem
pora
l exp
ress
ion
profi
les
Yeoi
n Yo
on, K
wan
g-H
yun
Cho
FN31
In
fere
nce
of tr
ansc
ript
iona
l reg
ulat
ory
netw
orks
bas
ed o
n in
itia
l mR
NA
exp
ress
ion
profi
les
and
DN
A-b
indi
ng m
otif
sH
youn
g-Se
ok C
hoi,
San
g-M
ok C
hoo,
Jeo
ng-R
ae K
im, K
wan
g-H
yun
Cho
FN32
M
odel
ing
and
sens
itiv
ity
anal
ysis
of
circ
adia
n os
cill
ator
y ne
twor
k of
dro
soph
ila
Yuki
no O
gaw
a, K
azuh
aru
Ara
kaw
a, F
umih
iko
Miy
oshi
, Kaz
unar
i Kai
zu,
Mas
aru
Tom
ita
FN33
A
n ev
olut
iona
ry s
yste
ms
biol
ogy
appr
oach
for
the
anal
ysis
of
the
dyna
mic
s of
red
uctiv
e ge
nom
e ev
olut
ion
Am
it K
hach
ane,
Jac
ek P
ucha
lka,
Ken
neth
Tim
mis
, Vit
or M
arti
ns d
os S
anto
s
FN34
M
essa
ge-a
djus
ted
netw
orks
(M
AN
) in
gas
tro-
ente
ro-p
ancr
eati
c (G
EP
) en
docr
ine
syst
emN
uri F
aruk
Ayk
an
42
FN35
R
ever
se e
ngin
eeri
ng b
iolo
gica
l net
wor
ks b
y no
nlin
ear
regr
essi
onD
iogo
Cam
acho
, Ped
ro M
ende
s
FN36
In
ferr
ing
hum
an p
rote
in in
tera
ctio
n ne
twor
k fr
om c
onse
rvat
ivel
y hi
dden
fam
ily-f
amily
in
tera
ctio
nsF
an-K
ai L
in, C
hung
-Yen
Lin
, Cha
o A
. Hsi
ung
FN37
H
ydro
phob
ic, h
ydro
phil
ic a
nd c
harg
ed a
min
o ac
ids'
net
wor
ks w
ithi
n pr
otei
nSu
dip
Kun
du, M
d. A
ftab
uddi
n
FN38
Id
enti
fica
tion
of
mou
se h
eart
-spe
cifi
c su
bnet
wor
k st
ruct
ures
infe
rred
fro
m th
e ex
pres
sion
pr
ofile
s co
mpe
ndiu
m u
sing
a n
ew s
earc
h al
gori
thm
Seon
g-E
ui H
ong,
Seo
ng-H
wan
Rho
, Do
Han
Kim
FN39
S
truc
tura
l tra
nsit
ion
in p
roka
ryot
ic m
etab
olic
net
wor
ks w
ith
grow
th te
mpe
ratu
reK
azuh
iro
Take
mot
o, J
ose
C. N
ache
r, Ta
tsuy
a A
kuts
u
FN40
To
war
d au
tom
atic
con
stru
ctio
n of
an
evol
utio
nary
net
wor
k of
pro
tein
fam
ilie
sF
ang
fang
Xia
, Ric
k St
even
s
FN41
C
lust
erin
g of
gen
e ne
twor
ks u
sing
a M
onte
-car
lo s
imul
atio
nA
dolf
o To
rres
, Jos
e G
onza
lez,
Har
et R
osu
FN42
C
ompa
riso
n of
met
abol
ite
prod
ucti
on c
apab
ilit
y in
dice
s ge
nera
ted
by n
etw
ork
anal
ysis
m
etho
dsK
yota
Ish
ii, S
eira
Nak
amur
a, M
ineo
Mor
ohas
hi, Y
oshi
aki O
hash
i, S
hini
chi K
ikuc
hi,
Mas
ahir
o Su
gim
oto,
Mas
aru
Tom
ita
FN43
P
rote
in-p
rote
in in
tera
ctio
n pa
thw
ays
reco
nstr
ucti
on f
rom
dom
ain-
dom
ain
inte
ract
ions
Ka-
Lok
Ng,
Hsi
ang-
Chu
an L
iu, C
hien
-Hun
g H
uang
FN44
In
tegr
ated
com
puta
tion
al a
nd e
xper
imen
tal a
ppro
ach
to id
enti
y th
e ta
rget
s of
P63
on
geno
me
scal
eM
ukes
h B
ansa
l, G
iusy
Del
la G
atta
, Alb
erto
Am
besi
, Die
go d
i Ber
nard
o
FN45
G
enes
and
fun
ctio
ns th
at r
egul
ate
redo
x st
atus
in a
pho
tosy
nthe
tic
orga
nism
Raj
eev
Aur
ora,
Ran
gesh
Kun
nava
kkam
, Abh
ay K
. Sin
gh,
Mai
tray
ee B
hatt
acha
rya-
Pak
rasi
, Him
adri
B. P
akra
si
FN46
A
sys
tem
s bi
olog
y ap
proa
ch to
und
erst
and
the
regu
lato
ry n
etw
ork
gove
rnin
g tr
ansc
ript
ion
of v
irul
ence
det
erm
inan
ts in
Sta
phyl
ococ
cus
aure
usE
rik
Gus
tafs
son,
Ste
fan
Kar
lsso
n, J
an O
scar
sson
, Pet
er S
ogar
d, P
atri
c N
ilss
on, S
taff
an
Arv
idso
n
FN47
S
yste
ms
evol
utio
nary
bio
logy
: mod
ular
evo
luti
on o
f ye
ast p
rote
in in
tera
ctio
n ne
twor
kSo
ichi
Ogi
shim
a, Y
asuh
iro
Suzu
ki, T
akes
hi H
ase,
So
Nak
agaw
a, H
iros
hi T
anak
a
FN48
S
earc
h fo
r ca
usat
ive
func
tion
al S
NP
s us
ing
in v
itro
vir
us m
etho
dH
itom
i Um
eki,
Shi
geo
Fuj
imor
i, N
aohi
ro Y
anag
isaw
a, T
akan
ori W
ashi
o,
Ets
uko
Miy
amot
o-Sa
to, M
asar
u To
mit
a, H
iros
hi Y
anag
awa
FN49
To
war
d a
com
preh
ensi
ves
anal
ysis
of
hum
an tr
ansc
ript
ion
fact
or n
etw
orks
usi
ng I
VV
Ets
uko
Miy
amot
o-Sa
to, M
asam
ichi
Ish
izak
a, S
hige
o F
ujim
ori,
Rin
taro
Sai
to,
Taka
nori
Was
hio,
Nao
ya H
irai
, Kaz
uyo
Mas
uoka
, Tat
suhi
ro Y
amas
hita
, Tom
ohir
o O
shik
ubo,
Hir
oshi
Yan
agaw
a
FN50
In
ferr
ing
prot
ein
netw
ork
by m
ulti
ple
dom
ain
inte
ract
ions
Yong
Wan
g, X
iang
-Sun
Zha
ng, L
uona
n C
hen
FN51
N
oise
indu
ced
robu
st c
olle
ctiv
e be
havi
ors
in a
mul
tice
llul
ar s
yste
mR
uiqi
Wan
g, L
uona
n C
hen,
Kaz
uyuk
i Aih
ara
Com
plex
Sys
tem
s B
iolo
gy
FX01
P
heno
men
olog
ical
mod
elin
g an
d st
udy
for
the
stab
ilit
y of
a m
icro
bial
com
mun
ity
Mas
ashi
Tac
hika
wa
FX02
G
enom
e-w
ide
anal
ysis
of
cell
cyc
le d
epen
dent
gen
e ex
pres
sion
Yoic
hi M
inam
i, Ta
keya
Kas
ukaw
a, K
enic
hiro
Uno
, Tam
ami H
irai
, Hir
oki R
. Ued
a
FX03
P
lank
ton
bloo
min
gA
ndre
i Kor
obei
niko
v, S
erge
i Pet
rovs
kii
FX04
M
odel
red
ucti
on f
or v
ario
us le
vels
of
mod
el d
evel
opm
ent
Gun
nar
Ced
ersu
nd, H
enni
ng S
chm
idt,
Mat
s Ji
rstr
and
FX05
R
egul
atio
n of
E.c
oli r
espi
rati
on: g
ene
netw
ork
reco
nstr
ucti
on a
nd m
athe
mat
ical
mod
elin
gA
lexa
nder
Rat
ushn
y, T
amar
a K
hleb
odar
ova,
Vit
aly
Lik
hosh
vai
FX06
A
mul
ti-o
mic
s an
alys
is o
f E
sche
rich
ia c
oli m
etab
olic
net
wor
kM
arti
n R
ober
t, K
enji
Nak
ahig
ashi
, Nob
uyos
hi I
shii
, Tom
oya
Bab
a, T
omoy
oshi
Sog
a,
Aki
o K
anai
, Tak
ashi
Tog
ashi
, Tak
ashi
Hir
asaw
a, M
iki N
aba,
Ken
ta H
irai
, Am
inul
Hoq
ue,
Yuji
Kak
azu,
Kao
ri S
ugaw
ara,
Sao
ri I
gara
shi,
Sato
shi H
arad
a, T
akes
hi M
asud
a,
Nao
yuki
Sug
iyam
a, K
atsu
yuki
Yug
i, K
azuh
aru
Ara
kaw
a, N
ayut
a Iw
ata,
Yos
hihi
ro T
oya,
Yo
ichi
Nak
ayam
a, A
kiko
Hag
iya,
Tak
aaki
Nis
hiok
a, K
azuy
uki S
him
izu,
Hir
otad
a M
ori,
Mas
aru
Tom
ita
FX07
M
icro
tubu
le d
ynam
ics
regu
late
spi
ndle
pol
e os
cill
atio
ns a
nd p
oste
rior
dis
plac
emen
t du
ring
ana
phas
e in
the
C.e
lega
ns e
mbr
yoC
leop
atra
Koz
low
ski,
Mar
tin
Sray
ko, F
ranc
ois
Ned
elec
FX08
A
top-
dow
n m
odel
ling
app
roac
h fo
r pl
ant s
yste
ms
biol
ogy
Ada
oha
E. C
. Ihe
kwab
a, D
ougl
as B
. Kel
l, Pe
dro
Men
des
FX09
A
naly
sis
of m
utat
ion
freq
uenc
y in
ant
ibod
y af
fini
ty m
atur
atio
n: a
hin
t at p
osit
ivel
y an
d ne
gativ
ely
sele
cted
mut
atio
nsL
ei Z
hang
, Arm
in A
. Wei
ser,
Ati
jeh
Vala
i, M
icha
l Or-
Gui
l
FX10
In
sil
ico
mod
elli
ng o
f em
bryo
nic
mor
phog
enes
isP
hili
ppe-
Ale
xand
re P
ouil
le, E
mm
anue
l Bea
urep
aire
, Em
man
uel F
arge
FX11
N
on-s
uper
vise
d ph
enot
ype
lear
ning
and
phe
noty
pe m
odel
rec
onst
ruct
ion
in th
e fu
ncti
onal
ge
nom
ic s
cree
ning
s: c
oord
inat
ed a
ctiv
ity
of e
arly
end
osom
e m
otor
sYa
nnis
Kal
aidz
idis
, Joc
hen
Rin
k, M
arin
o Z
eria
l
FX12
IL
3-In
duce
d JA
K-S
TAT
sig
nali
ng: a
com
plex
sys
tem
s bi
olog
y ap
proa
chR
adin
a P.
Soe
biya
nto,
Jay
ant A
vva,
Che
ng-K
ui Q
u, K
evin
D. B
unti
ng, K
enne
th A
. Lop
aro,
M
ihaj
lo M
esar
ovic
, Sre
e N
. Sre
enat
h
43
FX13
N
FkB
and
PI3
K/A
kt p
athw
ay in
pro
stat
e ca
ncer
Jaya
nt A
vva,
Mic
hael
Wei
s, R
adin
a P.
Soe
biya
nto,
Ken
neth
A. L
opar
o, S
anja
y G
upta
, Sr
ee N
. Sre
enat
h
FX14
D
ynam
ic b
ehav
ior
of b
uffe
red
calc
ium
ions
in s
toch
asti
c an
d de
term
inis
tic
sim
ulat
ions
Juer
gen
Pah
le, S
ven
Sahl
e, U
rsul
a K
umm
er
FX16
T
he g
enet
ic c
ode
is n
earl
y op
tim
al f
or a
llow
ing
arbi
trar
y ad
diti
onal
cod
es w
ithi
n pr
otei
n-co
ding
seq
uenc
esSh
alev
Itz
kovi
tz, U
ri A
lon
FX17
G
raph
ical
cau
sal r
easo
ning
tool
for
sys
tem
s bi
olog
y: C
MA
PG
abri
el W
einr
eb, K
en J
acob
son,
Tim
othy
Els
ton
FX18
E
nzym
e I
of th
e P
EP
-dep
ende
nt p
hosp
hotr
ansf
eras
e sy
stem
: mat
hem
atic
al m
odel
ing
appr
oach
Taty
ana
Kar
elin
a, O
leg
Dem
in
FX19
S
yste
mat
ic d
eter
min
atio
n of
bio
logi
cal n
etw
ork
topo
logy
: non
-int
egra
l con
nect
ivit
y m
etho
d (N
ICM
)K
umar
Sel
vara
joo,
Mas
a Ts
uchi
ya
FX20
B
ond
grap
hs o
f ne
twor
k th
erm
odyn
amic
s ca
n ex
pres
s ph
enom
enol
ogic
al e
quat
ions
in
biol
ogic
al s
yste
ms
Yusu
ke I
mai
FX21
G
enom
e-w
ide
syst
em id
enti
fica
tion
and
ana
lysi
s re
veal
s st
able
yet
flex
ible
net
wor
k dy
nam
ics
in y
east
Mik
a G
usta
fsso
n, M
icha
el H
ornq
uist
, Joh
an B
jork
egre
n, J
espe
r Te
gner
FX22
M
odel
ing
Hsp
70-m
edia
ted
prot
ein
fold
ing
Bin
Hu,
Mat
thia
s P.
May
er, M
asar
u To
mit
a
FX23
A
spe
ctra
l app
roac
h fo
r a
prio
ri in
tegr
atio
n of
gen
e ne
twor
k kn
owle
dge
into
mic
roar
ray
clas
sifi
cati
on.
Fra
nck
Rap
apor
t, A
ndre
i Zin
ovye
v, E
mm
anue
l Bar
illo
t, J
ean-
Phi
lipp
e V
ert
FX24
R
ule-
base
d m
odel
ing
of b
ioch
emic
al n
etw
orks
bas
ed o
n pr
otei
n in
tera
ctio
ns: t
heor
y,
soft
war
e, a
nd a
ppli
cati
ons
Jam
es R
. Fae
der,
Mic
hael
L. B
lino
v, J
in Y
ang,
Byr
on G
olds
tein
, Wil
liam
S. H
lava
cek
FX25
Fa
ctor
ing
gluc
okin
ase
sequ
estr
atio
n in
sil
ico
affe
cts
glyc
olyt
ic n
etw
ork
kine
tics
Saty
a N
anda
Vel
Arj
unan
, Kum
ar S
elva
rajo
o
FX26
S
ingl
e-ce
ll a
naly
sis
and
mod
elin
g re
veal
that
HIV
& H
erpe
s us
e fe
edba
ck c
ircu
its
to
cont
rol l
ifec
ycle
Leo
r W
einb
erge
r, T
hom
as S
henk
FX27
C
haot
ic th
erm
oreg
ulat
ion
in th
e sp
adix
of
skun
k ca
bbag
e, S
ympl
ocar
pus
foet
idus
Taka
nori
Ito
, Hir
oshi
Osa
da, K
ikuk
atsu
Ito
FX28
A
djoi
nt b
ased
par
amet
er id
enti
fica
tion
alg
orit
hm f
or p
rote
in n
etw
orks
wit
h ap
plic
atio
n to
pl
anar
cel
l pol
arit
yR
obin
L. R
affa
rd, C
lair
e J.
Tom
lin,
Kei
th A
mon
lird
vim
an, J
effr
ey D
. Axe
lrod
FX29
S
elec
tion
of
opti
mal
gro
wth
sta
te b
y st
ocha
stic
noi
seC
hika
ra F
urus
awa,
Kun
ihik
o K
anek
o
FX30
“S
yste
ms
ener
geti
cs”
-a n
ew a
ppro
ach
for
cell
ular
sys
tem
s dy
nam
ics
Nor
iko
Hir
oi, A
kira
Fun
ahas
hi, H
iroa
ki S
uzuk
i, T
akat
oki Y
amam
oto,
Dou
glas
Mur
ray
FX31
C
hara
cter
izat
ion
of p
rote
ins
from
the
mat
rix
of s
cler
ites
fro
m th
e al
cyon
aria
n,
Lob
ophy
tum
cra
ssum
.M
. Azi
zur
Rah
man
, Yei
shin
Isa
, Tsu
yosh
i Ueh
ara
FX32
A
n at
tem
pt a
t usi
ng th
e ap
proa
ches
in s
yste
ms
biol
ogy
to e
xplo
re tr
adit
iona
l Chi
nese
m
edic
ine
Chu
-shi
ang
Che
n, S
heng
-Yin
g Pa
o, S
ong-
shia
ng L
in, K
athe
rine
Che
n
FX33
T
he b
enefi
t of
com
bini
ng s
yste
ms
biol
ogy
and
expe
rim
ents
for
und
erst
andi
ng c
ompl
ex
biol
ogic
al s
yste
ms
Mag
nus
Fag
erli
nd, E
rik
Gus
tafs
son,
Eli
e Ja
rnm
ark,
Mar
ia S
vens
son,
Pet
er S
ogar
d
FX34
Q
uant
itat
ive
biol
ogy
of e
mbr
yo-m
ater
nal c
omm
unic
atio
n an
d im
plan
tati
onSt
efan
Bau
ersa
chs,
Cla
udia
Kle
in, F
rank
Ber
endt
, Tho
mas
Fro
hlic
h, H
elm
ut B
lum
, G
eorg
J. A
rnol
d, U
lric
h M
ansm
ann,
Eck
hard
Wol
f
Con
trol
and
Sys
tem
The
ory
for
Syst
ems
Bio
logy
FT01
A
fini
te m
odel
for
the
rand
om b
ehav
ior
in th
e la
ctos
e re
gula
tion
sys
tem
of
Esc
heri
chia
co
liA
. Agu
ng J
uliu
s, A
dam
Hal
asz,
Vij
ay K
umar
, Geo
rge
J. P
appa
s
FT02
In
viv
o re
acti
on m
odel
ing
by D
RR
KN
orik
o H
iroi
, Aki
ra F
unah
ashi
, Hir
oaki
Kit
ano
FT03
M
odel
ing,
sim
ulat
ion
& s
tabi
lity
ana
lysi
s of
p53
-mdm
2 os
cill
atio
nsA
run
Kri
shna
n, M
asar
u To
mit
a
FT04
Pa
ram
eter
per
turb
atio
n an
alys
is o
f ba
cter
ial c
hem
otax
isTa
e-H
wan
Kim
, Sun
g H
oon
Jung
, Kw
ang-
Hyu
n C
ho
FT05
E
xper
imen
t des
ign
for
para
met
er e
stim
atio
n in
mod
els
com
bini
ng s
igna
l tra
nsdu
ctio
n an
d m
etab
olic
pat
hway
s: c
ontr
ol o
f ni
trog
en u
ptak
e in
yea
stN
atal
A. W
. Van
Rie
l
FT06
P
ropo
rtio
n pr
eser
vati
on in
a g
row
ing
tiss
ueA
kihi
ko N
akaj
ima,
Kun
ihik
o K
anek
o
FT07
E
xper
imen
t des
ign
for
opti
mal
exc
itat
ion
of g
ene
regu
lato
ry n
etw
orks
Torb
joer
n E
. M. N
ordl
ing,
Ell
ing
W. J
acob
sen
FT08
E
volu
tion
ary
desi
gn p
rinc
iple
s of
bac
teri
al c
hem
otax
isM
arku
s K
ollm
ann,
Lin
da L
ovdo
k, K
ilia
n B
arth
olom
e, J
ens
Tim
mer
, Vic
tor
Sour
jik
FT09
E
nsem
ble
mod
elli
ng r
evea
ls a
nov
el lo
gic
of T
OR
sig
nall
ing
in y
east
Lar
s K
uepf
er, M
atth
ias
Pet
er, U
we
Saue
r, J
oerg
Ste
llin
g
FT10
S
yste
ms
biol
ogy
of b
one
rem
odel
ing
in o
steo
poro
sis
Kal
yan
Myn
ampa
ti, W
en W
an L
ing,
Pet
er L
ee
44
FT11
Fr
om b
urst
s to
mol
ecul
ar m
emor
y: fi
ndin
g th
e fu
ndam
enta
l uni
ts o
f bi
oche
mic
al
fluc
tuat
ions
Juan
M. P
edra
za, J
ohan
Pau
lsso
n
FT12
Ta
ckli
ng th
e un
cert
aint
y of
tum
our
dyna
mic
sA
bhik
Muk
herj
ee, D
urjo
y M
ajum
der,
Sur
yasa
rath
i Bar
at
FT14
R
obus
t ide
ntifi
cati
on o
f bi
oche
mic
al n
etw
orks
fro
m n
oisy
mea
sure
men
tsJo
ngra
e K
im, D
ecla
n G
. Bat
es, I
an P
ostl
ethw
aite
, Pat
Hes
lop-
Har
riso
n,
Kw
ang-
Hyu
n C
ho
FT15
C
ello
gica
: a to
ol to
ana
lyze
and
con
trol
the
dyna
mic
s of
cis
-reg
ulat
ory
syst
ems
Saty
a N
anda
Vel
Arj
unan
, Zhe
n X
uan
Yeo,
Mas
aru
Tom
ita,
Mas
a T
such
iya
FT16
A
naly
zing
rob
ustn
ess
in b
ioph
ysic
al n
etw
orks
: app
lica
tion
to a
popt
osis
Jaso
n E
. Sho
emak
er, F
ranc
is J
. Doy
le I
II
FT17
E
xper
imen
tal d
esig
n an
d m
odel
sel
ecti
on f
or s
igna
l tra
nsdu
ctio
n pa
thw
ays
Tho
mas
Mai
wal
d, C
lem
ens
Kre
utz,
Seb
asti
an B
ohl,
Mar
cel S
chil
ling
, Urs
ula
Kli
ngm
uell
er,
Jens
Tim
mer
FT18
A
MD
E p
ersp
ectiv
e on
cod
ing
of s
yste
ms
biol
ogy:
pro
of o
f co
ncep
t usi
ng tr
ansf
orm
atio
ns
to B
ioA
mbi
ents
and
ana
lysi
sD
ebor
a Sc
huch
da
Ros
a, M
agal
i Rou
x-R
ouqu
ie, M
arie
-Noe
lle
Terr
asse
, Cor
rado
Pri
ami
FT19
B
iolo
gica
l reg
ulat
ions
as
fini
te m
arko
v pr
oces
sR
eiko
J. T
anak
a, H
iden
ori K
imur
a, H
iroy
uki O
kano
FT20
G
enom
e si
ze e
stim
ates
and
kar
yoty
pes
for
thre
e im
port
ant f
resh
wat
er m
ollu
scs,
the
Lym
naea
nat
alen
sis
and
the
schi
stos
omia
sis
vect
or s
nail
s ( B
iom
phal
aria
ale
xand
rina
and
B
ulin
us tr
unca
tus)
Fay
ez A
. Bak
ry, A
hmed
T. S
hara
f El-
Din
FT21
T
Sim
, a p
latf
orm
for
sim
ulat
ion
of m
ulti
-cel
lula
r sy
stem
sA
rios
to S
ique
ira
Silv
a, J
ose
And
res Y
unes
FT22
D
ynam
ics
of H
IV in
fect
ion
stud
ied
wit
h C
onfo
rmon
-P s
yste
ms
Dav
id W
. Cor
ne, P
ierl
uigi
Fri
sco
FT23
A
sys
tem
atic
mod
elin
g fr
amew
ork
for
bioc
hem
ical
and
bio
logi
cal s
yste
ms
Hen
ning
Sch
mid
t, M
ats
Jirs
tran
d, G
unna
r C
eder
sund
FT24
Pa
ram
eter
est
imat
ion
usin
g al
tern
ativ
e co
st f
unct
ions
Hen
ning
Sch
mid
t, G
unna
r C
eder
sund
, Mat
s Ji
rstr
and
FT26
M
omen
t clo
sure
app
roxi
mat
ions
for
stu
dyin
g st
ocha
stic
ity
in b
iolo
gica
l sys
tem
sA
bhyu
dai S
ingh
, Joa
o Pe
dro
Hes
panh
a
FT27
U
nrav
elin
g fe
edba
ck s
truc
ture
s in
gen
e re
gula
tory
net
wor
ks w
ith
appl
icat
ion
to th
e m
amm
alia
n ci
rcad
ian
cloc
kC
amil
la T
rane
, Ell
ing
W. J
acob
sen
Synt
heti
c B
iolo
gy
FS01
Te
stin
g bi
olog
ical
erg
odic
ity
of to
ggle
sw
itch
and
rec
onst
ruct
ion
of s
ingl
e-ce
ll-b
ehav
ior
from
pop
ulat
ion-
leve
l-m
easu
rem
ent
Hir
okaz
u To
zaki
, Tet
suya
J. K
obay
ashi
, Hir
oyuk
i Oka
no, R
yo Y
amam
oto,
Kaz
uyuk
i Aih
ara,
H
iden
ori K
imur
a
FS02
S
topp
ing
mam
mal
ian
circ
adia
n cl
ock
by c
riti
cal l
ight
pul
se: d
eath
of
indi
vidu
al o
scil
lato
rs
or d
esyn
chro
niza
tion
of
osci
llat
ors?
Tets
uya
J. K
obay
ashi
, Hid
eki U
kai,
Hir
oki R
. Ued
a
FS03
C
onst
ruct
ion
and
perf
orm
ance
cha
ract
eris
tics
of
a se
lf-g
ener
atin
g in
vit
ro m
etab
olic
re
acti
onN
ancy
Kel
ley-
Lou
ghna
ne, M
auri
cio
Rod
rigu
ez, M
arli
n L
inge
r, L
atha
Nar
ayan
an,
John
Fra
zier
FS05
P
rogr
amm
able
bac
teri
al c
atal
ysts
Mig
uel G
odin
ho d
e A
lmei
da, J
acek
Puc
halk
a, A
mit
Kha
chan
e, K
enne
th T
imm
is,
Vit
or M
arti
ns d
os S
anto
s
FS06
R
egul
ator
y dy
nam
ics
of s
ynth
etic
gen
e ne
twor
ks w
ith
posi
tive
feed
back
Yusu
ke T
. Mae
da, M
asak
i San
o
FS07
D
e no
vo c
onst
ruct
ion
of g
ene
regu
lati
on n
etw
ork
in s
mal
l ves
icle
Dai
suke
Kig
a, M
asah
iro
Taki
noue
, Koh
-ich
iroh
Sho
hda,
Aki
ra S
uyam
a
FS08
In
sil
ico
geno
me-
scal
e an
alys
is o
f th
e hy
pert
herm
ophi
lic
bact
eriu
m, T
herm
otog
a ne
apol
itan
aJi
n Si
k K
im, J
ae J
ong
Kim
, Ki J
ung
Par
k, S
ang
Yup
Lee
FS09
E
ngin
eeri
ng s
ynth
etic
tran
s-sp
lici
ng r
iboz
yme
syst
ems
Aus
tin
Che
FS10
Po
pula
tion
ana
lysi
s of
lipo
som
es w
ith
prot
ein
synt
hesi
s an
d a
casc
adin
g ge
neti
c ne
twor
kTa
kesh
i Sun
ami,
Kan
etom
o Sa
to, K
eita
ro I
shik
awa,
Tet
suya
Yom
o
Nov
el C
ompu
tati
onal
Env
iron
men
ts f
or S
yste
ms
Bio
logy
FI01
S
BM
L le
vel 2
ver
sion
2A
ndre
w F
inne
y, M
icha
el H
ucka
, Nic
olas
Le
Nov
ere
FI02
T
he S
BM
L la
yout
ext
ensi
on a
nd b
eyon
dR
alph
Gau
ges,
Sve
n Sa
hle,
Urs
ula
Ros
t, K
atja
Weg
ner
FI03
T
he s
yste
ms
biol
ogy
onto
logy
Mel
anie
Cou
rtot
, Mic
hael
Huc
ka, N
icol
as L
e N
over
e
FI04
M
IRIA
M d
atab
ase
and
web
serv
ices
Cam
ille
Lai
be, M
elan
ie C
ourt
ot, M
arco
Don
izel
li, C
hen
Li,
Nic
olas
Le
Nov
ere
FI05
B
ioM
odel
s da
taba
se, a
cur
ated
res
ourc
e of
ann
otat
ed p
ubli
shed
mod
els
Che
n L
i, M
arco
Don
izel
li, L
u L
i, H
aris
h D
haru
ry, A
rnau
d H
enry
, Mic
hael
Huc
ka,
Nic
olas
Le
Nov
ere
45
FI06
R
ecen
t upd
ates
to li
bSB
ML
, Mat
hSB
ML
, SB
MLT
oolb
ox, a
nd th
e S
BM
L.o
rg o
nlin
e va
lida
tor
Ben
jam
in B
orns
tein
, Sar
ah M
. Kea
ting
, Bru
ce S
hapi
ro, J
oann
a M
urak
ami,
Mic
hael
H
ucka
FI07
S
BM
Led
itor
: an
edit
or f
or m
odel
s in
the
syst
ems
biol
ogy
mar
kup
lang
uage
Nic
olas
Rod
rigu
ez, N
icol
as L
e N
over
e, M
arco
Don
izel
li
FI08
C
ellD
esig
ner3
.1: a
pro
cess
dia
gram
edi
tor
for
gene
-reg
ulat
ory
and
bioc
hem
ical
net
wor
ksA
kira
Fun
ahas
hi, A
kiya
Jou
raku
, Yuk
iko
Mat
suok
a, N
orih
iro
Kik
uchi
, Hir
oaki
Kit
ano
FI09
In
tegr
atin
g to
ols
for
com
puta
tion
al s
yste
ms
biol
ogy:
PyS
CeS
and
JW
S o
nlin
eB
rett
G. O
livi
er, J
ohan
n M
. Roh
wer
, Jac
ky L
. Sno
ep, J
an-H
endr
ik S
. Hof
mey
r
FI10
Ta
vern
a w
orkfl
ows
for
syst
ems
biol
ogy
Pet
er L
i, A
ndy
Bra
ss, J
ohn
Pin
ney,
Tom
Oin
n, D
ougl
as K
ell,
Car
ole
Gob
le
FI11
C
OPA
SI
- a
com
plex
pat
hway
sim
ulat
orSv
en S
ahle
, Ste
fan
Hoo
ps, R
alph
Gau
ges,
Jue
rgen
Pah
le, P
edro
Men
des,
Urs
ula
Kum
mer
FI12
S
yste
ms
biol
ogy
soft
war
e su
ppor
t in
mat
hem
atic
a: r
ecen
t dev
elop
men
ts in
cel
lera
tor
Bru
ce E
. Sha
piro
, Ale
xey
Voro
byov
, Joa
nna
G. M
urak
ami,
Eri
c D
. Mjo
lsne
ss
FI13
S
IBio
Net
: SB
ML
app
lica
tion
for
sys
tem
iden
tifi
cati
on o
f bi
oche
mic
al r
eact
ion
netw
orks
Ats
ushi
Shi
nkai
, Jun
ichi
ro Y
oshi
mot
o, K
enji
Doy
a
FI14
D
ynaB
ioS
.Cel
l: a
new
gen
eral
sim
ulat
or f
or c
ell p
hysi
olog
ical
mod
els
to f
acil
itat
e si
mul
atio
n of
exp
erim
enta
l pro
toco
lsTa
kao
Shim
ayos
hi, A
kira
Am
ano,
Tet
suya
Mat
suda
FI15
C
AD
LIV
E: c
ompu
ter-
aide
d de
sign
of
livin
g sy
stem
sK
enta
rou
Inou
e, H
iroy
uki K
urat
a
FI16
C
ompr
ehen
sive
stu
dy o
f nu
mer
ical
sol
vers
in c
ompl
ex o
scil
lato
ry b
ioch
emic
al s
yste
ms
mod
elin
gM
ay W
ang,
Cha
ng F
Quo
FI17
A
tool
for
ana
lysi
s in
"dy
nam
ical
cha
nge
beha
vior
ove
r m
otif
s"Ji
ttis
ak S
enac
hak,
Tom
oyuk
i Yam
amot
o, K
okic
hi F
utat
sugi
FI18
F
ly-D
PI:
dat
abas
e of
pro
tein
inte
ract
omes
for
D. m
elan
ogas
ter
in th
e ap
proa
ch o
f sy
stem
s bi
olog
yC
hung
-Yen
Lin
, Chi
-Shi
ang
Cho
, Chi
a-L
ing
Che
n, F
an-K
ai L
in, C
hieh
-Hua
Lin
, P
ao-Y
ang
Che
n, S
hu-H
wa
Che
n, C
hen-
Zen
Lo,
Cha
o A
. Hsi
ung
FI19
D
atab
ase
driv
en a
ppro
ach
for
auto
mat
ic c
onst
ruct
ion
of d
ynam
ic c
ell-
wid
e m
etab
olic
pa
thw
ay m
odel
sK
azuh
aru
Ara
kaw
a, Y
ukin
o O
gaw
a, M
asar
u To
mit
a
FI20
V
isua
liza
tion
of
Cel
lML
mod
els
Sara
la D
issa
naya
ke, M
att H
alst
ead,
Pou
l Nie
lsen
FI21
A
gra
phic
al n
otat
ion
to d
escr
ibe
the
logi
cal i
nter
acti
ons
of b
iolo
gica
l pat
hway
sSt
uart
L. M
oodi
e, A
nato
ly S
orok
in, I
gor
Gor
yani
n, P
eter
Gha
zal
FI22
G
oogl
ing
cred
ible
inte
ract
ions
fro
m p
rote
in-p
rote
in in
tera
ctio
n ne
twor
ksK
inya
Oka
da, M
asan
ori A
rita
, Kiy
oshi
Asa
i
FI23
A
n in
tegr
ativ
e da
taba
se f
or b
ioch
emic
al r
eact
ion
kine
tics
: SA
BIO
-RK
Ren
ate
Kan
ia, U
lrik
e W
itti
g, M
arti
n G
oleb
iew
ski,
And
reas
Wei
dem
ann,
Olg
a K
rebs
, Sa
qib
Mir
, Isa
bel R
ojas
FI24
In
tegr
atio
n of
gen
e ex
pres
sion
dat
a w
ith
bio-
mol
ecul
ar in
tera
ctio
n ne
twor
ks b
y us
ing
repo
rter
fea
ture
s al
gori
thm
Ana
Pau
la O
live
ira,
Kir
an R
aosa
heb
Pati
l, Je
ns N
iels
en
FI25
U
sing
var
iabl
e se
lect
ion
met
hod
to in
fer
gene
reg
ulat
ory
netw
orks
fro
m ti
me
seri
es
mic
roar
ray
data
Dou
gu N
am, C
heol
-Gu
Hur
, Jih
yun
F. K
im
FI26
To
war
ds a
sig
nal t
rans
duct
ion
netw
ork
of y
east
Kut
lu O
. Ulg
en, K
. Yal
cin
Arg
a, Z
. Ils
en O
nsan
, Bet
ul K
irda
r, Je
ns N
iels
en
FI27
C
ompu
ter-
base
d sc
reen
ing
of f
unct
iona
l con
form
ers
of p
rote
ins
Hec
tor
M M
onti
el M
olin
a, G
abri
el D
el R
io
FI28
A
n in
fras
truc
ture
to c
onst
ruct
gen
ome-
scal
e m
etab
olic
mod
els
auto
mat
ical
lyX
ingh
ua S
hi, R
ick
Stev
ens
FI29
T
RN
Dy:
a b
ioin
form
atic
s to
ol f
or in
vest
igat
ing
the
topo
logi
cal d
ynam
ics
of d
iffe
rent
ially
ex
pres
sed
gene
s in
tran
scri
ptio
nal r
egul
ator
y ne
twor
ksD
uang
dao
Wic
hada
kul,
Ram
Sam
udra
la
FI30
P
rote
in n
etw
ork
cons
truc
tion
of
Can
dida
alb
ican
s fr
om S
acch
arom
yces
cer
evis
iae’
s pr
otei
n-pr
otei
n in
tera
ctio
nsC
hieh
-Hua
Lin
, Chu
ng-Y
en L
in, F
an-K
ai L
in, C
hi-S
hian
g C
ho, C
hia-
Lin
g C
hen,
P
ao-Y
ang
Che
n, C
hen-
Zen
Lo,
Cha
o A
. Hsi
ung
FI31
In
tera
ctiv
e vi
sual
izat
ion
of c
ompl
ex a
nd s
truc
ture
d bi
olog
ical
net
wor
ksSe
bast
ian
Mir
sche
l, M
arti
n G
inke
l, J
ulio
Sae
z-R
odri
guez
, Ern
st D
iete
r G
ille
s
FI32
K
inet
ikon
HT,
a d
atab
ase
of k
inet
ic p
aram
eter
s, c
reat
ed u
sing
hig
h th
roug
hput
tech
niqu
es.
Axe
l Kow
ald,
Seb
asti
an S
chm
eier
, Mar
vin
Schu
lz, W
olfr
am L
iebe
rmei
ster
, Si
mon
Bor
ger,
Edd
a K
lipp
FI33
Po
tter
sWhe
el: u
ser-
frie
ndly
hig
h-pe
rfor
man
ce p
aram
eter
est
imat
ion
& m
odel
sel
ecti
on
Mat
lab
fram
ewor
kT
hom
as M
aiw
ald,
Cle
men
s K
reut
z, J
ens
Tim
mer
FI34
S
yste
ms
biol
ogy
anal
ysis
of
endo
cyto
sis
and
sign
alli
ng in
mam
mal
ian
cell
sM
arin
o Z
eria
l, J
oche
n R
ink,
Cla
udio
Col
line
t, C
harl
es B
rads
haw
, Bia
nca
Hab
erm
ann,
Ya
nnis
Kal
aidz
idis
, Per
la D
el C
onte
-Zer
ial,
Lut
z B
rusc
h, A
ndre
as D
euts
ch
FI35
T
herm
odyn
amic
al m
odel
of
DN
A h
ybri
diza
tion
on
shor
t oli
gonu
cleo
tide
mic
roar
ray
Nao
aki O
no, S
hing
o Su
zuki
, Chi
kara
Fur
usaw
a, A
kiko
Kas
hiw
agi,
Tet
suya
Yom
o
FI36
P
redi
ctin
g de
lete
riou
s S
NP
s w
ith
site
-spe
cifi
c ev
olut
iona
ry m
odel
sA
nna
A. C
hern
ova,
Ben
jam
in P
. Bla
ckbu
rne,
Ric
hard
A. G
olds
tein
FI37
E
valu
atin
g th
e fu
ncti
onal
coh
eren
ce o
f pr
otei
n gr
oups
via
pro
tein
-sem
anti
c ne
twor
kB
in Z
heng
, Xin
ghua
Lu
46
FI38
Fr
om in
sil
ico
QT
Ls
to s
yste
m b
iolo
gy: a
n ex
ampl
e of
usi
ng in
sil
ico
map
ping
to id
enti
fy
gene
tic
cont
ribu
tion
to v
aria
tion
of
bono
mas
s de
nsit
y in
inbr
ed s
trai
nsP
aul L
. F. T
ang,
Mat
thew
S. Y
. Cha
n, P
ak C
. Sha
m, Y
ou-q
iang
Son
g
FI39
N
umer
ical
sim
ulat
ion
and
mol
ecul
ar s
yste
ms
biol
ogy
Koi
chi T
akah
ashi
FI40
Pa
ram
eter
est
imat
ion
for
stif
f eq
uati
ons
of b
iosy
stem
s us
ing
radi
al b
asis
fun
ctio
n ne
twor
ksYo
shiy
a M
atsu
bara
, Shi
nich
i Kik
uchi
, Mas
ahir
o Su
gim
oto,
Mas
aru
Tom
ita
FI41
B
ioU
ML
− o
pen
sour
ce e
xten
sibl
e w
orkb
ench
for
sys
tem
s bi
olog
yFe
dor
A. K
olpa
kov,
Mik
hail
V. P
uzan
ov, A
lexa
nder
V. K
oshu
kov
FI42
A
uni
vers
al r
ate
equa
tion
for
com
puta
tion
al s
yste
ms
biol
ogy
Joha
nn M
. Roh
wer
, Arn
o J.
Han
ekom
, Jan
-Hen
drik
S. H
ofm
eyr
FI43
M
etaF
luxN
et2:
an
inte
grat
ed e
nvir
onm
ent f
or m
odel
ing
and
sim
ulat
ion
of g
enom
e-sc
ale
met
abol
ic n
etw
ork
mod
elH
ongs
eok
Yun,
Cho
amun
Yun
, Hyu
n U
k K
im, S
ang
Yup
Lee
FI44
S
yste
m-l
evel
iden
tifi
cati
on o
f tr
ansc
ript
iona
l cir
cuit
s un
derl
ying
dro
soph
ila
circ
adia
n cl
ocks
usi
ng d
roso
phil
a ti
ling
arr
ays
Rik
uhir
o G
. Yam
ada,
Mak
i Uka
i Tad
enum
a, K
en-i
chir
o D
. Uno
, Tak
eya
Kas
ukaw
a,
Aki
ra M
atsu
mot
o, H
irok
i R. U
eda
FI45
Id
enti
fyin
g ge
nes
wit
h si
gnifi
cant
inte
ract
ion
effe
cts
in to
xico
logi
cal t
ime-
cour
se
mic
roar
ray
data
Yan
Ma,
E. J
ames
Har
ner
FI46
D
evel
opm
ent o
f co
mpu
tati
onal
met
hods
for
ana
lysi
s of
met
abol
ite
scre
enin
g da
taP
riti
Tal
war
, Tho
mas
Len
gaue
r, C
hris
toph
Wit
tman
n, V
idya
Vel
agap
udhi
, Elm
ar H
einz
le
FI47
To
p-do
wn
appr
oach
for
dec
iphe
ring
cha
ract
eris
tics
of
met
abol
ic r
eact
ions
fro
m
expe
rim
enta
l dat
aJu
ng-W
ook
Ban
g, T
im E
bbel
s, F
lore
ncio
Paz
os
FI48
A
gen
eric
mas
s sp
ectr
omet
ry-b
ased
pla
tfor
m f
or e
nzym
e ki
netic
dat
a ac
quis
ition
and
an
alys
isR
icha
rd B
aran
, Tak
amas
a Is
hika
wa,
Nat
sum
i Sai
to, Y
uji K
akaz
u, T
omoy
oshi
Sog
a,
Taka
aki N
ishi
oka,
Mar
tin
Rob
ert,
Mas
aru
Tom
ita
FI49
R
ole
of th
e bg
l ope
ron
of E
sche
rich
ia c
oli i
n st
atio
nary
pha
seR
anjn
a M
adan
, S. M
ahad
evan
FI50
T
he M
anch
este
r ce
ntre
for
inte
grat
ive
syst
ems
biol
ogy
Dou
glas
B. K
ell,
Dav
id S
. Bro
omhe
ad, S
imon
J. G
aske
ll, J
ohn
McC
arth
y,
Step
hen
G. O
live
r, N
orm
an P
aton
, Han
s V.
Wes
terh
off
FI51
A
kin
etic
app
roac
h to
the
anal
ysis
of
non-
stea
dy s
tate
isot
ope
trac
er d
ata
Vit
aly
Seli
vano
v, S
ilvi
a M
arin
, Ant
onio
Ram
os-M
onto
ya, J
osep
Cen
tell
es, P
aul L
ee,
Mar
ta C
asca
nte
FI52
In
terp
ret l
ipid
met
abol
omic
pat
hway
dat
a us
ing
visu
aliz
atio
nG
eoff
rey
Wan
g, J
in-Y
oung
Hon
g, A
lfre
d M
erri
ll, M
ay D
. Wan
g
FI53
R
ever
se e
ngin
eeri
ng f
or e
mbr
yoni
c ge
ne r
egul
ator
y ne
twor
k in
zeb
rafi
sh v
ia e
volu
tion
ary
opti
miz
atio
n w
ith
data
col
loca
tion
Wen
-Hun
g H
unag
, Chi
ou-H
wa
Yuh,
Fen
g-Sh
eng
Wan
g
FI54
G
enom
e an
nota
tion
and
met
abol
ic n
etw
ork
cons
truc
tion
of
Asp
ergi
llus
ory
zae
Wan
wip
a V
ongs
angn
ak, P
eter
Bja
rke
Ols
en, S
teen
Kro
gsga
ard,
Jen
s N
iels
en
FI55
C
hara
cter
izat
ion
of r
egul
ator
y m
odul
es a
ssoc
iate
d w
ith
stem
cel
l dif
fere
ntia
tion
by
late
nt
vari
able
mod
els
Je-G
un J
oung
, Don
gho
Shin
, Rho
Hyu
n Se
ong,
Byo
ung-
Tak
Zha
ng
FI56
V
irtu
al m
icro
scop
y -
mod
ular
mod
elin
g of
exp
erim
enta
l pro
toco
ls a
nd in
stru
men
tati
onJa
mes
Sch
aff,
Anu
radh
a L
aksh
min
aray
ana,
Ion
Mor
aru,
Les
lie
Loe
w
FI57
H
igh-
thro
ughp
ut im
age
anal
ysis
of
subc
ellu
lar
loca
liza
tion
pat
tern
s of
fluo
resc
ently
la
bele
d pr
otei
nsF
abia
n K
ampe
r, O
laf S
elch
ow, D
imit
rios
Kal
amat
iano
s, H
aral
d W
ajan
t,
Kla
us P
fizen
mai
er, E
ric
Bul
ling
er
FI58
A
ppli
ed g
enom
e-sc
ale
mod
elli
ng o
f as
perg
illu
s ni
ger
Mik
ael R
. And
erse
n, M
icha
el L
. Nie
lsen
, Jen
s N
iels
en
FI59
Q
uali
ty c
ontr
ol a
nd im
prov
ed q
uant
itat
ive
wes
tern
blo
ttin
g w
ith
the
geli
nspe
ctor
Tho
mas
Mai
wal
d, M
arce
l Sch
illi
ng, S
ebas
tian
Boh
l, C
lem
ens
Kre
utz,
U
rsul
a K
ling
mue
ller
, Jen
s T
imm
er
FI60
In
tegr
atio
n of
bio
logi
cal p
athw
ays
Yu-T
ai W
ang,
Yei
ng-W
en D
eng,
Che
ng-M
in W
ei, U
eng-
Che
ng Y
ang
FI61
B
ayes
ian
syst
em id
enti
fica
tion
of
bioc
hem
ical
sig
nali
ng p
athw
ays
Juni
chir
o Yo
shim
oto,
Ats
ushi
Shi
nkai
, Ken
ji D
oya
FI62
In
tegr
ativ
e bi
oinf
orm
atic
s an
alys
is th
at d
econ
volu
tes
the
chan
ges
of tr
ansc
ript
iona
l re
gula
tory
pro
gram
s du
ring
car
cino
gene
sis
Ats
ushi
Nii
da, S
huic
h Ts
utsu
mi,
And
rew
Sm
ith,
Mic
hael
Q. Z
hang
, Hir
oyuk
i Abu
rata
ni,
Tets
u A
kiya
ma
FI63
G
enom
ic s
igna
ture
s fo
r dr
ug-i
nduc
ed a
popt
osis
in c
ance
r ce
ll li
nes:
a c
ombi
ned
expe
rim
enta
l and
sta
tL
aure
nt G
auti
er, C
hris
toph
er T
aylo
r, H
arol
d B
rook
s, P
hili
p Iv
erse
n, C
harl
es S
penc
er,
Xia
ng Y
ang,
Gre
g Tu
cker
-Kel
logg
FI64
O
ptim
izat
ion
of c
DN
A m
icro
arra
ys u
sing
cri
teri
a th
at d
o no
t rel
y on
ext
erna
l sta
ndar
dsTo
runn
Bru
land
, End
re A
nder
ssen
, Ber
it D
oset
h E
itre
m, H
allg
eir
Ber
gum
, V
idar
Bei
svag
, Ast
rid
Lae
grei
d
FI65
Id
enti
fica
tion
and
des
ign
of in
ter-
and
intr
a-m
olec
ular
ato
mic
net
wor
k by
usi
ng th
e ge
nom
ic s
eque
nces
and
the
stru
ctur
al in
form
atio
nYo
hei K
oyam
a, T
etsu
ya J
. Kob
ayas
hi, S
huji
Tom
oda,
Hir
oki R
. Ued
a
FI66
C
ompo
siti
on a
nd a
ggre
gati
on f
or b
iolo
gica
l pat
hway
mod
elin
gR
anji
t Ran
dhaw
a, C
liffo
rd A
. Sha
ffer,
John
J. T
yson
47
FI67
A
n ac
cele
rati
on o
f a
bioc
hem
ical
sim
ulat
or o
n pr
ogra
mm
able
har
dwar
eYo
w I
wao
ka, Y
asun
ori O
sana
, Mas
ato
Yosh
imi,
Tos
inor
i Koj
ima,
Yur
i Nis
hika
wa,
A
kira
Fun
ahas
hi, N
orik
o H
iroi
, Yui
chir
o Sh
ibat
a, N
aoki
Iw
anag
a, H
iroa
ki K
itan
o,
Hid
ehar
u A
man
o
FI68
Fi
D -
a to
ol f
or p
redi
ctio
n of
mol
ecul
ar f
ragm
ents
fro
m ta
ndem
mas
s sp
ectr
omet
ry d
ata
Mar
kus
Hei
none
n, A
ri R
anta
nen,
Tan
eli M
ieli
kain
en, E
sa P
itka
nen,
Juh
o R
ousu
FI69
C
ompa
rativ
e ‘O
mic
s’ a
naly
sis
of E
sche
rich
ia c
oli B
and
K-1
2Su
ng H
o Yo
on, H
aeyo
ung
Jeon
g, C
heol
-Goo
Hur
, Tae
Kw
ang
Oh,
Jih
yun
F. K
im
FI70
S
yste
ms
biol
ogy
grap
hica
l not
atio
n (S
BG
N)
proj
ect
Hir
oaki
Kit
ano,
Mic
hael
Huc
ka, N
icol
as L
e N
over
e, A
kira
Fun
ahas
hi
FI71
P
redi
ctin
g an
tige
nic
drif
t in
hum
an in
flue
nza
A v
irus
H3
hem
aggl
utin
inYu
-Chi
eh L
iao,
Chi
n-Yu
Ko,
Min
-Shi
Lee
, Cha
o A
. Hsi
ung
FI72
W
ebC
ell:
a w
eb-b
ased
inte
grat
ed e
nvir
onm
ent f
or m
anag
ing
and
anal
yzin
g ce
llul
ar
netw
ork
mod
els
Cho
amun
Yun
, Don
g-Yu
p L
ee, A
youn
Cho
, Sun
won
Par
k, S
ang
Yup
Lee
FI73
L
inea
r an
d co
nfor
mat
iona
l epi
tope
s pr
edic
tion
fro
m m
embe
r of
pro
tein
fam
ilie
sTu
n-W
en P
ai, W
ei-J
un Z
hung
, Chi
h-H
ong
Liu
, Wen
-Shy
ong
Tzou
FI74
Id
enti
fica
tion
of
hete
roge
neou
s na
med
ent
itie
s in
bio
logy
text
s an
d re
solu
tion
of
anap
hora
Juli
en L
orec
, Ger
ard
Ram
stei
n, Y
anni
ck J
acqu
es
FI75
B
ioC
AD
: web
ser
vice
bas
ed in
tegr
ated
sys
tem
for
infe
rrin
g ge
neti
c re
gula
tory
cir
cuit
sSa
ngw
oo K
im, K
iryo
ng H
a, D
oheo
n L
ee
FI76
In
tegr
atin
g m
icro
arra
y da
ta a
naly
sis
and
prot
ein-
prot
ein
inte
ract
ion
data
base
to c
onst
ruct
dy
nam
ic b
iolo
gica
l net
wor
ks w
hich
rep
rese
nt th
e ch
arac
teri
stic
s of
gen
e ex
pres
sion
pa
tter
nP
eter
Kua
n-Ye
u P
an, C
hen-
Hsi
ung
Cha
n, S
heng
-An
Lee
, Che
ng-Y
an K
au, I
-Min
g C
hu
FI77
A
vie
w to
the
evol
utio
n of
bio
logi
cal p
athw
ays
usin
g PA
NT
HE
R.
Hua
iyu
Mi,
Nan
Guo
, Ani
sh K
ejar
iwal
, Pau
l Tho
mas
FI78
S
BW
− a
mod
ular
fra
mew
ork
for
Sys
tem
s B
iolo
gyF
rank
T. B
ergm
ann,
Her
bert
M. S
auro
FI79
G
ene
func
tion
pre
dict
ion
usin
g on
e-cl
ass
tech
niqu
eX
ian-
Min
g Z
hao,
Luo
nan
Che
n, K
azuy
uki A
ihar
a
Oth
ers
Oth
ers
OT01
A
ccur
ate
quan
tifi
cati
on o
f co
mpo
nent
sto
ichi
omet
ry o
f a
mul
tipr
otei
n co
mpl
ex b
y m
eans
of
mas
s sp
ectr
omet
ry w
ith
a pe
ptid
e-co
ncat
enat
ed s
tand
ard
prot
ein
Kei
ji K
ito,
Tom
oko
Fuj
ita,
Kaz
uhis
a O
ta, T
akas
hi I
to
OT02
S
yste
ms
mic
robi
olog
ical
inve
stig
atio
ns in
to th
e tw
o-co
mpo
nent
sys
tem
s in
E. c
oli
Jeon
g-R
ae K
im, H
youn
g-Se
ok C
hoi,
Jun
il K
im, D
ongs
an K
im, Y
eoin
Yoo
n,
Sang
-Woo
Lee
, Kw
ang-
Hyu
n C
ho
OT03
Fi
ndin
g hu
man
miR
NA
gen
es lo
cate
d w
ithin
pro
mot
er r
egio
ns a
nd a
ssoc
iate
d w
ith C
pG
isla
nds
Min
g-C
heng
Tsa
i, J
an-G
owth
Cha
ng, K
a-L
ok N
g
4848
Tutorials
Sunday, October 8
Venue: Pacifico Yokohama
Room 9:30-12:30 14:00-17:00
411+
412
T2: Structural and functional analysis of signaling networksSteffen Klamt, Julio Saez-Rodriguez (Max Planck Institute Magdeburg, Germany)
T4: Tutorial on the Systems Biology Toolbox for MATLAB Henning Schmidt (Fraunhofer Chalmers Research Centre)
413T1: Engineering design principles for biologistsKyaw Tun, (Univ.Singapore), Arun Krishnan (Keio Univ.), Pawan K Dhar (RIKEN GSC) (*2 hours)
T5: Pathway Modeling with Teranode XDAMike Kellen (Teranode)
414+
415
T3: New Mathematical Methods for Systems BiologyEric Mjolsness (UC Irvine)
416T12: The Systems Biology Markup Language (SBML) Level 2 Version 2Michael Hucka (California Institute of Technology)
T6: Analyzing Biochemical Systems using the E-Cell SystemSatya Arjunan (Keio University)
417T8: Modeling, simulating, and analyzing biochemical systems with CopasiPedro Mendes (Virginia Bioinformatics Institute)
T9: Advanced model analysis with CopasiPedro Mendes (Virginia Bioinformatics Institute)
418T11: Application of Experimental Design and Model Selection to Signal Transduction Pathway ModelingThomas Maiwald, Marcel Schilling, Sebastian Bohl(University of Freiburg, German Cancer Research Center ) (*1 day)
419T7: Computational Cell Biology with the Virtual CellIon I. Moraru and James C. Schaff (University of Connecticut Health Center)
T10: CellDesignerAkira Funahashi (The Systems Biology Institute/JST)
4949
Workshops
A. Systems Biology Graphical Notation (SBGN Workshop)Date: Saturday, October 7, 2006 09:30 – 18:00Venue: Yokohama World Porters Building (5 min. walk from Pacifico Yokohama)Organizers: Hiroaki Kitano (SBI & Sony CSL), Yukiko Matsuoka (SBI & JST), Akira Funahashi (SBI & JST), Michael Hucka (California Institute of Technology), Nicolas Le Novère (EBI)
B. RTK workshop: Receptor tyrosine kinases (RTK) training courseDate: Thursday-Friday, October 12-13 2006 09:15 – 17:30Venue: AIST Tokyo Waterfront Bio-IT Research Building, OdaibaOrganizers: RTK Consortium & RIKEN Genomic Sciences Center (GSC)
C. Systems Biology Markup Language (SBML) Forum Meeting; The 11th Workshop on Software Platforms for Systems BiologyDate: Thursday-Friday, October 12-13 2006 09:30 – 17:30Venue: National Museum of Emerging Science and Innovation “Miraikan”Organizers: Michael Hucka (California Institute of Technology), The Systems Biology Markup Language (SBML) Team
D. International Workshop on Synthetic Biology “Synthetic Approaches to Cellular Functions”Date: Thursday, October 12, 2006 09:30 – 18:00Venue: National Museum of Emerging Science and Innovation “Miraikan”Organizers: Daisuke Kiga (Tokyo Institute of Technology), Drew Endy (MIT), Vitor Martins dos Santos (German Research Centre for Biotechnology), Hiroki Ueda (RIKEN)
E. Systems Biology Workshop: “Systems Biology and the Human Health Risks of Environmental Chemicals”Date: Thursday, October 12, 2006 09:00 – 15:00Venue: National Museum of Emerging Science and Innovation “Miraikan”Organizers: Rory Conolly (U.S. Environmental Protection Agency)
RestroomsMultiple Use ToiletBabyʼs bedRefreshment AreaEscalators/StairsElevatorsRestaurant
Exhibition AreaResearchArea
LoungeInnovation Hall
Restaurant
Conference Room 2
Conference Room 1Conference Room 3
ABLNG
INH
HAL
CR2 CR1
CR3
MIRAICANHall
Floor Map, "Miraikan" (7F)
Venue Map (October 12-13 Workshops)
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5050
Access
lAnnex Hall
Bus/Large Vehicle Parking Lot
Kannai Area
Shinko Area
YokohamaPortside Area
Breezbay Hotel
On foot
YokohamaMuseum of Art
YokohamaMedia Tower
LeafMinato Mirai
HomecenterSekichu
Metropolitan Expressway(Yokohama-Haneda Line)Minato Mirai Ramp
Route16
1etu
oR
Yokohama Municipal Subway
Minato Mirai Line.(Tokyu Toyoko Direct Line)
Takashimacho Station
Yokohama Jackmall
Sea Bass Terminal
YokohamaTakashimayaDept.Store
tixE
tsaE
ama
hoko
Yno
itat
Sti
xE ts
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Yokohama Sky Bldg.Marui Department StoreYCAT
(Yokohama City Air Terminal)
Yokohama SogoDept.Store
Post Office
Taxi Terminal
Yokohama-Minato MiraiManyo-club
Navios Yokohama
YokohamaCosmo World
JICA YokohamaInternational Center
Mitsubishi Heavy Industries Bldg.
JR LineSakuragicho Station
Sakuragicho Station
Bus Taxi Terminal
Cross GateYokokhamaSakuragichoWashinton Hotel
Pukarisanbashi PierSea Bass Terminal
Shinko Park
Unga Park
GENTOYOKOHAMA
Aka-Renga Soko
Aka-Renga Park
Shinko Pier
(Yokohama Red Brick Warehouse)
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Yokohama Bay
to Yamashita Park
Sea Bassto Yokohama
Police box
Rinko Park
Rinko Park Parking Lot
Minato MiraiBusiness Square
Cross-Patio
Keiyu Hospital
Minato Mirai Sta.
Yokohama Sakuragi Post Office
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Kokusai Odori Boulevard
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Minato Mirai Odori Boulevard
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From Minato Mirai Sta.Take Queen's Square Yokohama Exit
and go upto 2nd Floorby Red Escalator
Marinos town
P3
P2
P1
MAP
1-1-1 Minatomirai, Nishi-ku, Yokohama200-0012, JapanInformation TEL: +81(45)221-2155URL:http://www.pacifico.co.jp
P1
P1Annex HallExhibition Hall
Kokusai Odori Boulevard
NationalConvention Hallof Yokohama
Inter ContinentalThe Grand Yokohama
ConferenceCenter
To Parking
To Parking
r rHarbor Lounge
P1To Parking
World Porters
Moving Walkway
Shinagawa
Fune-noKagakukan
Tokyo
Narita
Narita ExpressJR LineYurikamome
AirportTerminal 2 Stn.
NaritaAirport Stn.(Terminal 1)
NaritaAirport
Tokyo Bay
Akihabara
Shinbashi
National Museum of EmergingScience and Innovation (Miraikan)AIST/CBRC
Minato MiraiYokohama
PACIFICOYOKOHAMA
WorldPorters
Minato Mirai Line
(Odaiba Area)
� Minato Mirai 21Information Center� Kenmin Kyosai Plaza Bldg.� Yokohama Royal Park Hotel / The Landmark Tower Yokohama� Landmark Plaza� Nippon-Maru Memorial Park� Queen's Square Yokohama
� Pan Pacific Hotel Yokohama� Yokohama MinatoMirai Hall� Kokusaibashi Bridge� Yokohama World Porters
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Foyer
Sub Hall 1Sub Hall 1
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Sub Hall 1Sub Hall 2
Tutorials (8th Oct.)Poster Sessions (9th, 10th Oct.)
Registration DeskICSB-2006 OfficePreview Room
Main HallSponsor Exhibitions
Sub Hall 2
Sub Hall 1
Poster Display
Registration DeskPreview Room
ICSB-2006 Office
Main Hall
Sponsor Exhibitions
© ICSB-2006 Conference Committee