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Progress WP4, WP7Memodyn – Application Scenario – Organizational
Coarse-Graining
Jan Huwald
Richard Henze
Bashar Ibrahim
Peter Dittrich
Bio Systems Analysis Group, Institute of Computer Science,
Friedrich-Schiller-University Jena
Application scenario in collaboration with: Diekmann Group and
Hemmerich Group, FLI Jena
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OverviewI. Memodyn (WP4)
Report in D4.2Software / source code in D4.2
II. Artificial chemistries and organizational coarse-graining
(WP4, WP7)
Paper in D4.2: Keyssig et al., Bioinformatics, 2014
III. Application scenario – Mitotic checkpoint (WP7)
Paper in D7.1: Ibrahim&Henze, Int. J. Mol. Sci., 2014 Paper
in D7.1: Henze et al., Biosystems, 2014
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Part I MEMODYN
WP 4
Jan Huwald
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Memodyn
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Memodyn „Learning Cycle“
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Continuous sample generation
1. Random unbiased sampling
2. Constraint propagation
3. Force-based search
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Unbiased random sampling
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Constraint propagation(using GECODE)
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Force-based approach
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Force-based approach
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Force-based approach
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Force-based approach
For all combination all solutions are found!
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Continuous simulation
1. Micro-simulation border
2. Energy guided distance quantization
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Micro-simulation border
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Micro-simulation ersatz field
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Micro-simulation border for three particles
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Software
Source code implementing the methods mentioned above attached to
D4.2.
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Part II Organizational Coarse-Graining
WP 4 / WP 7
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1. Basic Idea
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Chemical OrganizationTheory
OrganizationsReaction network
1
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Organization
[P. Dittrich, P. Speroni di Fenizi, Chemical Organization
Theory, Bull. Math. Biol., 2007]
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1. Basic Idea
{1}
{2, 3}
{1,2,3,4}
{ }
Hasse diagram of organizations
OrganizationsReaction network
Chemical OrganizationTheory
1
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[P. Dittrich, P. Speroni di Fenizi, Chemical Organization
Theory, Bull. Math. Biol., 2007]
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1. Basic Idea
1
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Thoerie chemischerOrganization
{1}
{2, 3}
{1,2,3,4}
{ }
Dynamics
[2][3]
[4][1]
Chemical OrganizationTheory
Hasse diagram of organizations
OrganizationsReaction network
[P. Dittrich, P. Speroni di Fenizi, Chemical Organization
Theory, Bull. Math. Biol., 2007]
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Organisational Coarse-graining Results
1. Discrete organizations (Kreyssig et al. 2014)2. Measuring
organizations3. Hierarchical dynamics
(Boolean / Neuronal networks example)
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1. Discrete organization
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[Kreyssig et al., Bioinformatics, 2014]
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1. Discrete Organizations
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[Kreyssig et al., Bioinformatics, 2014]
2 C
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1. Discrete Organizations
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[Kreyssig et al., Bioinformatics, 2014]
{A, B, C} is a purely discrete organization
2 C
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2. Measuring Organizations
So far, a reaction network was necessary.
Now, measuring organizations and the hierarchical organizational
structure directly, without the need to identify individual species
or reactions.
“natural” coarse-graining, since it is derived from (physical)
measurements
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2. Measuring Organizations - Recipe
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2. Measuring Organizations - Status
- Basic theory ready- Prototypic software ready- 16 species
artificial chemistry with 50
organizations ready for testing.
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3. Hierarchical dynamics Boolean and neural networks
Is there a hierarchy of attractors?
How is the hierarchy of attractors related to the hierarchy of
organizations?
Attractors and organizations for coarse-graining
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[SORN Network by Triesch et al. ]
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3. Hierarchy of attractors
[Lukas Klimmasch] - Example
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Subset of active neurons
Set of active neurons within one attractor =“brain region”
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3. Another Hierarchy of Attractors
[Lukas Klimmasch] - Example
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Part III Application Scenario
WP 7Richard Henze, Bashar Ibrahim
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16.11.06, Asselsheim Peter Dittrich (FSU Jena) 33
Wait until all kinetochores are correctly attached
http://library.thinkquest.org/C004535/mitosis .html
WAIT!
http://library.thinkquest.org/C004535/mitosis%20.html
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16.11.06, Asselsheim Peter Dittrich (FSU Jena) 34
Wait until all kinetochores are correctly attached
http://library.thinkquest.org/C004535/mitosis .html
GO!
http://library.thinkquest.org/C004535/mitosis%20.html
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16.11.06, Asselsheim Peter Dittrich (FSU Jena) 35
Wait until all kinetochores are correctly attached
http://library.thinkquest.org/C004535/mitosis .html
GO!
http://library.thinkquest.org/C004535/mitosis%20.html
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Application Scenario Results
1. Preliminary studies: a) Active transport of Mad2
(Ibrahim&Henze, Int. J. Mol. Sci., 2014)b) Rule-based
modeling of kinetochore mutants.
(Henze et al, Biosystems, 2014)2. Checkpoint Scenario3. PML
nuclear bodies (potentially another
application scenario)
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1. Preliminary Work and Results
Various models at different scales of coarse-graining now
available.
From ODE to detailed rule-based spatial particle simulation.
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1. Example: 3-D Rule-Based Model of Full Kinetochore
38Henze / Dittrich et al. - FSU Jena11.12.2014 Brussels,
HIERATICby R. Henze, B. Ibrahim, et al., FSU Jena, 2014
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2. Mitotic Checkpoint Scenario
Microlevel: Simulate all kinetochores (92), in a realistic 3D
space, and realistic particle numbers (1 Mio) of inhibitors and
activators.
Why: To have a trustworthy model that is- Understandable by
domain experts (biologists)- Takes directly the rules from domain
expertsDrawback: Computation time Coarse graining need for
efficient computation,
e.g., if predictions. Also getting additional understanding, by
extracting
more general laws.
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2. Mitotic Checkpoint Scenario
Unatched-Kinetochor activates Inhibitor
No inhibitor around a kinetochore GO signal
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Start
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End
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Preliminary simulation of mitotic checkpoint
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SummaryI. Memodyn (WP4)
Report in D4Software / source code in D4.2
II. Artificial chemistries and organizational coarse-graining
(WP4, WP7)
Paper in D4.2: Keyssig et al., Bioinformatics, 2014
III. Application scenario – Mitotic checkpoint (WP7)
Paper in D7.1: Ibrahim&Henze, Int. J. Mol. Sci., 2014 Paper
in D7.1: Henze et al., Biosystems, 2014
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Progress WP4, WP7�Memodyn – Application Scenario –
Organizational Coarse-GrainingOverviewPart I �MEMODYNMemodynMemodyn
„Learning Cycle“Continuous sample generationUnbiased random
samplingConstraint propagation �(using GECODE)Force-based
approachForce-based approachForce-based approachForce-based
approachContinuous simulationMicro-simulation
borderMicro-simulation ersatz fieldMicro-simulation border for
three particlesSoftwarePart II �Organizational Coarse-Graining 1.
Basic Idea1. Basic Idea1. Basic IdeaOrganisational Coarse-graining
Results1. Discrete organization1. Discrete Organizations1. Discrete
Organizations2. Measuring Organizations2. Measuring Organizations -
Recipe2. Measuring Organizations - Status3. Hierarchical dynamics
Boolean and neural networks 3. Hierarchy of attractors 3. Another
Hierarchy of AttractorsPart III �Application ScenarioWait until all
kinetochores are correctly attachedWait until all kinetochores are
correctly attachedWait until all kinetochores are correctly
attachedApplication Scenario Results1. Preliminary Work and
Results1. Example: 3-D Rule-Based Model of Full Kinetochore 2.
Mitotic Checkpoint Scenario2. Mitotic Checkpoint
ScenarioStartEndPreliminary simulation of mitotic
checkpointSummary