Progress WP4, WP7 Memodyn – 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 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 1
Overview I. Memodyn (WP4) Report in D4.2 Software / 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 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 2
Part I MEMODYN WP 4 Jan Huwald Henze / Dittrich et al. - FSU Jena 11.12.2014 Brussels, HIERATIC 3
Memodyn Henze / Dittrich et al. - FSU Jena 11.12.2014 Brussels, HIERATIC 4
Memodyn „Learning Cycle“ Henze / Dittrich et al. - FSU Jena 11.12.2014 Brussels, HIERATIC 5
Continuous sample generation 1. Random unbiased sampling 2. Constraint propagation 3. Force-based search 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 6
Unbiased random sampling Henze / Dittrich et al. - FSU Jena 11.12.2014 Brussels, HIERATIC 7
Constraint propagation (using GECODE) Henze / Dittrich et al. - FSU Jena 11.12.2014 Brussels, HIERATIC 8
Force-based approach 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 9
Force-based approach 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 10
Force-based approach 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 11
Force-based approach For all combination all solutions are found! 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 12
Continuous simulation 1. Micro-simulation border 2. Energy guided distance quantization 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 13
Micro-simulation border 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 14
Micro-simulation ersatz field 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 15
Micro-simulation border for three particles 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 16
Software Source code implementing the methods mentioned above attached to D4.2. 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 17
Part II Organizational Coarse-Graining WP 4 / WP 7 Henze / Dittrich et al. - FSU Jena 11.12.2014 Brussels, HIERATIC 18
1. Basic Idea Organization 4 4 Chemical Organization 1 1 Theory 2 3 2 3 Organizations Reaction network [P. Dittrich, P. Speroni di Fenizi, Chemical Organization Theory, Bull. Math. Biol ., 2007] 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 19
1. Basic Idea Hasse diagram of organizations {1,2,3,4} 4 Chemical {2, 3} Organization 1 Theory {1} 2 3 { } Organizations Reaction network [P. Dittrich, P. Speroni di Fenizi, Chemical Organization Theory, Bull. Math. Biol ., 2007] 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 20
1. Basic Idea Hasse diagram of organizations {1,2,3,4} 4 Chemical Thoerie chemischer {2, 3} Organization Organization 1 Theory {1} 2 3 { } [2] Organizations Reaction [3] network [4] [1] Dynamics [P. Dittrich, P. Speroni di Fenizi, Chemical Organization Theory, Bull. Math. Biol ., 2007] 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 21
Organisational Coarse-graining Results 1. Discrete organizations (Kreyssig et al. 2014) 2. Measuring organizations 3. Hierarchical dynamics (Boolean / Neuronal networks example)
1. Discrete organization [Kreyssig et al., Bioinformatics, 2014] 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 23
1. Discrete Organizations 2 C [Kreyssig et al., Bioinformatics, 2014] 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 24
1. Discrete Organizations 2 C {A, B, C} is a purely discrete organization [Kreyssig et al., Bioinformatics, 2014] 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 25
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 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 26
2. Measuring Organizations - Recipe 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 27
2. Measuring Organizations - Status - Basic theory ready - Prototypic software ready - 16 species artificial chemistry with 50 organizations ready for testing. 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 28
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 [SORN Network by Triesch et al. ] for coarse-graining 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 29
3. Hierarchy of attractors [Lukas Klimmasch] - Example Set of active neurons within one attractor = “brain region” Subset of active neurons 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 30
3. Another Hierarchy of Attractors [Lukas Klimmasch] - Example 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 31
Part III Application Scenario WP 7 Richard Henze, Bashar Ibrahim Henze / Dittrich et al. - FSU Jena 11.12.2014 Brussels, HIERATIC 32
Wait until all kinetochores are correctly attached WAIT! http://library.thinkquest.org/C004535/mitosis .html 16.11.06, Asselsheim Peter Dittrich (FSU Jena) 33
Wait until all kinetochores are correctly attached GO! http://library.thinkquest.org/C004535/mitosis .html 16.11.06, Asselsheim Peter Dittrich (FSU Jena) 34
Wait until all kinetochores are correctly attached GO! http://library.thinkquest.org/C004535/mitosis .html 16.11.06, Asselsheim Peter Dittrich (FSU Jena) 35
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 Scenario 3. PML nuclear bodies (potentially another application scenario) 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 36
1. Preliminary Work and Results Various models at different scales of coarse- graining now available. From ODE to detailed rule-based spatial particle simulation. 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 37
1. Example: 3-D Rule-Based Model of Full Kinetochore by R. Henze, B. Ibrahim, et al., FSU Jena, 2014 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 38
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 experts Drawback: Computation time Coarse graining need for efficient computation, e.g., if predictions. Also getting additional understanding, by extracting more general laws. 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 39
2. Mitotic Checkpoint Scenario Unatched-Kinetochor activates Inhibitor No inhibitor around a kinetochore GO signal 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 40
Start 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 41
End 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 42
Preliminary simulation of mitotic checkpoint 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 43
Summary I. Memodyn (WP4) Report in D4 Software / 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 11.12.2014 Brussels, HIERATIC Henze / Dittrich et al. - FSU Jena 44
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