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Scalable agent-based simulations: a blood clotting demonstrator Results of the 8 week Nuffield project Gregory Goltsov

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What is blood clotting

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What is hemostasis

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Physical modelling of clot formation Xu Z, Lioi J, Mu J, Kamocka MM, Liu X, Chen DZ, Rosen ED, & Alber M (2010). A multiscale model of venous thrombus formation with surface-mediated control of blood coagulation cascade. Biophysical journal, 98 (9), 1723-32 PMID: 20441735

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Physical modelling of clot formation Xu Z, Lioi J, Mu J, Kamocka MM, Liu X, Chen DZ, Rosen ED, & Alber M (2010). A multiscale model of venous thrombus formation with surface-mediated control of blood coagulation cascade. Biophysical journal, 98 (9), 1723-32 PMID: 20441735

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Pathology Thromboembolism Formation in a blood vessel of a clot (thrombus) that breaks loose and is carried by the blood stream to plug another vessel. Pulmonary embolism Blockage of the main artery of the lung.

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Pathology Thromboembolism Formation in a blood vessel of a clot (thrombus) that breaks loose and is carried by the blood stream to plug another vessel. Pulmonary embolism Blockage of the main artery of the lung. Aspirin

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Aspirin Everyone aged over 45 should consider a small daily dose of aspirin to help protect themselves against heart disease and cancer “

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Clotting modelling: ODEs

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Clotting modelling: ODEs Great attention to uid dynamics

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Clotting modelling: ODEs Great attention to uid dynamics Not so much to internal representation of platelet

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Clotting modelling: ODEs Great attention to uid dynamics Not so much to internal representation of platelet Probabilistic representation of space

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Platelet

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Vs

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Clotting modelling: agents

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Clotting modelling: agents Agent-based simulation — platelets are agents.

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Clotting modelling: agents Agent-based simulation — platelets are agents. Each individual platelet has its own behaviour.

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Clotting modelling: agents Agent-based simulation — platelets are agents. Each individual platelet has its own behaviour. Explicit account of space — allows for near-neighbour interactions.

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What’s been done

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TUNA TECHNOLOGY UNDERPINNING N A N O T E C H ASSEMBLERS

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TUNA TECHNOLOGY UNDERPINNING N A N O T E C H ASSEMBLERS

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TUNA TECHNOLOGY UNDERPINNING N A N O T E C H ASSEMBLERS CoSMoS C O M P L E X S Y S T E M S MODELLING & SIMULATION

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TUNA TECHNOLOGY UNDERPINNING N A N O T E C H ASSEMBLERS CoSMoS C O M P L E X S Y S T E M S MODELLING & SIMULATION +

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TUNA TECHNOLOGY UNDERPINNING N A N O T E C H ASSEMBLERS CoSMoS C O M P L E X S Y S T E M S MODELLING & SIMULATION + CrISp CENTRE FOR RESEARCH IN SYSTEMS PATHOLOGY

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What is inside of each platelet?

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Hybrid functional Petri net of platelet activation TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc Hybrid functional Petri net of platelet activation

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc AA

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc AA

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc AA COX1

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc AA COX1

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc AA TXA2int COX1

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc AA TXA2int COX1

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc AA TXA2ext TXA2int COX1

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc AA TXA2ext TXA2int COX1

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TXA2ext TP receptors PLC PIP2 PIP3 IP3R calcium receptor Ca2+ in cytozole PLA2 PL AA COX-1 PGH2 TXA2int TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8 TR9 TR10 Aspirin PGTF continuous place continuous transition normal arc test arc inhibitory arc AA TXA2ext TXA2int ASA COX1

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COX1 AA TXA2int TR1 TR2 TXA2ext TR4 COX1inact TR3 ASA acytCOX1 TR5

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COX1 AA TXA2int TR1 TR2 TXA2ext TR4 COX1inact TR3 ASA acytCOX1 TR5 Model

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COX1 AA TXA2int TR1 TR2 TXA2ext TR4 COX1inact TR3 ASA acytCOX1 TR5 Model

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COX1 AA TXA2int TR1 TR2 TXA2ext TR4 COX1inact TR3 ASA acytCOX1 TR5 Model // Place(name, initial_concentration) NodePtr txa2_ext (new Place("TXA2_ext" NodePtr aa (new Place("AA" NodePtr cox1 (new Place("COX1" NodePtr txa2_int (new Place("TXA2_int" // Transition(name, substrate, product, NodePtr tr1 (new Transition("TR1", tr1_e NodePtr tr2 (new Transition("TR2", tr2_e NodePtr tr3 (new Transition("TR3", tr3_e DSL D O M A I N - S P E C I F I C LANGUAGE

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Visualisation

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Visualisation +

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Visualisation interactive +

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Visualisation interactive +tweakable

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Visualisation interactive +tweakable

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Demo

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EMITTED TXA2 ~20 cells WOUND VESSEL WALL TUNA model

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WOUND VESSEL WALL New model EMITTED TXA2

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WOUND VESSEL WALL New model EMITTED TXA2

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WOUND VESSEL WALL New model EMITTED TXA2

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WOUND VESSEL WALL New model AMPLIFIED ACTIVATION EMITTED TXA2

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~5 cells WOUND VESSEL WALL New model AMPLIFIED ACTIVATION EMITTED TXA2

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Future work

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Future work Applications

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Improvements

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Improvements: Physics Realistic uid dynamics model for the blood ow.

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Improvements: DSL Editor Epsilon editor for easy pathway creation and integration.

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{ } MODELLING SIMULATION VISUALISATION

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CrISp CENTRE FOR RESEARCH IN SYSTEMS PATHOLOGY { } MODELLING SIMULATION VISUALISATION

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CrISp CENTRE FOR RESEARCH IN SYSTEMS PATHOLOGY { } MODELLING SIMULATION VISUALISATION DR UG T EST ING, PHARMACOKINE TICS, PHARMACODYNAMI CS, DRUG D IS TRI BUT ION, DRUG INTER AC TION

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Thank you! Special thanks to Supervisor Dr Adam Sampson Prof James Bown GREGORY@GOLTSOV.INFO WWW.GREGORY.GOLTSOV.INFO