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BIOMD0000000334 - Bungay2003_Thrombin_Generation

 

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Reference Publication
Publication ID: 12974500
Bungay SD, Gentry PA, Gentry RD.
A mathematical model of lipid-mediated thrombin generation.
Math Med Biol 2003 Mar; 20(1): 105-129
Department of Mathematics and Statistics, University of Guelph, Guelph, Ontario, Canada N1G 2W1.  [more]
Model
Original Model: BIOMD0000000334.origin
Submitter: Harish Dharuri
Submission ID: MODEL9852292468
Submission Date: 20 Mar 2008 00:03:15 UTC
Last Modification Date: 28 May 2014 13:24:41 UTC
Creation Date: 08 Jan 2008 18:06:42 UTC
Encoders:  Harish Dharuri
   Nick Juty
   Michael Schubert
set #1
bqbiol:hasTaxon Taxonomy Homo sapiens
set #2
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
set #3
bqbiol:isVersionOf Gene Ontology blood coagulation
Notes

This model is from the article:
A mathematical model of lipid-mediated thrombin generation
Bungay Sharene D., Gentry Patricia A., Gentry Rodney D. Mathematical Medicine and BiologyVolume 20, Issue 1, 1 March 2003, Pages 105-29 12974500,
Abstract:
Thrombin is an enzyme that is generated in both vascular and non-vascular systems. In blood coagulation, a fundamental process in all species, thrombin induces the formation of a fibrin clot. A dynamical model of thrombin generation in the presence of lipid surfaces is presented. This model also includes the self-regulating thrombin feedback reactions, the thrombomodulin-protein C-protein S inhibitory system, tissue factor pathway inhibitor (TFPI), and the inhibitor, antithrombin (AT). The dynamics of this complex system were found to be highly lipid dependent, as would be expected from experimental studies. Simulations of this model indicate that a threshold lipid level is required to generate physiologically relevant amounts of thrombin. The dependence of the onset, the peak levels, and the duration of thrombin generation on lipid was saturable. The lipid concentration affects the way in which the inhibitors modulate thrombin production. A novel feature of this model is the inclusion of the dynamical protein C pathway, initiated by thrombin feedback. This inhibitory system exerts its effects on the lipid surface, where its substrates are formed. The maximum impact of TFPI occurs at intermediate vesicle concentrations. Inhibition by AT is only indirectly affected by the lipid since AT irreversibly binds only to solution phase proteins. In a system with normal plasma concentrations of the proteins involved in thrombin formation, the combination of these three inhibitors is sufficient both to effectively stop thrombin generation prior to the exhaustion of its precursor, prothrombin, and to inhibit all thrombin formed. This model can be used to predict thrombin generation under extreme lipid conditions that are difficult to implement experimentally and to examine thrombin generation in non-vascular systems.

This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
For more information see the terms of use.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Model
Publication ID: 12974500 Submission Date: 20 Mar 2008 00:03:15 UTC Last Modification Date: 28 May 2014 13:24:41 UTC Creation Date: 08 Jan 2008 18:06:42 UTC
Mathematical expressions
Reactions
Factor II lipid binding Factor mIIa lipid binding Factor V lipid binding Factor Va lipid binding
Factor VII lipid binding Factor VIIa lipid binding Factor VIII lipid binding Factor VIIIa lipid binding
Factor IX lipid binding Factor IXa lipid binding Factor X lipid binding Factor Xa lipid binding
APC lipid binding PS lipid binding Factor VIIIai lipid binding Factor Vai lipid binding
PC lipid binding TF_VIIa binding TF_VII binding IX_TF_VIIa binding
Factor IX activation X_TF_VIIa complex formation Factor X activation Factor Xa release
Xa_TF_VII binding TF_VII activation VIIIa_IXa binding Va_Xa binding
X_IXa_VIIIa complex formation Factor X activation V_Xa binding Factor V activation
Xa_VIII binding Factor VIII activation R11 R11b
R12 R12b R13 R14
R15 R15b R16 R16b
R17 R17b R18 R18b
R19 R19b R20 R21
R22 R23 R24 R25
R25b R26 R26b R27
R28 R28b R29 R30
R31 R31b    
Physical entities
Compartments Species
Cell II_f II_l mIIa_f
mIIa_l V_f V_l
Va_f Va_l VII_f
VII_l VIIa_f VIIa_l
VIII_f VIII_l VIIIa_f
VIIIa_l IX_f IX_l
IXa_f IXa_l X_f
X_l Xa_f Xa_l
APC_f APC_l PS_f
PS_l VIIIai_f VIIIai_l
Vai_f Vai_l PC_f
PC_l TF_l TF_VIIa_l
TF_VII_l TF_VIIa_IX_l TF_VIIa_IXa_l
TF_VIIa_X_l TF_VIIa_Xa_l TF_VII_Xa_l
IXa_VIIIa_l Xa_Va_l IXa_VIIIa_X_l
V_Xa_l VIII_Xa_l IIa_f
V_IIa_l VIII_IIa_l Xa_Va_II_l
Xa_Va_mIIa_l XI_f XI_IIa_l
XIa_l APC_PS_l APC_PS_VIIIa_l
TFPI_f AT_f IIa_AT_f
TFPI_Xa_l TFPI_Xa_TF_VIIa_l APC_PS_Va_l
IXa_AT_f Xa_AT_f VII_Xa_l
V_mIIa_l VIII_mIIa_l TM_l
IIa_TM_l IIa_TM_PC_l mIIa_AT_l
XIa_IX_l LIPID  
Global parameters
konII nva koffII konmIIa
koffmIIa konV koffV konVa
koffVa konVII koffVII konVIIa
koffVIIa konVIII koffVIII konVIIIa
koffVIIIa konIX koffIX konIXa
koffIXa konX koffX konXa
koffXa konAPC koffAPC konPS
koffPS konVIIIai koffVIIIai konVai
koffVai konPC koffPC k1
k2 k3 k4 k5
k6 k7 k8 k9
k10 k75 k11 k12
k13 k14 k15 k16
k17 k18 k19 k20
k21 k22 k23 k24
k25 k26 k27 k28
k29 k30 k31 k32
k33 k34 k35 k36
k37 k38 k39 k40
k41 k42 k43 k44
k45 k46 k47 k48
k49 k50 k51 k52
k53 k54 k55 k56
k57 k58 k59 k60
k61 k62 k63 k64
k65 k66 k67 k68
k69 k70 k71 k72
k73 k74    
Reactions (66)
 
 Factor II lipid binding [II_f] + 100.0 × [LIPID] → [II_l];  
 
 Factor mIIa lipid binding [mIIa_f] + 100.0 × [LIPID] → [mIIa_l];  
 
 Factor V lipid binding [V_f] + 100.0 × [LIPID] → [V_l];  
 
 Factor Va lipid binding [Va_f] + 100.0 × [LIPID] → [Va_l];  
 
 Factor VII lipid binding [VII_f] + 100.0 × [LIPID] → [VII_l];  
 
 Factor VIIa lipid binding [VIIa_f] + 100.0 × [LIPID] → [VIIa_l];  
 
 Factor VIII lipid binding [VIII_f] + 100.0 × [LIPID] → [VIII_l];  
 
 Factor VIIIa lipid binding [VIIIa_f] + 100.0 × [LIPID] → [VIIIa_l];  
 
 Factor IX lipid binding [IX_f] + 100.0 × [LIPID] → [IX_l];  
 
 Factor IXa lipid binding [IXa_f] + 100.0 × [LIPID] → [IXa_l];  
 
 Factor X lipid binding [X_f] + 100.0 × [LIPID] → [X_l];  
 
 Factor Xa lipid binding [Xa_f] + 100.0 × [LIPID] → [Xa_l];  
 
 APC lipid binding [APC_f] + 100.0 × [LIPID] → [APC_l];  
 
 PS lipid binding [PS_f] + 100.0 × [LIPID] → [PS_l];  
 
 Factor VIIIai lipid binding [VIIIai_f] + 100.0 × [LIPID] → [VIIIai_l];  
 
 Factor Vai lipid binding [Vai_f] + 100.0 × [LIPID] → [Vai_l];  
 
 PC lipid binding [PC_f] + 100.0 × [LIPID] → [PC_l];  
 
 TF_VIIa binding [VIIa_l] + [TF_l] → [TF_VIIa_l];  
 
 TF_VII binding [VII_l] + [TF_l] → [TF_VII_l];  
 
 IX_TF_VIIa binding [IX_l] + [TF_VIIa_l] → [TF_VIIa_IX_l];  
 
 Factor IX activation [TF_VIIa_IX_l] → [TF_VIIa_l] + [IXa_l];  
 
 X_TF_VIIa complex formation [X_l] + [TF_VIIa_l] → [TF_VIIa_X_l];  
 
 Factor X activation [TF_VIIa_X_l] → [TF_VIIa_Xa_l];  
 
 Factor Xa release [TF_VIIa_Xa_l] → [Xa_l] + [TF_VIIa_l];  
 
 Xa_TF_VII binding [Xa_l] + [TF_VII_l] → [TF_VII_Xa_l];  
 
 TF_VII activation [TF_VII_Xa_l] → [Xa_l] + [TF_VIIa_l];  
 
 VIIIa_IXa binding [VIIIa_l] + [IXa_l] → [IXa_VIIIa_l];  
 
 Va_Xa binding [Va_l] + [Xa_l] → [Xa_Va_l];  
 
 X_IXa_VIIIa complex formation [X_l] + [IXa_VIIIa_l] → [IXa_VIIIa_X_l];  
 
 Factor X activation [IXa_VIIIa_X_l] → [Xa_l] + [IXa_VIIIa_l];  
 
 V_Xa binding [Xa_l] + [V_l] → [V_Xa_l];  
 
 Factor V activation [V_Xa_l] → [Xa_l] + [Va_l];  
 
 Xa_VIII binding [Xa_l] + [VIII_l] → [VIII_Xa_l];  
 
 Factor VIII activation [VIII_Xa_l] → [Xa_l] + [VIIIa_l];  
 
 R11 [IIa_f] + [V_l] → [V_IIa_l];  
 
 R11b [V_IIa_l] → [IIa_f] + [Va_l];  
 
 R12 [IIa_f] + [VIII_l] → [VIII_IIa_l];  
 
 R12b [VIII_IIa_l] → [IIa_f] + [VIIIa_l];  
 
 R13 [II_l] + [Xa_Va_l] → [Xa_Va_II_l];  
 
 R14 [mIIa_l] + [Xa_Va_l] → [Xa_Va_mIIa_l];  
 
 R15 [Xa_Va_II_l] → [Xa_Va_mIIa_l];  
 
 R15b [Xa_Va_mIIa_l] → [IIa_f] + [Xa_Va_l];  
 
 R16 [Xa_l] + [VII_l] → [VII_Xa_l];  
 
 R16b [VII_Xa_l] → [Xa_l] + [VIIa_l];  
 
 R17 [IIa_f] + [XI_f] → [XI_IIa_l];  
 
 R17b [XI_IIa_l] → [IIa_f] + [XIa_l];  
 
 R18 [VIIIa_l] + [APC_PS_l] → [APC_PS_VIIIa_l];  
 
 R18b [APC_PS_VIIIa_l] → [VIIIai_l] + [APC_PS_l];  
 
 R19 [Va_l] + [APC_PS_l] → [APC_PS_Va_l];  
 
 R19b [APC_PS_Va_l] → [Vai_l] + [APC_PS_l];  
 
 R20 [Xa_f] + [TFPI_f] → [TFPI_Xa_l];  
 
 R21 [TF_VIIa_l] + [TFPI_Xa_l] → [TFPI_Xa_TF_VIIa_l];  
 
 R22 [AT_f] + [IXa_f] → [IXa_AT_f];  
 
 R23 [AT_f] + [Xa_f] → [Xa_AT_f];  
 
 R24 [AT_f] + [IIa_f] → [IIa_AT_f];  
 
 R25 [mIIa_l] + [V_l] → [V_mIIa_l];  
 
 R25b [V_mIIa_l] → [mIIa_l] + [Va_l];  
 
 R26 [mIIa_l] + [VIII_l] → [VIII_mIIa_l];  
 
 R26b [VIII_mIIa_l] → [mIIa_l] + [VIIIa_l];  
 
 R27 [TM_l] + [IIa_f] → [IIa_TM_l];  
 
 R28 [PC_l] + [IIa_TM_l] → [IIa_TM_PC_l];  
 
 R28b [IIa_TM_PC_l] → [APC_l] + [IIa_TM_l];  
 
 R29 [AT_f] + [mIIa_f] → [mIIa_AT_l];  
 
 R30 [PS_l] + [APC_l] → [APC_PS_l];  
 
 R31 [IX_l] + [XIa_l] → [XIa_IX_l];  
 
 R31b [XIa_IX_l] → [IXa_l] + [XIa_l];  
 
   Cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 II_f
Compartment: Cell
Initial concentration: 1400.0
 
 II_l
Compartment: Cell
Initial concentration: 0.0
 
 mIIa_f
Compartment: Cell
Initial concentration: 0.0
 
 mIIa_l
Compartment: Cell
Initial concentration: 0.0
 
 V_f
Compartment: Cell
Initial concentration: 20.0
 
 V_l
Compartment: Cell
Initial concentration: 0.0
 
 Va_f
Compartment: Cell
Initial concentration: 0.0
 
 Va_l
Compartment: Cell
Initial concentration: 0.0
 
 VII_f
Compartment: Cell
Initial concentration: 10.0
 
 VII_l
Compartment: Cell
Initial concentration: 0.0
 
 VIIa_f
Compartment: Cell
Initial concentration: 0.1
 
 VIIa_l
Compartment: Cell
Initial concentration: 0.0
 
 VIII_f
Compartment: Cell
Initial concentration: 0.7
 
 VIII_l
Compartment: Cell
Initial concentration: 0.0
 
 VIIIa_f
Compartment: Cell
Initial concentration: 0.0
 
 VIIIa_l
Compartment: Cell
Initial concentration: 0.0
 
 IX_f
Compartment: Cell
Initial concentration: 90.0
 
 IX_l
Compartment: Cell
Initial concentration: 0.0
 
 IXa_f
Compartment: Cell
Initial concentration: 0.0
 
 IXa_l
Compartment: Cell
Initial concentration: 0.0
 
 X_f
Compartment: Cell
Initial concentration: 170.0
 
 X_l
Compartment: Cell
Initial concentration: 0.0
 
 Xa_f
Compartment: Cell
Initial concentration: 0.0
 
 Xa_l
Compartment: Cell
Initial concentration: 0.0
 
 APC_f
Compartment: Cell
Initial concentration: 0.0
 
 APC_l
Compartment: Cell
Initial concentration: 0.0
 
 PS_f
Compartment: Cell
Initial concentration: 300.0
 
 PS_l
Compartment: Cell
Initial concentration: 0.0
 
 VIIIai_f
Compartment: Cell
Initial concentration: 0.0
 
 VIIIai_l
Compartment: Cell
Initial concentration: 0.0
 
 Vai_f
Compartment: Cell
Initial concentration: 0.0
 
 Vai_l
Compartment: Cell
Initial concentration: 0.0
 
 PC_f
Compartment: Cell
Initial concentration: 60.0
 
 PC_l
Compartment: Cell
Initial concentration: 0.0
 
 TF_l
Compartment: Cell
Initial concentration: 0.0050
 
 TF_VIIa_l
Compartment: Cell
Initial concentration: 0.0
 
 TF_VII_l
Compartment: Cell
Initial concentration: 0.0
 
 TF_VIIa_IX_l
Compartment: Cell
Initial concentration: 0.0
 
 TF_VIIa_IXa_l
Compartment: Cell
Initial concentration: 0.0
 
 TF_VIIa_X_l
Compartment: Cell
Initial concentration: 0.0
 
 TF_VIIa_Xa_l
Compartment: Cell
Initial concentration: 0.0
 
 TF_VII_Xa_l
Compartment: Cell
Initial concentration: 0.0
 
 IXa_VIIIa_l
Compartment: Cell
Initial concentration: 0.0
 
 Xa_Va_l
Compartment: Cell
Initial concentration: 0.0
 
 IXa_VIIIa_X_l
Compartment: Cell
Initial concentration: 0.0
 
 V_Xa_l
Compartment: Cell
Initial concentration: 0.0
 
 VIII_Xa_l
Compartment: Cell
Initial concentration: 0.0
 
 IIa_f
Compartment: Cell
Initial concentration: 0.0
 
 V_IIa_l
Compartment: Cell
Initial concentration: 0.0
 
 VIII_IIa_l
Compartment: Cell
Initial concentration: 0.0
 
 Xa_Va_II_l
Compartment: Cell
Initial concentration: 0.0
 
 Xa_Va_mIIa_l
Compartment: Cell
Initial concentration: 0.0
 
 XI_f
Compartment: Cell
Initial concentration: 30.0
 
 XI_IIa_l
Compartment: Cell
Initial concentration: 0.0
 
 XIa_l
Compartment: Cell
Initial concentration: 0.0
 
 APC_PS_l
Compartment: Cell
Initial concentration: 0.0
 
 APC_PS_VIIIa_l
Compartment: Cell
Initial concentration: 0.0
 
 TFPI_f
Compartment: Cell
Initial concentration: 2.5
 
 AT_f
Compartment: Cell
Initial concentration: 3400.0
 
 IIa_AT_f
Compartment: Cell
Initial concentration: 0.0
 
 TFPI_Xa_l
Compartment: Cell
Initial concentration: 0.0
 
 TFPI_Xa_TF_VIIa_l
Compartment: Cell
Initial concentration: 0.0
 
 APC_PS_Va_l
Compartment: Cell
Initial concentration: 0.0
 
 IXa_AT_f
Compartment: Cell
Initial concentration: 0.0
 
 Xa_AT_f
Compartment: Cell
Initial concentration: 0.0
 
 VII_Xa_l
Compartment: Cell
Initial concentration: 0.0
 
 V_mIIa_l
Compartment: Cell
Initial concentration: 0.0
 
 VIII_mIIa_l
Compartment: Cell
Initial concentration: 0.0
 
 TM_l
Compartment: Cell
Initial concentration: 1.0
 
 IIa_TM_l
Compartment: Cell
Initial concentration: 0.0
 
 IIa_TM_PC_l
Compartment: Cell
Initial concentration: 0.0
 
 mIIa_AT_l
Compartment: Cell
Initial concentration: 0.0
 
 XIa_IX_l
Compartment: Cell
Initial concentration: 0.0
 
 LIPID
Compartment: Cell
Initial concentration: 849079.0
 
Global Parameters (110)
 
   konII
Value: 0.0043
Constant
 
   nva
Value: 100.0
Constant
 
   koffII
Value: 1.0
Constant
 
   konmIIa
Value: 0.05
Constant
 
   koffmIIa
Value: 0.475
Constant
 
   konV
Value: 0.05
Constant
 
   koffV
Value: 0.145
Constant
 
   konVa
Value: 0.057
Constant
 
   koffVa
Value: 0.17
Constant
 
   konVII
Value: 0.05
Constant
 
   koffVII
Value: 0.66
Constant
 
   konVIIa
Value: 0.05
Constant
 
   koffVIIa
Value: 0.227
Constant
 
   konVIII
Value: 0.05
Constant
 
   koffVIII
Value: 0.1
Constant
 
   konVIIIa
Value: 0.05
Constant
 
   koffVIIIa
Value: 0.335
Constant
 
   konIX
Value: 0.05
Constant
 
   koffIX
Value: 0.115
Constant
 
   konIXa
Value: 0.05
Constant
 
   koffIXa
Value: 0.115
Constant
 
   konX
Value: 0.01
Constant
 
   koffX
Value: 1.9
Constant
 
   konXa
Value: 0.029
Constant
 
   koffXa
Value: 3.3
Constant
 
   konAPC
Value: 0.05
Constant
 
   koffAPC
Value: 3.5
Constant
 
   konPS
Value: 0.05
Constant
 
   koffPS
Value: 0.2
Constant
 
   konVIIIai
Value: 0.05
Constant
 
   koffVIIIai
Value: 0.335
Constant
 
   konVai
Value: 0.057
Constant
 
   koffVai
Value: 0.17
Constant
 
   konPC
Value: 0.05
Constant
 
   koffPC
Value: 11.5
Constant
 
   k1
Value: 0.5
Constant
 
   k2
Value: 0.0050
Constant
 
   k3
Value: 0.0050
Constant
 
   k4
Value: 0.0050
Constant
 
   k5
Value: 0.01
Constant
 
   k6
Value: 2.09
Constant
 
   k7
Value: 0.34
Constant
 
   k8
Value: 0.1
Constant
 
   k9
Value: 32.5
Constant
 
   k10
Value: 1.5
Constant
 
   k75
Value: 1.0
Constant
 
   k11
Value: 0.05
Constant
 
   k12
Value: 44.8
Constant
 
   k13
Value: 15.2
Constant
 
   k14
Value: 0.1
Constant
 
   k15
Value: 0.2
Constant
 
   k16
Value: 1.0
Constant
 
   k17
Value: 1.0
Constant
 
   k18
Value: 0.1
Constant
 
   k19
Value: 10.7
Constant
 
   k20
Value: 8.3
Constant
 
   k21
Value: 0.1
Constant
 
   k22
Value: 1.0
Constant
 
   k23
Value: 0.043
Constant
 
   k24
Value: 0.1
Constant
 
   k25
Value: 2.1
Constant
 
   k26
Value: 0.023
Constant
 
   k27
Value: 0.1
Constant
 
   k28
Value: 6.94
Constant
 
   k29
Value: 0.23
Constant
 
   k30
Value: 0.1
Constant
 
   k31
Value: 13.8
Constant
 
   k32
Value: 0.9
Constant
 
   k33
Value: 0.1
Constant
 
   k34
Value: 100.0
Constant
 
   k35
Value: 0.1
Constant
 
   k36
Value: 66.0
Constant
 
   k37
Value: 13.0
Constant
 
   k38
Value: 15.0
Constant
 
   k39
Value: 0.05
Constant
 
   k40
Value: 44.8
Constant
 
   k41
Value: 15.2
Constant
 
   k42
Value: 0.1
Constant
 
   k43
Value: 10.0
Constant
 
   k44
Value: 1.43
Constant
 
   k45
Value: 0.1
Constant
 
   k46
Value: 1.6
Constant
 
   k47
Value: 0.4
Constant
 
   k48
Value: 0.1
Constant
 
   k49
Value: 1.6
Constant
 
   k50
Value: 0.4
Constant
 
   k51
Value: 0.016
Constant
 
   k52
Value: 3.3E-4
Constant
 
   k53
Value: 0.01
Constant
 
   k54
Value: 0.0011
Constant
 
   k55
Value: 4.9E-7
Constant
 
   k56
Value: 2.3E-6
Constant
 
   k57
Value: 6.83E-5
Constant
 
   k58
Value: 0.1
Constant
 
   k59
Value: 6.94
Constant
 
   k60
Value: 1.035
Constant
 
   k61
Value: 0.1
Constant
 
   k62
Value: 13.8
Constant
 
   k63
Value: 0.9
Constant
 
   k64
Value: 1.0
Constant
 
   k65
Value: 0.5
Constant
 
   k66
Value: 0.1
Constant
 
   k67
Value: 6.4
Constant
 
   k68
Value: 3.6
Constant
 
   k69
Value: 6.83E-6
Constant
 
   k70
Value: 0.1
Constant
 
   k71
Value: 0.5
Constant
 
   k72
Value: 0.01
Constant
 
   k73
Value: 1.417
Constant
 
   k74
Value: 0.183
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000334

Curator's comment: (updated: 12 May 2011 14:06:57 BST)

Thrombin generation model. Factors are denoted by their numbers, with _l and _f suffixes depending on whether they are lipid-bound or fluid phase. Vesicle concentration is derived from LIPID (concentration of head groups) using the formula [vesicle] * 4*10nm^2*pi / 0.74nm^2 per head group.

The model was integrated and simulated using Copasi 4.6.32 and plotted using Matplotlib to reproduce figure 4 of the article.

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