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BIOMD0000000537 - Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody

 

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Reference Publication
Publication ID: 24402116
Dwivedi G, Fitz L, Hegen M, Martin SW, Harrold J, Heatherington A, Li C.
A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development.
CPT Pharmacometrics Syst Pharmacol 2014; 3: e89
The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.  [more]
Model
Original Model: BIOMD0000000537.origin
Submitter: Vincent Knight-Schrijver
Submission ID: MODEL1408050002
Submission Date: 05 Aug 2014 13:46:06 UTC
Last Modification Date: 13 Jan 2017 16:03:17 UTC
Creation Date: 06 Aug 2014 12:45:54 UTC
Encoders:  Vincent Knight-Schrijver
set #1
bqbiol:hasTaxon Taxonomy Homo sapiens
set #2
bqbiol:hasVersion Human Disease Ontology Crohn's disease
set #3
bqbiol:isVersionOf Gene Ontology interleukin-6 receptor activity
set #4
bqbiol:hasPart Gene Ontology JAK-STAT cascade
set #5
bqbiol:isPartOf Reactome REACT_27307.1
Notes
Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody
This model is comprised of four models:
Possible avenues for Interleukin-6 (IL-6) inhibition in treating Crohn's disease are compared here. Each model refers to separate ligands. The system simulates differential activity of the ligands on the signalling of IL-6. This affects Signal Transducer and Activator of Transcription 3 (STAT3) activity on the production of biomarker C-Reactive Protein (CRP) expression.
Figures referring to this Crohn's Disease model are 3a, 4d, 4e, 4f and 5b.

This model is described in the article:

Dwivedi G, Fitz L, Hegen M, Martin SW, Harrold J, Heatherington A, Li C.
CPT Pharmacometrics Syst Pharmacol 2014; 3: e89

Abstract:

In this study, we have developed a multiscale systems model of interleukin (IL)-6-mediated immune regulation in Crohn's disease, by integrating intracellular signaling with organ-level dynamics of pharmacological markers underlying the disease. This model was linked to a general pharmacokinetic model for therapeutic monoclonal antibodies and used to comparatively study various biotherapeutic strategies targeting IL-6-mediated signaling in Crohn's disease. Our work illustrates techniques to develop mechanistic models of disease biology to study drug-system interaction. Despite a sparse training data set, predictions of the model were qualitatively validated by clinical biomarker data from a pilot trial with tocilizumab. Model-based analysis suggests that strategies targeting IL-6, IL-6R?, or the IL-6/sIL-6R? complex are less effective at suppressing pharmacological markers of Crohn's than dual targeting the IL-6/sIL-6R? complex in addition to IL-6 or IL-6R?. The potential value of multiscale system pharmacology modeling in drug discovery and development is also discussed.CPT: Pharmacometrics & Systems Pharmacology (2014) 3, e89; doi:10.1038/psp.2013.64; advance online publication 8 January 2014.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 24402116 Submission Date: 05 Aug 2014 13:46:06 UTC Last Modification Date: 13 Jan 2017 16:03:17 UTC Creation Date: 06 Aug 2014 12:45:54 UTC
Mathematical expressions
Reactions
reaction_1 reaction_2 reaction_3 reaction_4
reaction_5 reaction_6 reaction_7 reaction_8
reaction_16 reaction_9 reaction_10 reaction_15
reaction_11 reaction_12 reaction_13 reaction_14
reaction_41 reaction_46 reaction_42 reaction_43
reaction_44 reaction_45 mwb675e13a_26c0_4b18_a8c3_0f5a62090ba4 mw64df7c9e_35da_4c7f_be56_c5dabfb060b6
mw391f3b8e_5649_4851_b2e2_782cb3e015b6 mw4a00a3a4_778f_4952_8100_2dc3cc2b7046 mw6db30657_4e56_4c3a_8575_9c67393dde4f mw6f470e13_f0e4_4294_83d8_59dd5670d10c
mwfb35eca9_7afc_4ba8_a46c_738cab57eb9f mw61d2af92_6da5_41ce_b90e_aa6f430e6ba1 mw4c099d5c_200f_474e_8ec1_59e9223a8afd mwbe8567ce_3349_4442_8b12_53cd9bc168e7
mw12a9fa7e_a273_4c1e_b970_ed33f3a9a705 mw1046000b_e1e8_4f6f_82a1_532d2aa793bb mw8e8b65a8_6830_4091_9a40_19645e8fe554 mwa812f08f_1035_42bd_82d2_72d691308f88
mwab0012ac_e5f2_4904_9893_820fd210402e mwcdc24bd4_d9e4_47fe_8300_d222d853111c mwff2ebcf1_dcf1_47b9_9cac_7306fc6f7f76 mw1c5a5ff7_5130_490f_a740_6a744ccf8a94
mw7b56053c_7256_4703_a8c3_4fd46b2c23d0 mw8be158f1_ea81_45bf_80d4_6e31cd83fe6c mwd77df15b_fed7_41a8_a3d6_b0f6c590c5f6 mw01babcdf_0f03_46b0_81b1_201cc846e361
mwae5dbb44_7de5_46ab_8c20_ac4f8956b0f0 mw432fde6e_59ab_47f0_9fb1_086433a602e3 mw41c27823_d7ee_4554_9eac_3d5beec8e854 mw50c6744c_e883_4612_8663_e38750cbad1b
mwb6a99eb5_ea4c_4733_98dd_1daf5ec6b0db mw1ce0c484_681f_4d85_8ffe_392d0c100cfa mwf913ea0b_785a_4701_ac91_b18ab5dd5a89 mw71d90b81_8211_4039_8807_12a7fe03206c
mwdf4ba845_7271_4ada_b43f_fdac83df3b5c mwb1879013_5fcd_490c_8b01_eaf84df15b9a mw30abb016_4300_4f40_a1b3_f865d0a45707 mwba7f4605_8571_439b_b3ab_eb0b43808db8
mw8b4e96ed_0bcc_4ad6_b560_366e173a6e6b mwa3cb4a9b_d628_4807_8847_bdcd9b40c7f1 mw8fb6c0a7_b05d_4c2a_8866_77eb81f063d1 mw3e76b10b_5420_4828_8c70_b91b767132d0
mw131e3c9d_e77d_48c0_bdbb_77b2c10aaf3d mw14940d1f_6a1f_47cb_8170_801ba645f4c1 mwa2f4d966_ae2c_4ed2_b522_12755f12ff15 mw700e677e_d3b6_4a97_991f_279605a9abeb
mw2ae288ab_7d03_4a84_a024_c711ad2b77e6 mw9629d028_fcc0_4886_9e4d_36eecdb0381d mw6b46c550_674f_4857_b947_d31221cd8dd3 mw920e142e_b2c4_42b2_88f4_9f68cc50142e
mw1b09ae22_e4c7_4830_b566_f263cf4e3f9c mwf9c93372_1c4e_4988_b8a7_7b9981192b30 mw5e1e306a_63ed_43a8_b79f_b403516e7963 mwfeae4233_1272_453f_a97f_70982c445b43
mwe84cc3ad_af35_43a8_aa6a_9f68a6d68185      
Rules
Assignment Rule (variable: CRP Suppression (%)) Assignment Rule (variable: CRP (% of baseline)) Assignment Rule (variable: CRP) Assignment Rule (variable: geneProduct)
Events
Week0 Week4 Week8 Week2
Week6 Week10    
Physical entities
Compartments Species
serum IL6 sgp130 sR_IL6_sgp130
CRP sR sR_IL6
Ab Ab_sR Ab_sR_IL6
CRP Suppression (%) CRP (% of baseline)  
liver gp130 R_IL6_gp130 sR_IL6
R IL6 R_IL6
Ractive STAT3 pSTAT3
CRP sR CRPExtracellular
sgp130 sR_IL6_sgp130 Ab_sR
Ab Ab_R Ab_sR_IL6
     
gut sR_IL6 gp130 R_IL6_gp130
Ractive STAT3 pSTAT3
geneProduct sR IL6
sgp130 sR_IL6_sgp130 Ab
Ab_sR Ab_sR_IL6  
peripheral Ab    
Global parameters
kRLOn kRLOff kgp130On kgp130Off
kRAct kRint kRsynth kRintBasal
ksynthIL6 kdegIL6 kdegCRP KmSTATDephos
VmSTATDephos VmRDephos KmRDephos kcatSTATPhos
KmSTATPhos KmProtSynth VmProtSynth kCRPSecretion
ksynthCRP ksynthsR kdegsR ksynthsgp130
kdegsgp130 ksynthIL6Gut kdegIL6Gut kdistTissueToSerum
kdistSerumToTissue kRShedding kintActiveR kIL6RBind
kIL6RUnbind infusionTime kAbSerumToLiver kAbLiverToSerum
kAbSerumToGut kAbGutToSerum VSerum VLiver
VGut VPeriph QSerumLiver QSerumGut
QSerumPeriph kAbSerumToPeriph kAbPeriphToSerum kdegAb
Dose DoseQ2W Initial for CRP Initial for DoseQ2W
Initial for Dose      
Reactions (73)
 
 reaction_1 [sR] + [IL6] ↔ [sR_IL6];   {sR_IL6} , {sR} , {IL6}
 
 reaction_2 [sR_IL6] + [sgp130] ↔ [sR_IL6_sgp130];   {sR_IL6} , {sR_IL6_sgp130} , {sgp130}
 
 reaction_3  → [IL6];  
 
 reaction_4 [IL6] → ;   {IL6}
 
 reaction_5 [CRP] → ;   {CRP}
 
 reaction_6 [sR_IL6] + [gp130] ↔ [R_IL6_gp130];   {sR_IL6} , {gp130} , {R_IL6_gp130}
 
 reaction_7 [R] + [IL6] ↔ [R_IL6];   {IL6} , {R} , {R_IL6}
 
 reaction_8 [R_IL6] + [gp130] ↔ [R_IL6_gp130];   {R_IL6} , {gp130} , {R_IL6_gp130}
 
 reaction_16 [R_IL6_gp130] → [Ractive];   {R_IL6_gp130}
 
 reaction_9 [STAT3] + [Ractive] → [pSTAT3] + [Ractive];   {Ractive} , {STAT3}
 
 reaction_10 [pSTAT3] → [STAT3];   {pSTAT3}
 
 reaction_15 [R] → ;   {R}
 
 reaction_11 [R_IL6] → ;   {R_IL6}
 
 reaction_12 [R_IL6_gp130] → ;   {R_IL6_gp130}
 
 reaction_13 [Ractive] → ;   {Ractive}
 
 reaction_14  → [R];  
 
 reaction_41 [sR_IL6] + [gp130] ↔ [R_IL6_gp130];   {sR_IL6} , {R_IL6_gp130} , {gp130}
 
 reaction_46 [R_IL6_gp130] → [Ractive];   {R_IL6_gp130}
 
 reaction_42 [STAT3] + [Ractive] → [pSTAT3] + [Ractive];   {STAT3} , {Ractive}
 
 reaction_43 [pSTAT3] → [STAT3];   {pSTAT3}
 
 reaction_44 [R_IL6_gp130] → ;   {R_IL6_gp130}
 
 reaction_45 [Ractive] → ;   {Ractive}
 
 mwb675e13a_26c0_4b18_a8c3_0f5a62090ba4 [Ractive] → [R_IL6_gp130];   {Ractive}
 
 mw64df7c9e_35da_4c7f_be56_c5dabfb060b6 [Ractive] → [R_IL6_gp130];   {Ractive}
 
 mw391f3b8e_5649_4851_b2e2_782cb3e015b6  → [gp130];  
 
 mw4a00a3a4_778f_4952_8100_2dc3cc2b7046 [gp130] → ;   {gp130}
 
 mw6db30657_4e56_4c3a_8575_9c67393dde4f  → [gp130];  
 
 mw6f470e13_f0e4_4294_83d8_59dd5670d10c [gp130] → ;   {gp130}
 
 mwfb35eca9_7afc_4ba8_a46c_738cab57eb9f [sR] ↔ [sR];   {sR} , {sR}
 
 mw61d2af92_6da5_41ce_b90e_aa6f430e6ba1 [IL6] ↔ [IL6];   {IL6} , {IL6}
 
 mw4c099d5c_200f_474e_8ec1_59e9223a8afd [sR] + [IL6] ↔ [sR_IL6];   {IL6} , {sR_IL6} , {sR}
 
 mwbe8567ce_3349_4442_8b12_53cd9bc168e7 [sR_IL6] ↔ [sR_IL6];   {sR_IL6} , {sR_IL6}
 
 mw12a9fa7e_a273_4c1e_b970_ed33f3a9a705 [sR] ↔ [sR];   {sR} , {sR}
 
 mw1046000b_e1e8_4f6f_82a1_532d2aa793bb [IL6] ↔ [IL6];   {IL6} , {IL6}
 
 mw8e8b65a8_6830_4091_9a40_19645e8fe554 [sR_IL6] ↔ [sR_IL6];   {sR_IL6} , {sR_IL6}
 
 mwa812f08f_1035_42bd_82d2_72d691308f88 [sR] + [IL6] ↔ [sR_IL6];   {IL6} , {sR} , {sR_IL6}
 
 mwab0012ac_e5f2_4904_9893_820fd210402e [CRP] → [CRPExtracellular];   {CRP}
 
 mwcdc24bd4_d9e4_47fe_8300_d222d853111c [CRP] ↔ [CRPExtracellular];   {CRP} , {CRPExtracellular}
 
 mwff2ebcf1_dcf1_47b9_9cac_7306fc6f7f76  → [CRP];  
 
 mw1c5a5ff7_5130_490f_a740_6a744ccf8a94 [sgp130] ↔ [sgp130];   {sgp130} , {sgp130}
 
 mw7b56053c_7256_4703_a8c3_4fd46b2c23d0 [sgp130] ↔ [sgp130];   {sgp130} , {sgp130}
 
 mw8be158f1_ea81_45bf_80d4_6e31cd83fe6c [sgp130] + [sR_IL6] ↔ [sR_IL6_sgp130];   {sR_IL6_sgp130} , {sR_IL6} , {sgp130}
 
 mwd77df15b_fed7_41a8_a3d6_b0f6c590c5f6 [sR_IL6] + [sgp130] ↔ [sR_IL6_sgp130];   {sgp130} , {sR_IL6} , {sR_IL6_sgp130}
 
 mw01babcdf_0f03_46b0_81b1_201cc846e361 [sR_IL6_sgp130] ↔ [sR_IL6_sgp130];   {sR_IL6_sgp130} , {sR_IL6_sgp130}
 
 mwae5dbb44_7de5_46ab_8c20_ac4f8956b0f0 [sR_IL6_sgp130] ↔ [sR_IL6_sgp130];   {sR_IL6_sgp130} , {sR_IL6_sgp130}
 
 mw432fde6e_59ab_47f0_9fb1_086433a602e3  → [sR];  
 
 mw41c27823_d7ee_4554_9eac_3d5beec8e854 [sR] → ;   {sR}
 
 mw50c6744c_e883_4612_8663_e38750cbad1b  → [sgp130];  
 
 mwb6a99eb5_ea4c_4733_98dd_1daf5ec6b0db [sgp130] → ;   {sgp130}
 
 mw1ce0c484_681f_4d85_8ffe_392d0c100cfa  → [IL6];  
 
 mwf913ea0b_785a_4701_ac91_b18ab5dd5a89 [IL6] → ;   {IL6}
 
 mw71d90b81_8211_4039_8807_12a7fe03206c [CRP] → [sR] + [CRP];   {CRP}
 
 mwdf4ba845_7271_4ada_b43f_fdac83df3b5c [Ab] ↔ [Ab];   {Ab} , {Ab}
 
 mwb1879013_5fcd_490c_8b01_eaf84df15b9a [Ab] + [sR] ↔ [Ab_sR];   {Ab_sR} , {sR} , {Ab}
 
 mw30abb016_4300_4f40_a1b3_f865d0a45707 [Ab_sR] → ;   {Ab_sR}
 
 mwba7f4605_8571_439b_b3ab_eb0b43808db8 [Ab] → ;   {Ab}
 
 mw8b4e96ed_0bcc_4ad6_b560_366e173a6e6b [Ab_sR] → ;   {Ab_sR}
 
 mwa3cb4a9b_d628_4807_8847_bdcd9b40c7f1 [Ab] + [sR] ↔ [Ab_sR];   {Ab_sR} , {sR} , {Ab}
 
 mw8fb6c0a7_b05d_4c2a_8866_77eb81f063d1 [Ab] + [sR] ↔ [Ab_sR];   {sR} , {Ab} , {Ab_sR}
 
 mw3e76b10b_5420_4828_8c70_b91b767132d0 [Ab_sR] → ;   {Ab_sR}
 
 mw131e3c9d_e77d_48c0_bdbb_77b2c10aaf3d [Ab] ↔ [Ab];   {Ab} , {Ab}
 
 mw14940d1f_6a1f_47cb_8170_801ba645f4c1 [Ab] ↔ [Ab];   {Ab} , {Ab}
 
 mwa2f4d966_ae2c_4ed2_b522_12755f12ff15 [Ab_sR] ↔ [Ab_sR];   {Ab_sR} , {Ab_sR}
 
 mw700e677e_d3b6_4a97_991f_279605a9abeb [Ab_sR] ↔ [Ab_sR];   {Ab_sR} , {Ab_sR}
 
 mw2ae288ab_7d03_4a84_a024_c711ad2b77e6 [Ab] → ;   {Ab}
 
 mw9629d028_fcc0_4886_9e4d_36eecdb0381d [Ab] → ;   {Ab}
 
 mw6b46c550_674f_4857_b947_d31221cd8dd3 [Ab] + [R] ↔ [Ab_R];   {R} , {Ab} , {Ab_R}
 
 mw920e142e_b2c4_42b2_88f4_9f68cc50142e [Ab_R] → ;   {Ab_R}
 
 mw1b09ae22_e4c7_4830_b566_f263cf4e3f9c [Ab_sR_IL6] ↔ [Ab_sR_IL6];   {Ab_sR_IL6} , {Ab_sR_IL6}
 
 mwf9c93372_1c4e_4988_b8a7_7b9981192b30 [Ab_sR_IL6] ↔ [Ab_sR_IL6];   {Ab_sR_IL6} , {Ab_sR_IL6}
 
 mw5e1e306a_63ed_43a8_b79f_b403516e7963 [Ab_sR_IL6] → ;   {Ab_sR_IL6}
 
 mwfeae4233_1272_453f_a97f_70982c445b43 [Ab_sR_IL6] → ;   {Ab_sR_IL6}
 
 mwe84cc3ad_af35_43a8_aa6a_9f68a6d68185 [Ab_sR_IL6] → ;   {Ab_sR_IL6}
 
Rules (4)
 
 Assignment Rule (name: CRP_Suppression___) CRP Suppression (%) = (mw114aa90f_5f5b_4fe8_9406_361c8489b6a1-Metabolite_40)/((-Metabolite_40)/100)
 
 Assignment Rule (name: CRP____of_baseline) CRP (% of baseline) = mw114aa90f_5f5b_4fe8_9406_361c8489b6a1/Metabolite_40*100
 
 Assignment Rule (name: mwd5313618_89eb_4c8c_bc82_66f10f966349) CRP = mw92d854a7_8aaf_458e_b5e2_20a63ce9b654*mw39c2e431_fdc3_4964_be29_6ca856620b1b/(mw08950572_81b0_4570_b2e4_b9c3462c1425+mw39c2e431_fdc3_4964_be29_6ca856620b1b)
 
 Assignment Rule (name: mw0083d743_836f_4238_a17f_4602193d5bc0) geneProduct = mw92d854a7_8aaf_458e_b5e2_20a63ce9b654*mw48867e93_f170_44e8_ac7a_185b23e1bf3b/(mw08950572_81b0_4570_b2e4_b9c3462c1425+mw48867e93_f170_44e8_ac7a_185b23e1bf3b)
 
Events (6)
 
 Week0
Ab = mwf345ed7a_0622_403c_b816_c8749a2c9ded+(ModelValue_99+ModelValue_98)*2.346
 
 Week4
Ab = mwf345ed7a_0622_403c_b816_c8749a2c9ded+(ModelValue_99+ModelValue_98)*2.346
 
 Week8
Ab = mwf345ed7a_0622_403c_b816_c8749a2c9ded+(ModelValue_99+ModelValue_98)*2.346
 
 Week2
Ab = mwf345ed7a_0622_403c_b816_c8749a2c9ded+ModelValue_99*2.346
 
 Week6
Ab = mwf345ed7a_0622_403c_b816_c8749a2c9ded+ModelValue_99*2.346
 
 Week10
Ab = mwf345ed7a_0622_403c_b816_c8749a2c9ded+ModelValue_99*2.346
 
Functions (55)
 
 Function for reaction_12_2_3_2 lambda(kRint, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a, kRint*mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mwd77df15b_fed7_41a8_a3d6_b0f6c590c5f6_2_3_2 lambda(kgp130Off, kgp130On, mw147d30ec_478e_4090_b496_128a131d29eb, mw4638f126_8cb8_4021_ab41_6ae195743ba0, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwab41493c_6349_45f1_a226_3030cfed0e06, (kgp130On*mw4638f126_8cb8_4021_ab41_6ae195743ba0*mw147d30ec_478e_4090_b496_128a131d29eb-kgp130Off*mwab41493c_6349_45f1_a226_3030cfed0e06)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for reaction_7_2_3_2 lambda(kRLOff, kRLOn, mw0adf3eb4_a196_4c48_b10d_4e9e9faaf9e1, mw10315fa3_6f13_4618_bda8_a8694bd3c374, mw7d86cc23_a1af_44c3_bdb9_71e9b1bb2a83, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, (kRLOn*mw10315fa3_6f13_4618_bda8_a8694bd3c374*mw0adf3eb4_a196_4c48_b10d_4e9e9faaf9e1-kRLOff*mw7d86cc23_a1af_44c3_bdb9_71e9b1bb2a83)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mw9629d028_fcc0_4886_9e4d_36eecdb0381d_2_3_2 lambda(mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, mwf7796221_1fea_4274_a93e_c00adbf5778c, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30*mwf7796221_1fea_4274_a93e_c00adbf5778c/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for reaction_2_2_3_2 lambda(kgp130Off, kgp130On, mw03db56ac_8dc6_4931_ae82_fef706d2ee3d, mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mw810ff751_fa4e_4143_bd50_169b3e325e1e, mwbbbce920_e8dd_4320_9386_fc94bfb2fc99, (kgp130On*mw03db56ac_8dc6_4931_ae82_fef706d2ee3d*mwbbbce920_e8dd_4320_9386_fc94bfb2fc99-kgp130Off*mw810ff751_fa4e_4143_bd50_169b3e325e1e)/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for mwe84cc3ad_af35_43a8_aa6a_9f68a6d68185_2_3_2 lambda(mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, mwedc1bc00_adf7_4144_a1c2_7dc1a9565dc2, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30*mwedc1bc00_adf7_4144_a1c2_7dc1a9565dc2/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for mwfeae4233_1272_453f_a97f_70982c445b43_2_3_2 lambda(mw2ba2b802_9f07_4f4d_94c6_24c8de1a95cf, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30*mw2ba2b802_9f07_4f4d_94c6_24c8de1a95cf/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mw5e1e306a_63ed_43a8_b79f_b403516e7963_2_3_2 lambda(mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mw9947742a_0e4b_4636_9a4b_b6eef2a8f6ac, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30*mw9947742a_0e4b_4636_9a4b_b6eef2a8f6ac/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for mw4a00a3a4_778f_4952_8100_2dc3cc2b7046_2_3_2 lambda(kRdeg, mw80848184_e2dd_47ce_86d7_7a21479342bd, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, kRdeg*mw80848184_e2dd_47ce_86d7_7a21479342bd/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for reaction_15_2_3_2 lambda(kRdeg, mw10315fa3_6f13_4618_bda8_a8694bd3c374, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, kRdeg*mw10315fa3_6f13_4618_bda8_a8694bd3c374/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for reaction_41_2_3_2 lambda(kgp130Off, kgp130On, mw7becb5fe_8da8_4285_a821_0d77ad811b62, mw824bc3d4_1ac3_4912_9b51_8f14ff1c96b9, mw8c9107e6_f51d_442d_b2dc_2bfdbb8482ca, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, (kgp130On*mw7becb5fe_8da8_4285_a821_0d77ad811b62*mw8c9107e6_f51d_442d_b2dc_2bfdbb8482ca-kgp130Off*mw824bc3d4_1ac3_4912_9b51_8f14ff1c96b9)/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for mw6f470e13_f0e4_4294_83d8_59dd5670d10c_2_3_2 lambda(kRdeg, mw8c9107e6_f51d_442d_b2dc_2bfdbb8482ca, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, kRdeg*mw8c9107e6_f51d_442d_b2dc_2bfdbb8482ca/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for reaction_45_2_3_2 lambda(mw6cce2109_0e32_4dd9_98ec_41173e8ef07d, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, mwf44f7f27_5bb1_4c7f_8964_560fa5e1743a, mwf44f7f27_5bb1_4c7f_8964_560fa5e1743a*mw6cce2109_0e32_4dd9_98ec_41173e8ef07d/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for reaction_1_2_3_2 lambda(kRLOff, kRLOn, mw03db56ac_8dc6_4931_ae82_fef706d2ee3d, mw30ae63db_6cd3_4b6f_93ad_3350cd360bcc, mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mwf626e95e_543f_41e4_aad4_c6bf60ab345b, (kRLOn*mw30ae63db_6cd3_4b6f_93ad_3350cd360bcc*mwf626e95e_543f_41e4_aad4_c6bf60ab345b-kRLOff*mw03db56ac_8dc6_4931_ae82_fef706d2ee3d)/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for mwa812f08f_1035_42bd_82d2_72d691308f88_2_3_2 lambda(kRLOff, kRLOn, mw0adf3eb4_a196_4c48_b10d_4e9e9faaf9e1, mw2e464cf3_a09c_4b7c_9f3c_06720016a48e, mw4638f126_8cb8_4021_ab41_6ae195743ba0, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, (kRLOn*mw2e464cf3_a09c_4b7c_9f3c_06720016a48e*mw0adf3eb4_a196_4c48_b10d_4e9e9faaf9e1-kRLOff*mw4638f126_8cb8_4021_ab41_6ae195743ba0)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mw8fb6c0a7_b05d_4c2a_8866_77eb81f063d1_2_3_2 lambda(mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead, mw2e464cf3_a09c_4b7c_9f3c_06720016a48e, mw3667a5e1_02c9_44a0_acb4_b0431faa822d, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwa09d6284_843e_404e_abbb_052fbb535197, mwf405687b_7401_44ec_a0d6_4a2b35c13e8a, (mwa09d6284_843e_404e_abbb_052fbb535197*mw3667a5e1_02c9_44a0_acb4_b0431faa822d*mw2e464cf3_a09c_4b7c_9f3c_06720016a48e-mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead*mwf405687b_7401_44ec_a0d6_4a2b35c13e8a)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mwab0012ac_e5f2_4904_9893_820fd210402e_2_3_2 lambda(mw862f1480_c60c_4863_a565_b2c1c77e238e, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwd5313618_89eb_4c8c_bc82_66f10f966349, mw862f1480_c60c_4863_a565_b2c1c77e238e*mwd5313618_89eb_4c8c_bc82_66f10f966349/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mw30abb016_4300_4f40_a1b3_f865d0a45707_2_3_2 lambda(mw1da111f2_a036_4392_8512_015005bdcbb7, mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30*mw1da111f2_a036_4392_8512_015005bdcbb7/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for mw2ae288ab_7d03_4a84_a024_c711ad2b77e6_2_3_2 lambda(mw3667a5e1_02c9_44a0_acb4_b0431faa822d, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30*mw3667a5e1_02c9_44a0_acb4_b0431faa822d/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mw391f3b8e_5649_4851_b2e2_782cb3e015b6_2_3_2 lambda(kRsynth, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, kRsynth/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for reaction_13_2_3_2 lambda(mw0eb6c959_d408_45a0_a450_928b8c5876bb, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwf44f7f27_5bb1_4c7f_8964_560fa5e1743a, mwf44f7f27_5bb1_4c7f_8964_560fa5e1743a*mw0eb6c959_d408_45a0_a450_928b8c5876bb/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for reaction_6_2_3_2 lambda(kgp130Off, kgp130On, mw4638f126_8cb8_4021_ab41_6ae195743ba0, mw80848184_e2dd_47ce_86d7_7a21479342bd, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a, (kgp130On*mw4638f126_8cb8_4021_ab41_6ae195743ba0*mw80848184_e2dd_47ce_86d7_7a21479342bd-kgp130Off*mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mw432fde6e_59ab_47f0_9fb1_086433a602e3_2_3_2 lambda(mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mwc4c58db7_5535_4590_aaa5_bbc8ed53cdab, mwc4c58db7_5535_4590_aaa5_bbc8ed53cdab/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for mw6b46c550_674f_4857_b947_d31221cd8dd3_2_3_2 lambda(mw10315fa3_6f13_4618_bda8_a8694bd3c374, mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead, mw3667a5e1_02c9_44a0_acb4_b0431faa822d, mw772cbf20_3fc1_4800_ae59_77884f1ae333, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwa09d6284_843e_404e_abbb_052fbb535197, (mwa09d6284_843e_404e_abbb_052fbb535197*mw3667a5e1_02c9_44a0_acb4_b0431faa822d*mw10315fa3_6f13_4618_bda8_a8694bd3c374-mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead*mw772cbf20_3fc1_4800_ae59_77884f1ae333)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mw41c27823_d7ee_4554_9eac_3d5beec8e854_2_3_2 lambda(mw30ae63db_6cd3_4b6f_93ad_3350cd360bcc, mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mw88a75379_f9a1_4acc_baeb_94c32bb736a5, mw88a75379_f9a1_4acc_baeb_94c32bb736a5*mw30ae63db_6cd3_4b6f_93ad_3350cd360bcc/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for reaction_3_2_3_2 lambda(kIL6Synth, mw53ffe9e6_beef_45c4_90a5_a79197ed506e, kIL6Synth/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for reaction_5_2_3_2 lambda(kCRPDecay, mw114aa90f_5f5b_4fe8_9406_361c8489b6a1, mw53ffe9e6_beef_45c4_90a5_a79197ed506e, kCRPDecay*mw114aa90f_5f5b_4fe8_9406_361c8489b6a1/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for mwba7f4605_8571_439b_b3ab_eb0b43808db8_2_3_2 lambda(mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30, mwf345ed7a_0622_403c_b816_c8749a2c9ded, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30*mwf345ed7a_0622_403c_b816_c8749a2c9ded/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for mw4c099d5c_200f_474e_8ec1_59e9223a8afd_2_3_2 lambda(kRLOff, kRLOn, mw2c9b0499_3325_4394_8af3_bbf653a944a0, mw7becb5fe_8da8_4285_a821_0d77ad811b62, mwd31f52cc_04e7_40e0_885f_c7b2d9e62215, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, (kRLOn*mwd31f52cc_04e7_40e0_885f_c7b2d9e62215*mw2c9b0499_3325_4394_8af3_bbf653a944a0-kRLOff*mw7becb5fe_8da8_4285_a821_0d77ad811b62)/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for reaction_14_2_3_2 lambda(kRsynth, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, kRsynth/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mw3e76b10b_5420_4828_8c70_b91b767132d0_2_3_2 lambda(mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30, mwf405687b_7401_44ec_a0d6_4a2b35c13e8a, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30*mwf405687b_7401_44ec_a0d6_4a2b35c13e8a/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for reaction_4_2_3_2 lambda(kIL6Decay, mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mwf626e95e_543f_41e4_aad4_c6bf60ab345b, kIL6Decay*mwf626e95e_543f_41e4_aad4_c6bf60ab345b/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for mwb1879013_5fcd_490c_8b01_eaf84df15b9a_2_3_2 lambda(mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead, mw1da111f2_a036_4392_8512_015005bdcbb7, mw30ae63db_6cd3_4b6f_93ad_3350cd360bcc, mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mwa09d6284_843e_404e_abbb_052fbb535197, mwf345ed7a_0622_403c_b816_c8749a2c9ded, (mwa09d6284_843e_404e_abbb_052fbb535197*mwf345ed7a_0622_403c_b816_c8749a2c9ded*mw30ae63db_6cd3_4b6f_93ad_3350cd360bcc-mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead*mw1da111f2_a036_4392_8512_015005bdcbb7)/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for mw71d90b81_8211_4039_8807_12a7fe03206c_2_3_2 lambda(mw114aa90f_5f5b_4fe8_9406_361c8489b6a1, mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mw5832a2dc_ee18_44df_aa59_ccb21cb74df2, mw5832a2dc_ee18_44df_aa59_ccb21cb74df2*mw114aa90f_5f5b_4fe8_9406_361c8489b6a1/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for reaction_44_2_3_2 lambda(kRint, mw824bc3d4_1ac3_4912_9b51_8f14ff1c96b9, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, kRint*mw824bc3d4_1ac3_4912_9b51_8f14ff1c96b9/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for reaction_11_2_3_2 lambda(kRint, mw7d86cc23_a1af_44c3_bdb9_71e9b1bb2a83, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, kRint*mw7d86cc23_a1af_44c3_bdb9_71e9b1bb2a83/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mw64df7c9e_35da_4c7f_be56_c5dabfb060b6_2_3_2 lambda(mw1667a8e0_9d20_4e59_ba51_596148aba787, mw6cce2109_0e32_4dd9_98ec_41173e8ef07d, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, mwfcf06900_5f2f_4bb3_bb1f_12023612b8a8, mw1667a8e0_9d20_4e59_ba51_596148aba787*mw6cce2109_0e32_4dd9_98ec_41173e8ef07d/(mwfcf06900_5f2f_4bb3_bb1f_12023612b8a8+mw6cce2109_0e32_4dd9_98ec_41173e8ef07d)/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for reaction_10_2_3_2 lambda(mw39c2e431_fdc3_4964_be29_6ca856620b1b, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwd36b0261_2480_4cab_9222_2cf8fb0e65dc, mwfd291862_195f_4979_94b5_b4e5ae1b7d52, mwd36b0261_2480_4cab_9222_2cf8fb0e65dc*mw39c2e431_fdc3_4964_be29_6ca856620b1b/(mwfd291862_195f_4979_94b5_b4e5ae1b7d52+mw39c2e431_fdc3_4964_be29_6ca856620b1b)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mwa3cb4a9b_d628_4807_8847_bdcd9b40c7f1_2_3_2 lambda(mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead, mw5d764bb8_5693_4ac8_9557_f65992cc5eb0, mwa09d6284_843e_404e_abbb_052fbb535197, mwd31f52cc_04e7_40e0_885f_c7b2d9e62215, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, mwf7796221_1fea_4274_a93e_c00adbf5778c, (mwa09d6284_843e_404e_abbb_052fbb535197*mwf7796221_1fea_4274_a93e_c00adbf5778c*mwd31f52cc_04e7_40e0_885f_c7b2d9e62215-mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead*mw5d764bb8_5693_4ac8_9557_f65992cc5eb0)/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for reaction_9_2_3_2 lambda(mw0eb6c959_d408_45a0_a450_928b8c5876bb, mw42054cd7_17af_46da_970c_7f99151906ad, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mw9442cd0e_4d7c_4ba6_a695_f84919bdf569, mwe8fc1900_f07d_468b_b5c8_15400a583c3d, mw9442cd0e_4d7c_4ba6_a695_f84919bdf569*mw0eb6c959_d408_45a0_a450_928b8c5876bb*mw42054cd7_17af_46da_970c_7f99151906ad/(mwe8fc1900_f07d_468b_b5c8_15400a583c3d+mw42054cd7_17af_46da_970c_7f99151906ad)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mwb6a99eb5_ea4c_4733_98dd_1daf5ec6b0db_2_3_2 lambda(mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mwbbbce920_e8dd_4320_9386_fc94bfb2fc99, mwbcb5a310_9b67_405e_89ec_43d25e8cc93d, mwbcb5a310_9b67_405e_89ec_43d25e8cc93d*mwbbbce920_e8dd_4320_9386_fc94bfb2fc99/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for mw920e142e_b2c4_42b2_88f4_9f68cc50142e_2_3_2 lambda(mw772cbf20_3fc1_4800_ae59_77884f1ae333, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30*mw772cbf20_3fc1_4800_ae59_77884f1ae333/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for reaction_8_2_3_2 lambda(kgp130Off, kgp130On, mw7d86cc23_a1af_44c3_bdb9_71e9b1bb2a83, mw80848184_e2dd_47ce_86d7_7a21479342bd, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a, (kgp130On*mw7d86cc23_a1af_44c3_bdb9_71e9b1bb2a83*mw80848184_e2dd_47ce_86d7_7a21479342bd-kgp130Off*mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mw50c6744c_e883_4612_8663_e38750cbad1b_2_3_2 lambda(mw1f41474c_c399_4a60_a53a_9926dd092e8d, mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mw1f41474c_c399_4a60_a53a_9926dd092e8d/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for mw8be158f1_ea81_45bf_80d4_6e31cd83fe6c_2_3_2 lambda(kgp130Off, kgp130On, mw6335d5d7_c7b0_4bc0_b883_f7ee4915c2c3, mw7becb5fe_8da8_4285_a821_0d77ad811b62, mwd65b5b39_dc1b_4e77_a999_67277a880e5e, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, (kgp130On*mwd65b5b39_dc1b_4e77_a999_67277a880e5e*mw7becb5fe_8da8_4285_a821_0d77ad811b62-kgp130Off*mw6335d5d7_c7b0_4bc0_b883_f7ee4915c2c3)/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for mw1ce0c484_681f_4d85_8ffe_392d0c100cfa_2_3_2 lambda(mwa8d72918_f6c2_4d81_bf3b_fc2b464d5e69, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, mwa8d72918_f6c2_4d81_bf3b_fc2b464d5e69/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for mw6db30657_4e56_4c3a_8575_9c67393dde4f_2_3_2 lambda(kRsynth, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, kRsynth/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for mw8b4e96ed_0bcc_4ad6_b560_366e173a6e6b_2_3_2 lambda(mw5d764bb8_5693_4ac8_9557_f65992cc5eb0, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30*mw5d764bb8_5693_4ac8_9557_f65992cc5eb0/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for reaction_43_2_3_2 lambda(mw48867e93_f170_44e8_ac7a_185b23e1bf3b, mwd36b0261_2480_4cab_9222_2cf8fb0e65dc, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, mwfd291862_195f_4979_94b5_b4e5ae1b7d52, mwd36b0261_2480_4cab_9222_2cf8fb0e65dc*mw48867e93_f170_44e8_ac7a_185b23e1bf3b/(mwfd291862_195f_4979_94b5_b4e5ae1b7d52+mw48867e93_f170_44e8_ac7a_185b23e1bf3b)/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for reaction_42_2_3_2 lambda(mw2b255f94_8018_4b99_bde8_918eeac45446, mw6cce2109_0e32_4dd9_98ec_41173e8ef07d, mw9442cd0e_4d7c_4ba6_a695_f84919bdf569, mwe8fc1900_f07d_468b_b5c8_15400a583c3d, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, mw9442cd0e_4d7c_4ba6_a695_f84919bdf569*mw6cce2109_0e32_4dd9_98ec_41173e8ef07d*mw2b255f94_8018_4b99_bde8_918eeac45446/(mwe8fc1900_f07d_468b_b5c8_15400a583c3d+mw2b255f94_8018_4b99_bde8_918eeac45446)/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for reaction_46_2_3_2 lambda(kRAct, mw824bc3d4_1ac3_4912_9b51_8f14ff1c96b9, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, kRAct*mw824bc3d4_1ac3_4912_9b51_8f14ff1c96b9/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for mwf913ea0b_785a_4701_ac91_b18ab5dd5a89_2_3_2 lambda(mw06241335_b5f2_47ed_bdcc_ef77b68a2b98, mw2c9b0499_3325_4394_8af3_bbf653a944a0, mwe9501423_9fb4_494b_b5b6_288f3fcb17b5, mw06241335_b5f2_47ed_bdcc_ef77b68a2b98*mw2c9b0499_3325_4394_8af3_bbf653a944a0/mwe9501423_9fb4_494b_b5b6_288f3fcb17b5)
 
 Function for mwb675e13a_26c0_4b18_a8c3_0f5a62090ba4_2_3_2 lambda(mw0eb6c959_d408_45a0_a450_928b8c5876bb, mw1667a8e0_9d20_4e59_ba51_596148aba787, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwfcf06900_5f2f_4bb3_bb1f_12023612b8a8, mw1667a8e0_9d20_4e59_ba51_596148aba787*mw0eb6c959_d408_45a0_a450_928b8c5876bb/(mwfcf06900_5f2f_4bb3_bb1f_12023612b8a8+mw0eb6c959_d408_45a0_a450_928b8c5876bb)/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 Function for mwff2ebcf1_dcf1_47b9_9cac_7306fc6f7f76_2_3_2 lambda(mw53ffe9e6_beef_45c4_90a5_a79197ed506e, mw65c85954_5ca0_4df2_9e22_ff2aa3fbe3f1, mw65c85954_5ca0_4df2_9e22_ff2aa3fbe3f1/mw53ffe9e6_beef_45c4_90a5_a79197ed506e)
 
 Function for reaction_16_2_3_2 lambda(kRAct, mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e, mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a, kRAct*mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a/mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e)
 
 serum Spatial dimensions: 3.0  Compartment size: 1.0
 
 IL6
Compartment: serum
Initial concentration: 4.35628896551166E-4
 
 sgp130
Compartment: serum
Initial concentration: 3.9
 
 sR_IL6_sgp130
Compartment: serum
Initial concentration: 0.0874060669217432
 
 CRP
Compartment: serum
Initial concentration: 221.06367608557
 
 sR
Compartment: serum
Initial concentration: 4.25350679194445
 
 sR_IL6
Compartment: serum
Initial concentration: 0.00109424263781451
 
 Ab
Compartment: serum
Initial concentration: 2.38181965637876E-29
 
 Ab_sR
Compartment: serum
Initial concentration: 6.10439110812442E-26
 
 Ab_sR_IL6
Compartment: serum
Initial concentration: -7.413309014E-29
 
  CRP Suppression (%)
Compartment: serum
Initial concentration: 0.0
 
  CRP (% of baseline)
Compartment: serum
Initial concentration: 100.0
 
 liver Spatial dimensions: 3.0  Compartment size: 1.0
 
 gp130
Compartment: liver
Initial concentration: 0.388958921403941
 
 R_IL6_gp130
Compartment: liver
Initial concentration: 6.59935877686372E-5
 
 sR_IL6
Compartment: liver
Initial concentration: 9.76164943878914E-4
 
 R
Compartment: liver
Initial concentration: 0.438235811135574
 
 IL6
Compartment: liver
Initial concentration: 7.2566581144648E-4
 
 R_IL6
Compartment: liver
Initial concentration: 1.60036523605187E-5
 
 Ractive
Compartment: liver
Initial concentration: 0.765416493681823
 
 STAT3
Compartment: liver
Initial concentration: 0.777537339578333
 
 pSTAT3
Compartment: liver
Initial concentration: 9.22246266042168
 
  CRP
Compartment: liver
Initial concentration: 158.325846781611
 
 sR
Compartment: liver
Initial concentration: 6.08704712819469
 
 CRPExtracellular
Compartment: liver
Initial concentration: 409.775322370541
 
 sgp130
Compartment: liver
Initial concentration: 5.5896988923534
 
 sR_IL6_sgp130
Compartment: liver
Initial concentration: 0.116343661809953
 
 Ab_sR
Compartment: liver
Initial concentration: 8.616193096436E-26
 
 Ab
Compartment: liver
Initial concentration: 2.20020723250569E-29
 
 Ab_R
Compartment: liver
Initial concentration: 2.03371981683734E-27
 
 Ab_sR_IL6
Compartment: liver
Initial concentration: -3.077934746E-29
 
 gut Spatial dimensions: 3.0  Compartment size: 1.0
 
 sR_IL6
Compartment: gut
Initial concentration: 0.00130682388893128
 
 gp130
Compartment: gut
Initial concentration: 0.374962692933961
 
 R_IL6_gp130
Compartment: gut
Initial concentration: 8.44890497633549E-5
 
 Ractive
Compartment: gut
Initial concentration: 0.980272509547246
 
 STAT3
Compartment: gut
Initial concentration: 0.610636013508212
 
 pSTAT3
Compartment: gut
Initial concentration: 9.38936398649179
 
  geneProduct
Compartment: gut
Initial concentration: 159.80359735889
 
 sR
Compartment: gut
Initial concentration: 6.06410682471754
 
 IL6
Compartment: gut
Initial concentration: 0.0093481986616084
 
 sgp130
Compartment: gut
Initial concentration: 5.56973864471412
 
 sR_IL6_sgp130
Compartment: gut
Initial concentration: 0.136303909449242
 
 Ab
Compartment: gut
Initial concentration: 2.1587895876493E-29
 
 Ab_sR
Compartment: gut
Initial concentration: 2.62059686237767E-26
 
 Ab_sR_IL6
Compartment: gut
Initial concentration: -1.209166949E-28
 
 peripheral Spatial dimensions: 3.0  Compartment size: 1.0
 
 Ab
Compartment: peripheral
Initial concentration: 1.67920947537896E-29
 
Global Parameters (53)
 
   kRLOn
Value: 0.384
Constant
 
   kRLOff
Value: 1.92
Constant
 
 kgp130On
Value: 20.52
Constant
 
 kgp130Off
Value: 1.026
Constant
 
   kRAct
Value: 155.0
Constant
 
 kRint
Value: 1.96
Constant
 
 kRsynth
Value: 0.0685
Constant
 
   kRintBasal
Value: 0.1561
Constant
 
   ksynthIL6
Value: 0.0063
Constant
 
 kdegIL6
Value: 34.82
Constant
 
   kdegCRP
Value: 0.36
Constant
 
   KmSTATDephos
Value: 5.34
Constant
 
 VmSTATDephos
Value: 0.62
Constant
 
 VmRDephos
Value: 0.525
Constant
 
 KmRDephos
Value: 155.3
Constant
 
 kcatSTATPhos
Value: 145.0
Constant
 
   KmSTATPhos
Value: 219.0
Constant
 
   KmProtSynth
Value: 10.0
Constant
 
 VmProtSynth
Value: 330.0
Constant
 
   kCRPSecretion
Value: 0.5
Constant
 
   ksynthCRP
Value: 0.42
Constant
 
   ksynthsR
Value: 0.1
Constant
 
 kdegsR
Value: 0.3
Constant
 
   ksynthsgp130
Value: 3.9
Constant
 
   kdegsgp130
Value: 1.0
Constant
 
   ksynthIL6Gut
Value: 0.036
Constant
 
 kdegIL6Gut
Value: 1.0
Constant
 
 kdistTissueToSerum
Value: 0.8473
Constant
 
   kdistSerumToTissue
Value: 1.2125
Constant
 
 kRShedding
Value: 0.0054
Constant
 
   kintActiveR
Value: 0.01
Constant
 
 kIL6RBind
Value: 1000.0
Constant
 
 kIL6RUnbind
Value: 2.5
Constant
 
 infusionTime
Value: 1.0
Constant
 
   kAbSerumToLiver
Value: 0.0208333333333333
Constant
 
   kAbLiverToSerum
Value: 0.0208333333333333
Constant
 
   kAbSerumToGut
Value: 0.0104166666666667
Constant
 
   kAbGutToSerum
Value: 0.0208333333333333
Constant
 
   VSerum
Value: 2.88
Constant
 
 VLiver
Value: 2.88
Constant
 
   VGut
Value: 1.44
Constant
 
 VPeriph
Value: 0.576
Constant
 
   QSerumLiver
Value: 0.06
Constant
 
   QSerumGut
Value: 0.03
Constant
 
   QSerumPeriph
Value: 0.001
Constant
 
   kAbSerumToPeriph
Value: 3.47222222222222E-4
Constant
 
   kAbPeriphToSerum
Value: 0.00173611111111111
Constant
 
 kdegAb
Value: 0.0018
Constant
 
 Dose
Value: 300.0
Constant
 
 DoseQ2W
Constant
 
 Initial for CRP
Value: 221.06367608557
Constant
 
 Initial for DoseQ2W
Constant
 
 Initial for Dose
Value: 300.0
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000537

Curator's comment: (updated: 06 Aug 2014 16:42:23 GMT)

Figure 3a: Reduction of CRP from baseline with administration of Tocilizumab, an anti IL6-R antibody. Doses of 560 mg every 2 weeks and 4 weeks were simulated.
Simulated as two time courses, 2 weeks and 4 weeks. The antibody Kd was matched to Tocilizumab for this case (1 nmol/l).

Figure 4d: Concentration of serum IL6, gut IL6 serum CRP and Gut pSTAT3 with a monthly (672 h) 300 mg dose regimen of IL6-R antibody.
Simulated as a Time Course for 2016 h.

Figure 4e: Suppression of CRP by IL6-R antibody after 12 weeks of monthly (672 h) doses. Three separate Kd values were assessed: 2.5, 25 and 250 pmol/l.
Simulated with a two-paramater scan for Dose and Kd, Plotted using LibreCalc.

Figure 4f: IL6-R antibody concentration in serum for 200 and 500 mg doses administered monthly (672 hours).
Simulated as a parameter scan for Dose between 200 and 500 with 1 interval.

Figure 5b: Suppression of CRP after 12 weeks of varied
monthly (672 hours) doses. This simulation includes binding of the antibody to the ligand-receptor complex. Three separate Kd values were assessed: 2.5, 25 and 250 pmol/l.
Simulated with a two-paramater scan for Dose and Kd, Plotted using LibreCalc

Additional file(s)
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