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  <model id="MODEL1408050002" metaid="COPASI0" name="Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody">
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        <div class="dc:title">Dwivedi2014 - Crohns IL6 Disease model -
Anti-IL6R Antibody</div>
<div class="dc:description">This model is comprised of four models:
<br/>
<ul>
  <li>
  <a href="http://www.ebi.ac.uk/biomodels-main/BIOMD0000000534">[BIOMD0000000534]</a>
  Healthy Volunteer model
  <br/></li>
  <li>
  <a href="http://www.ebi.ac.uk/biomodels-main/BIOMD0000000535">[BIOMD0000000535]</a>
  Crohn's Disease - IL-6 Antibody
  <br/></li>
  <li>
  <a href="http://www.ebi.ac.uk/biomodels-main/BIOMD0000000536">[BIOMD0000000536]</a>
  Crohn's Disease - sgp130FC</li>
  <li>
  <a href="http://www.ebi.ac.uk/biomodels-main/BIOMD0000000537">[BIOMD0000000537]</a>
  Crohn's Disease - IL-6Ra Antibody
  <br/></li>
</ul>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.
<span class="st">This affects Signal Transducer and Activator of
Transcription 3</span> (STAT3) activity on the production of
biomarker C-Reactive Protein (CRP) expression.
<br/>Figures referring to this Crohn's Disease model are 3a, 4d,
4e, 4f and 5b.
<br/></div>
<div class="dc:bibliographicCitation">
  <p>This model is described in the article:</p>
  <div class="bibo:title">
    <a href="http://identifiers.org/pubmed/24402116" title="Access to this publication">A multiscale model of
    interleukin-6-mediated immune regulation in Crohn's disease and
    its application in drug discovery and development.</a>
  </div>
  <div class="bibo:authorList">Dwivedi G, Fitz L, Hegen M, Martin
  SW, Harrold J, Heatherington A, Li C.</div>
  <div class="bibo:Journal">CPT Pharmacometrics Syst Pharmacol
  2014; 3: e89</div>
  <p>Abstract:</p>
  <div class="bibo:abstract">
    <p>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 &amp; Systems Pharmacology
    (2014) 3, e89; doi:10.1038/psp.2013.64; advance online
    publication 8 January 2014.</p>
  </div>
</div>
<div class="dc:publisher">
  <p>This model is hosted on
  <a href="http://www.ebi.ac.uk/biomodels/">BioModels Database</a>
  and identified by:
  <a href="http://identifiers.org/biomodels.db/BIOMD0000000537">BIOMD0000000537</a>.</p>
  <p>To cite BioModels Database, please use:
  <a href="http://identifiers.org/pubmed/20587024" title="Latest BioModels Database publication">BioModels Database:
  An enhanced, curated and annotated resource for published
  quantitative kinetic models</a>.</p>
</div>
<div class="dc:license">
  <p>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
  <a href="http://creativecommons.org/publicdomain/zero/1.0/" title="Access to: CC0 1.0 Universal (CC0 1.0), Public Domain Dedication">CC0
  Public Domain Dedication</a> for more information.</p>
</div>
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              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw6f470e13_f0e4_4294_83d8_59dd5670d10c" metaid="_615fd0b9-8e52-4ba1-ae95-4c3e17bb0761" name="Function for mw6f470e13_f0e4_4294_83d8_59dd5670d10c_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kRdeg </ci>
            </bvar>
            <bvar>
              <ci> mw8c9107e6_f51d_442d_b2dc_2bfdbb8482ca </ci>
            </bvar>
            <bvar>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> kRdeg </ci>
                <ci> mw8c9107e6_f51d_442d_b2dc_2bfdbb8482ca </ci>
              </apply>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
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        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw6cce2109_0e32_4dd9_98ec_41173e8ef07d </ci>
            </bvar>
            <bvar>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </bvar>
            <bvar>
              <ci> mwf44f7f27_5bb1_4c7f_8964_560fa5e1743a </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> mwf44f7f27_5bb1_4c7f_8964_560fa5e1743a </ci>
                <ci> mw6cce2109_0e32_4dd9_98ec_41173e8ef07d </ci>
              </apply>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_reaction_1" metaid="_00c90f53-70fb-45ea-8490-5eb6706aaaae" name="Function for reaction_1_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kRLOff </ci>
            </bvar>
            <bvar>
              <ci> kRLOn </ci>
            </bvar>
            <bvar>
              <ci> mw03db56ac_8dc6_4931_ae82_fef706d2ee3d </ci>
            </bvar>
            <bvar>
              <ci> mw30ae63db_6cd3_4b6f_93ad_3350cd360bcc </ci>
            </bvar>
            <bvar>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </bvar>
            <bvar>
              <ci> mwf626e95e_543f_41e4_aad4_c6bf60ab345b </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> kRLOn </ci>
                  <ci> mw30ae63db_6cd3_4b6f_93ad_3350cd360bcc </ci>
                  <ci> mwf626e95e_543f_41e4_aad4_c6bf60ab345b </ci>
                </apply>
                <apply>
                  <times/>
                  <ci> kRLOff </ci>
                  <ci> mw03db56ac_8dc6_4931_ae82_fef706d2ee3d </ci>
                </apply>
              </apply>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mwa812f08f_1035_42bd_82d2_72d691308f88" metaid="_39b33ae7-ea1a-4c35-b2a5-0fb061909c87" name="Function for mwa812f08f_1035_42bd_82d2_72d691308f88_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kRLOff </ci>
            </bvar>
            <bvar>
              <ci> kRLOn </ci>
            </bvar>
            <bvar>
              <ci> mw0adf3eb4_a196_4c48_b10d_4e9e9faaf9e1 </ci>
            </bvar>
            <bvar>
              <ci> mw2e464cf3_a09c_4b7c_9f3c_06720016a48e </ci>
            </bvar>
            <bvar>
              <ci> mw4638f126_8cb8_4021_ab41_6ae195743ba0 </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> kRLOn </ci>
                  <ci> mw2e464cf3_a09c_4b7c_9f3c_06720016a48e </ci>
                  <ci> mw0adf3eb4_a196_4c48_b10d_4e9e9faaf9e1 </ci>
                </apply>
                <apply>
                  <times/>
                  <ci> kRLOff </ci>
                  <ci> mw4638f126_8cb8_4021_ab41_6ae195743ba0 </ci>
                </apply>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw8fb6c0a7_b05d_4c2a_8866_77eb81f063d1" metaid="cf3acdd7-45e9-481d-83f8-1e9178ddf1b6" name="Function for mw8fb6c0a7_b05d_4c2a_8866_77eb81f063d1_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead </ci>
            </bvar>
            <bvar>
              <ci> mw2e464cf3_a09c_4b7c_9f3c_06720016a48e </ci>
            </bvar>
            <bvar>
              <ci> mw3667a5e1_02c9_44a0_acb4_b0431faa822d </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <bvar>
              <ci> mwa09d6284_843e_404e_abbb_052fbb535197 </ci>
            </bvar>
            <bvar>
              <ci> mwf405687b_7401_44ec_a0d6_4a2b35c13e8a </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> mwa09d6284_843e_404e_abbb_052fbb535197 </ci>
                  <ci> mw3667a5e1_02c9_44a0_acb4_b0431faa822d </ci>
                  <ci> mw2e464cf3_a09c_4b7c_9f3c_06720016a48e </ci>
                </apply>
                <apply>
                  <times/>
                  <ci> mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead </ci>
                  <ci> mwf405687b_7401_44ec_a0d6_4a2b35c13e8a </ci>
                </apply>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mwab0012ac_e5f2_4904_9893_820fd210402e" metaid="ec28f7dd-6170-4524-aaa4-25a3dbee1aee" name="Function for mwab0012ac_e5f2_4904_9893_820fd210402e_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw862f1480_c60c_4863_a565_b2c1c77e238e </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <bvar>
              <ci> mwd5313618_89eb_4c8c_bc82_66f10f966349 </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> mw862f1480_c60c_4863_a565_b2c1c77e238e </ci>
                <ci> mwd5313618_89eb_4c8c_bc82_66f10f966349 </ci>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw30abb016_4300_4f40_a1b3_f865d0a45707" metaid="_57cfde3e-ad81-408c-84f8-0e30b931f5f9" name="Function for mw30abb016_4300_4f40_a1b3_f865d0a45707_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw1da111f2_a036_4392_8512_015005bdcbb7 </ci>
            </bvar>
            <bvar>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </bvar>
            <bvar>
              <ci> mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30 </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30 </ci>
                <ci> mw1da111f2_a036_4392_8512_015005bdcbb7 </ci>
              </apply>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw2ae288ab_7d03_4a84_a024_c711ad2b77e6" metaid="_7896d9c4-0b1f-4275-9f71-896e07ef6b9e" name="Function for mw2ae288ab_7d03_4a84_a024_c711ad2b77e6_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw3667a5e1_02c9_44a0_acb4_b0431faa822d </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <bvar>
              <ci> mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30 </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30 </ci>
                <ci> mw3667a5e1_02c9_44a0_acb4_b0431faa822d </ci>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw391f3b8e_5649_4851_b2e2_782cb3e015b6" metaid="_5e342cf6-c46d-46ad-8be4-6425d110a2e5" name="Function for mw391f3b8e_5649_4851_b2e2_782cb3e015b6_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kRsynth </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <apply>
              <divide/>
              <ci> kRsynth </ci>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_reaction_13" metaid="_4dc2a58a-35cc-4a2f-8918-c6a4a431aa8a" name="Function for reaction_13_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw0eb6c959_d408_45a0_a450_928b8c5876bb </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <bvar>
              <ci> mwf44f7f27_5bb1_4c7f_8964_560fa5e1743a </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> mwf44f7f27_5bb1_4c7f_8964_560fa5e1743a </ci>
                <ci> mw0eb6c959_d408_45a0_a450_928b8c5876bb </ci>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_reaction_6" metaid="af8caed7-fdb7-48aa-a9eb-9d458b2fd0f5" name="Function for reaction_6_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kgp130Off </ci>
            </bvar>
            <bvar>
              <ci> kgp130On </ci>
            </bvar>
            <bvar>
              <ci> mw4638f126_8cb8_4021_ab41_6ae195743ba0 </ci>
            </bvar>
            <bvar>
              <ci> mw80848184_e2dd_47ce_86d7_7a21479342bd </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <bvar>
              <ci> mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> kgp130On </ci>
                  <ci> mw4638f126_8cb8_4021_ab41_6ae195743ba0 </ci>
                  <ci> mw80848184_e2dd_47ce_86d7_7a21479342bd </ci>
                </apply>
                <apply>
                  <times/>
                  <ci> kgp130Off </ci>
                  <ci> mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a </ci>
                </apply>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw432fde6e_59ab_47f0_9fb1_086433a602e3" metaid="_74379726-c119-400d-bc83-bfaf97b609da" name="Function for mw432fde6e_59ab_47f0_9fb1_086433a602e3_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </bvar>
            <bvar>
              <ci> mwc4c58db7_5535_4590_aaa5_bbc8ed53cdab </ci>
            </bvar>
            <apply>
              <divide/>
              <ci> mwc4c58db7_5535_4590_aaa5_bbc8ed53cdab </ci>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw6b46c550_674f_4857_b947_d31221cd8dd3" metaid="ba03dd61-4cba-4afc-a991-3efb460852d5" name="Function for mw6b46c550_674f_4857_b947_d31221cd8dd3_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw10315fa3_6f13_4618_bda8_a8694bd3c374 </ci>
            </bvar>
            <bvar>
              <ci> mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead </ci>
            </bvar>
            <bvar>
              <ci> mw3667a5e1_02c9_44a0_acb4_b0431faa822d </ci>
            </bvar>
            <bvar>
              <ci> mw772cbf20_3fc1_4800_ae59_77884f1ae333 </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <bvar>
              <ci> mwa09d6284_843e_404e_abbb_052fbb535197 </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> mwa09d6284_843e_404e_abbb_052fbb535197 </ci>
                  <ci> mw3667a5e1_02c9_44a0_acb4_b0431faa822d </ci>
                  <ci> mw10315fa3_6f13_4618_bda8_a8694bd3c374 </ci>
                </apply>
                <apply>
                  <times/>
                  <ci> mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead </ci>
                  <ci> mw772cbf20_3fc1_4800_ae59_77884f1ae333 </ci>
                </apply>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw41c27823_d7ee_4554_9eac_3d5beec8e854" metaid="_676bd34a-eafd-4302-a61f-ce9d9376d743" name="Function for mw41c27823_d7ee_4554_9eac_3d5beec8e854_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw30ae63db_6cd3_4b6f_93ad_3350cd360bcc </ci>
            </bvar>
            <bvar>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </bvar>
            <bvar>
              <ci> mw88a75379_f9a1_4acc_baeb_94c32bb736a5 </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> mw88a75379_f9a1_4acc_baeb_94c32bb736a5 </ci>
                <ci> mw30ae63db_6cd3_4b6f_93ad_3350cd360bcc </ci>
              </apply>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_reaction_3" metaid="_5a4fc854-b8a0-49f3-b331-4f48a6377efc" name="Function for reaction_3_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kIL6Synth </ci>
            </bvar>
            <bvar>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </bvar>
            <apply>
              <divide/>
              <ci> kIL6Synth </ci>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_reaction_5" metaid="_264eb915-e864-48e5-84be-8a637a83dfa3" name="Function for reaction_5_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kCRPDecay </ci>
            </bvar>
            <bvar>
              <ci> mw114aa90f_5f5b_4fe8_9406_361c8489b6a1 </ci>
            </bvar>
            <bvar>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> kCRPDecay </ci>
                <ci> mw114aa90f_5f5b_4fe8_9406_361c8489b6a1 </ci>
              </apply>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mwba7f4605_8571_439b_b3ab_eb0b43808db8" metaid="_2ce5816a-00fb-4c9d-a988-1e91215e5b19" name="Function for mwba7f4605_8571_439b_b3ab_eb0b43808db8_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </bvar>
            <bvar>
              <ci> mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30 </ci>
            </bvar>
            <bvar>
              <ci> mwf345ed7a_0622_403c_b816_c8749a2c9ded </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30 </ci>
                <ci> mwf345ed7a_0622_403c_b816_c8749a2c9ded </ci>
              </apply>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw4c099d5c_200f_474e_8ec1_59e9223a8afd" metaid="_5d189da9-c10b-48c2-90e9-f52b4d0f56b0" name="Function for mw4c099d5c_200f_474e_8ec1_59e9223a8afd_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kRLOff </ci>
            </bvar>
            <bvar>
              <ci> kRLOn </ci>
            </bvar>
            <bvar>
              <ci> mw2c9b0499_3325_4394_8af3_bbf653a944a0 </ci>
            </bvar>
            <bvar>
              <ci> mw7becb5fe_8da8_4285_a821_0d77ad811b62 </ci>
            </bvar>
            <bvar>
              <ci> mwd31f52cc_04e7_40e0_885f_c7b2d9e62215 </ci>
            </bvar>
            <bvar>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> kRLOn </ci>
                  <ci> mwd31f52cc_04e7_40e0_885f_c7b2d9e62215 </ci>
                  <ci> mw2c9b0499_3325_4394_8af3_bbf653a944a0 </ci>
                </apply>
                <apply>
                  <times/>
                  <ci> kRLOff </ci>
                  <ci> mw7becb5fe_8da8_4285_a821_0d77ad811b62 </ci>
                </apply>
              </apply>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_reaction_14" metaid="a271a718-a040-43db-8459-82d739c2e9c3" name="Function for reaction_14_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kRsynth </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <apply>
              <divide/>
              <ci> kRsynth </ci>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw3e76b10b_5420_4828_8c70_b91b767132d0" metaid="_88f6f2b2-4067-4def-bece-7f743547a10e" name="Function for mw3e76b10b_5420_4828_8c70_b91b767132d0_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <bvar>
              <ci> mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30 </ci>
            </bvar>
            <bvar>
              <ci> mwf405687b_7401_44ec_a0d6_4a2b35c13e8a </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30 </ci>
                <ci> mwf405687b_7401_44ec_a0d6_4a2b35c13e8a </ci>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_reaction_4" metaid="_86a3c339-d0aa-421c-8022-d5efb6715ec4" name="Function for reaction_4_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kIL6Decay </ci>
            </bvar>
            <bvar>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </bvar>
            <bvar>
              <ci> mwf626e95e_543f_41e4_aad4_c6bf60ab345b </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> kIL6Decay </ci>
                <ci> mwf626e95e_543f_41e4_aad4_c6bf60ab345b </ci>
              </apply>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mwb1879013_5fcd_490c_8b01_eaf84df15b9a" metaid="d890dc96-c5f0-4fa8-b66a-2c6bd4d5b622" name="Function for mwb1879013_5fcd_490c_8b01_eaf84df15b9a_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead </ci>
            </bvar>
            <bvar>
              <ci> mw1da111f2_a036_4392_8512_015005bdcbb7 </ci>
            </bvar>
            <bvar>
              <ci> mw30ae63db_6cd3_4b6f_93ad_3350cd360bcc </ci>
            </bvar>
            <bvar>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </bvar>
            <bvar>
              <ci> mwa09d6284_843e_404e_abbb_052fbb535197 </ci>
            </bvar>
            <bvar>
              <ci> mwf345ed7a_0622_403c_b816_c8749a2c9ded </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> mwa09d6284_843e_404e_abbb_052fbb535197 </ci>
                  <ci> mwf345ed7a_0622_403c_b816_c8749a2c9ded </ci>
                  <ci> mw30ae63db_6cd3_4b6f_93ad_3350cd360bcc </ci>
                </apply>
                <apply>
                  <times/>
                  <ci> mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead </ci>
                  <ci> mw1da111f2_a036_4392_8512_015005bdcbb7 </ci>
                </apply>
              </apply>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw71d90b81_8211_4039_8807_12a7fe03206c" metaid="d1811b2e-6a96-4dc8-9dae-92376f522126" name="Function for mw71d90b81_8211_4039_8807_12a7fe03206c_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw114aa90f_5f5b_4fe8_9406_361c8489b6a1 </ci>
            </bvar>
            <bvar>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </bvar>
            <bvar>
              <ci> mw5832a2dc_ee18_44df_aa59_ccb21cb74df2 </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> mw5832a2dc_ee18_44df_aa59_ccb21cb74df2 </ci>
                <ci> mw114aa90f_5f5b_4fe8_9406_361c8489b6a1 </ci>
              </apply>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_reaction_44" metaid="_757d37a2-d334-4cfd-900e-7ffd7933be3b" name="Function for reaction_44_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kRint </ci>
            </bvar>
            <bvar>
              <ci> mw824bc3d4_1ac3_4912_9b51_8f14ff1c96b9 </ci>
            </bvar>
            <bvar>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> kRint </ci>
                <ci> mw824bc3d4_1ac3_4912_9b51_8f14ff1c96b9 </ci>
              </apply>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_reaction_11" metaid="_88fafa25-038c-4257-bec6-9909e92b9bc7" name="Function for reaction_11_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kRint </ci>
            </bvar>
            <bvar>
              <ci> mw7d86cc23_a1af_44c3_bdb9_71e9b1bb2a83 </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> kRint </ci>
                <ci> mw7d86cc23_a1af_44c3_bdb9_71e9b1bb2a83 </ci>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw64df7c9e_35da_4c7f_be56_c5dabfb060b6" metaid="_0f18965c-a7d2-472c-8769-378ea0bdcc6e" name="Function for mw64df7c9e_35da_4c7f_be56_c5dabfb060b6_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw1667a8e0_9d20_4e59_ba51_596148aba787 </ci>
            </bvar>
            <bvar>
              <ci> mw6cce2109_0e32_4dd9_98ec_41173e8ef07d </ci>
            </bvar>
            <bvar>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </bvar>
            <bvar>
              <ci> mwfcf06900_5f2f_4bb3_bb1f_12023612b8a8 </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <divide/>
                <apply>
                  <times/>
                  <ci> mw1667a8e0_9d20_4e59_ba51_596148aba787 </ci>
                  <ci> mw6cce2109_0e32_4dd9_98ec_41173e8ef07d </ci>
                </apply>
                <apply>
                  <plus/>
                  <ci> mwfcf06900_5f2f_4bb3_bb1f_12023612b8a8 </ci>
                  <ci> mw6cce2109_0e32_4dd9_98ec_41173e8ef07d </ci>
                </apply>
              </apply>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_reaction_10" metaid="_39364dd0-8e3f-4680-a053-5cd8c30c4b53" name="Function for reaction_10_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw39c2e431_fdc3_4964_be29_6ca856620b1b </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <bvar>
              <ci> mwd36b0261_2480_4cab_9222_2cf8fb0e65dc </ci>
            </bvar>
            <bvar>
              <ci> mwfd291862_195f_4979_94b5_b4e5ae1b7d52 </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <divide/>
                <apply>
                  <times/>
                  <ci> mwd36b0261_2480_4cab_9222_2cf8fb0e65dc </ci>
                  <ci> mw39c2e431_fdc3_4964_be29_6ca856620b1b </ci>
                </apply>
                <apply>
                  <plus/>
                  <ci> mwfd291862_195f_4979_94b5_b4e5ae1b7d52 </ci>
                  <ci> mw39c2e431_fdc3_4964_be29_6ca856620b1b </ci>
                </apply>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mwa3cb4a9b_d628_4807_8847_bdcd9b40c7f1" metaid="_25b3c4a5-2c77-4211-a740-ea4a94a88d9e" name="Function for mwa3cb4a9b_d628_4807_8847_bdcd9b40c7f1_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead </ci>
            </bvar>
            <bvar>
              <ci> mw5d764bb8_5693_4ac8_9557_f65992cc5eb0 </ci>
            </bvar>
            <bvar>
              <ci> mwa09d6284_843e_404e_abbb_052fbb535197 </ci>
            </bvar>
            <bvar>
              <ci> mwd31f52cc_04e7_40e0_885f_c7b2d9e62215 </ci>
            </bvar>
            <bvar>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </bvar>
            <bvar>
              <ci> mwf7796221_1fea_4274_a93e_c00adbf5778c </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> mwa09d6284_843e_404e_abbb_052fbb535197 </ci>
                  <ci> mwf7796221_1fea_4274_a93e_c00adbf5778c </ci>
                  <ci> mwd31f52cc_04e7_40e0_885f_c7b2d9e62215 </ci>
                </apply>
                <apply>
                  <times/>
                  <ci> mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead </ci>
                  <ci> mw5d764bb8_5693_4ac8_9557_f65992cc5eb0 </ci>
                </apply>
              </apply>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_reaction_9" metaid="d39917a8-ad62-4f97-8ed0-ba160ae512e3" name="Function for reaction_9_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw0eb6c959_d408_45a0_a450_928b8c5876bb </ci>
            </bvar>
            <bvar>
              <ci> mw42054cd7_17af_46da_970c_7f99151906ad </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <bvar>
              <ci> mw9442cd0e_4d7c_4ba6_a695_f84919bdf569 </ci>
            </bvar>
            <bvar>
              <ci> mwe8fc1900_f07d_468b_b5c8_15400a583c3d </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <divide/>
                <apply>
                  <times/>
                  <ci> mw9442cd0e_4d7c_4ba6_a695_f84919bdf569 </ci>
                  <ci> mw0eb6c959_d408_45a0_a450_928b8c5876bb </ci>
                  <ci> mw42054cd7_17af_46da_970c_7f99151906ad </ci>
                </apply>
                <apply>
                  <plus/>
                  <ci> mwe8fc1900_f07d_468b_b5c8_15400a583c3d </ci>
                  <ci> mw42054cd7_17af_46da_970c_7f99151906ad </ci>
                </apply>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mwb6a99eb5_ea4c_4733_98dd_1daf5ec6b0db" metaid="_68cfa6fe-07dc-47bf-b783-3928c960b136" name="Function for mwb6a99eb5_ea4c_4733_98dd_1daf5ec6b0db_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </bvar>
            <bvar>
              <ci> mwbbbce920_e8dd_4320_9386_fc94bfb2fc99 </ci>
            </bvar>
            <bvar>
              <ci> mwbcb5a310_9b67_405e_89ec_43d25e8cc93d </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> mwbcb5a310_9b67_405e_89ec_43d25e8cc93d </ci>
                <ci> mwbbbce920_e8dd_4320_9386_fc94bfb2fc99 </ci>
              </apply>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw920e142e_b2c4_42b2_88f4_9f68cc50142e" metaid="d40fabc1-96ad-4235-920f-d0874ee580ce" name="Function for mw920e142e_b2c4_42b2_88f4_9f68cc50142e_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw772cbf20_3fc1_4800_ae59_77884f1ae333 </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <bvar>
              <ci> mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30 </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <times/>
                <ci> mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30 </ci>
                <ci> mw772cbf20_3fc1_4800_ae59_77884f1ae333 </ci>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_reaction_8" metaid="_68d9ddc0-02ec-496f-b215-f5ae8f6fafac" name="Function for reaction_8_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kgp130Off </ci>
            </bvar>
            <bvar>
              <ci> kgp130On </ci>
            </bvar>
            <bvar>
              <ci> mw7d86cc23_a1af_44c3_bdb9_71e9b1bb2a83 </ci>
            </bvar>
            <bvar>
              <ci> mw80848184_e2dd_47ce_86d7_7a21479342bd </ci>
            </bvar>
            <bvar>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </bvar>
            <bvar>
              <ci> mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a </ci>
            </bvar>
            <apply>
              <divide/>
              <apply>
                <minus/>
                <apply>
                  <times/>
                  <ci> kgp130On </ci>
                  <ci> mw7d86cc23_a1af_44c3_bdb9_71e9b1bb2a83 </ci>
                  <ci> mw80848184_e2dd_47ce_86d7_7a21479342bd </ci>
                </apply>
                <apply>
                  <times/>
                  <ci> kgp130Off </ci>
                  <ci> mwd2d9d93a_3bd1_4f17_bac1_baba9ef2d55a </ci>
                </apply>
              </apply>
              <ci> mw88ca8d9a_f5cf_41bf_9d9d_fc48f6e1a19e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw50c6744c_e883_4612_8663_e38750cbad1b" metaid="_1f817eb2-bd3c-406b-be73-396a54366d49" name="Function for mw50c6744c_e883_4612_8663_e38750cbad1b_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> mw1f41474c_c399_4a60_a53a_9926dd092e8d </ci>
            </bvar>
            <bvar>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </bvar>
            <apply>
              <divide/>
              <ci> mw1f41474c_c399_4a60_a53a_9926dd092e8d </ci>
              <ci> mw53ffe9e6_beef_45c4_90a5_a79197ed506e </ci>
            </apply>
          </lambda>
        </math>
            </functionDefinition>
      <functionDefinition id="Function_for_mw8be158f1_ea81_45bf_80d4_6e31cd83fe6c" metaid="a7a05cd6-14b9-4733-9cd3-739603bfb3cf" name="Function for mw8be158f1_ea81_45bf_80d4_6e31cd83fe6c_2_3_2">
        <math xmlns="http://www.w3.org/1998/Math/MathML">
          <lambda>
            <bvar>
              <ci> kgp130Off </ci>
            </bvar>
            <bvar>
              <ci> kgp130On </ci>
            </bvar>
            <bvar>
              <ci> mw6335d5d7_c7b0_4bc0_b883_f7ee4915c2c3 </ci>
            </bvar>
            <bvar>
              <ci> mw7becb5fe_8da8_4285_a821_0d77ad811b62 </ci>
            </bvar>
            <bvar>
              <ci> mwd65b5b39_dc1b_4e77_a999_67277a880e5e </ci>
            </bvar>
            <bvar>
              <ci> mwe9501423_9fb4_494b_b5b6_288f3fcb17b5 </ci>
            </bvar>
            <apply>
              <divide/>
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	<rdf:Bag>
	<rdf:li rdf:resource="http://identifiers.org/uniprot/P08887"/>
	<rdf:li rdf:resource="http://identifiers.org/uniprot/P05231"/>
	<rdf:li rdf:resource="http://identifiers.org/fma/FMA:62871"/>
	</rdf:Bag>
	</bqbiol:hasProperty>
	</rdf:Description>




	</rdf:RDF>
	</annotation>
            </species>
      <species boundaryCondition="false" compartment="mw8fbcbf3b_47d8_4adc_8ad4_f9fc547d3e87" constant="false" hasOnlySubstanceUnits="false" id="mwbc2f5464_81e5_43fd_8b39_f5a2756af72f" initialConcentration="1.67920947537896E-29" metaid="_5033b57a-1aea-4ac3-949d-117345b532a9" name="Ab">
        <annotation>
	<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/">
            <rdf:Description rdf:about="#_5033b57a-1aea-4ac3-949d-117345b532a9">
	<bqbiol:isVersionOf>
	<rdf:Bag>
	<rdf:li rdf:resource="http://identifiers.org/fma/FMA:62871"/>
	</rdf:Bag>
	</bqbiol:isVersionOf>
	</rdf:Description>




	</rdf:RDF>
	</annotation>
            </species>
    </listOfSpecies>
    <listOfParameters>
      <parameter constant="true" id="kRLOn" metaid="_790adc1c-b6df-4b58-a198-c6ceee0fb7a0" name="kRLOn" value="0.384"/>
      <parameter constant="true" id="kRLOff" metaid="dd718da0-31cc-457a-a53d-d85476793aa7" name="kRLOff" value="1.92"/>
      <parameter constant="true" id="kgp130On" metaid="COPASI20" name="kgp130On" value="20.52">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI20">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-31T13:31:31Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="kgp130Off" metaid="_3f0b2d38-3124-41c8-aaba-404353abe42c" name="kgp130Off" value="1.026">
        <notes>
          <body xmlns="http://www.w3.org/1999/xhtml">1/hr
Kd = 50 pM
</body>
        </notes>
      </parameter>
      <parameter constant="true" id="kRAct" metaid="f8083c11-841a-4b49-9e5f-5af683f3fda1" name="kRAct" value="155"/>
      <parameter constant="true" id="kRint" metaid="COPASI21" name="kRint" value="1.96">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI21">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-31T13:31:33Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="kRsynth" metaid="_6bedd423-d7f6-4969-975b-4f274b9b504b" name="kRsynth" value="0.0685">
        <notes>
          <body xmlns="http://www.w3.org/1999/xhtml">nM/hr

Estimated at 115 receptor/cell/hr using the receptor model for HepG2 cells. With HepG2 cell volume of 2.8 pL/cell, this translates to 0.0685 nM/hr. Since this rate in terms of concentration is independent of cell volume, it can be used directly for cells with different volumes but similar receptor dynamics.</body>
        </notes>
      </parameter>
      <parameter constant="true" id="kRdeg" metaid="d23fb4f0-d5c9-47ff-a315-b7c4fdddbbef" name="kRintBasal" value="0.1561"/>
      <parameter constant="true" id="kIL6Synth" metaid="_630f42df-0dbd-4384-82ac-4829ecdd4c9f" name="ksynthIL6" value="0.0063"/>
      <parameter constant="true" id="kIL6Decay" metaid="bd84a2bb-0490-497e-8fc0-0b2b4ede0e90" name="kdegIL6" value="34.82">
        <notes>
          <body xmlns="http://www.w3.org/1999/xhtml">1/hr

Estimated from drug PK models</body>
        </notes>
      </parameter>
      <parameter constant="true" id="kCRPDecay" metaid="f1a0ac48-ba12-44f2-8acd-f90cc876ccd6" name="kdegCRP" value="0.36"/>
      <parameter constant="true" id="mwfd291862_195f_4979_94b5_b4e5ae1b7d52" metaid="aea80b8c-dc31-40f9-92fb-ce983326a5fa" name="KmSTATDephos" value="5.34"/>
      <parameter constant="true" id="mwd36b0261_2480_4cab_9222_2cf8fb0e65dc" metaid="COPASI8" name="VmSTATDephos" value="0.62">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI8">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-18T13:02:16Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="mw1667a8e0_9d20_4e59_ba51_596148aba787" metaid="COPASI9" name="VmRDephos" value="0.525">
        <notes>
          <body xmlns="http://www.w3.org/1999/xhtml">18 nM/hr</body>
        </notes>
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI9">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-18T13:02:16Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="mwfcf06900_5f2f_4bb3_bb1f_12023612b8a8" metaid="COPASI22" name="KmRDephos" value="155.3">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI22">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-31T13:31:32Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="mw9442cd0e_4d7c_4ba6_a695_f84919bdf569" metaid="_00edacba-ef75-4ea0-b343-c59f0c33d7d0" name="kcatSTATPhos" value="145">
        <notes>
          <body xmlns="http://www.w3.org/1999/xhtml">1/hr</body>
        </notes>
      </parameter>
      <parameter constant="true" id="mwe8fc1900_f07d_468b_b5c8_15400a583c3d" metaid="_6b969820-3bb4-42f7-9cfd-47c0477fb2c8" name="KmSTATPhos" value="219"/>
      <parameter constant="true" id="mw08950572_81b0_4570_b2e4_b9c3462c1425" metaid="_2f0eb01e-cd22-476b-8554-c38b7c275b76" name="KmProtSynth" value="10"/>
      <parameter constant="true" id="mw92d854a7_8aaf_458e_b5e2_20a63ce9b654" metaid="_4b49e821-b981-4ac6-a054-d6f775669f14" name="VmProtSynth" value="330">
        <notes>
          <body xmlns="http://www.w3.org/1999/xhtml">nM

Commonly used model of protein synthesis:
mRNA: dm/dt = Sm*TF/(C + TF) - Dm*m
Protein: dn/dt = Sn*m - Dn*n
Solving for st. st: n(ss) = (Sn/Dn)*(Sm/Dm)*TF/(C+TF)
VmProtSynth = (Sn/Dn)*(Sm/Dm) = 4875000
KmProtSynth = C = 108
The parameters are obtained from Moya et al. (2010), who estimate these parameters for IL6 signaling.
The actual value used may be different, as it was optimized to fit the data
</body>
        </notes>
      </parameter>
      <parameter constant="true" id="mw862f1480_c60c_4863_a565_b2c1c77e238e" metaid="b9c3e94f-bb42-47c4-8ea0-1154c5e43e83" name="kCRPSecretion" value="0.5"/>
      <parameter constant="true" id="mw65c85954_5ca0_4df2_9e22_ff2aa3fbe3f1" metaid="_46e3992d-7949-4981-bf3c-f6168103259d" name="ksynthCRP" value="0.42"/>
      <parameter constant="true" id="mwc4c58db7_5535_4590_aaa5_bbc8ed53cdab" metaid="_409d0e2d-d25e-48c5-8530-829d8b9c92ee" name="ksynthsR" value="0.1"/>
      <parameter constant="true" id="mw88a75379_f9a1_4acc_baeb_94c32bb736a5" metaid="COPASI23" name="kdegsR" value="0.3">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI23">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-31T13:31:30Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="mw1f41474c_c399_4a60_a53a_9926dd092e8d" metaid="_6e4a5416-55a9-48ea-b399-889d60aa1ce2" name="ksynthsgp130" value="3.9"/>
      <parameter constant="true" id="mwbcb5a310_9b67_405e_89ec_43d25e8cc93d" metaid="_1f7c069c-a3aa-47c6-ad57-894c3ae124a4" name="kdegsgp130" value="1"/>
      <parameter constant="true" id="mwa8d72918_f6c2_4d81_bf3b_fc2b464d5e69" metaid="cec5491d-d5f9-4125-90ea-1803cc4a27a0" name="ksynthIL6Gut" value="0.036"/>
      <parameter constant="true" id="mw06241335_b5f2_47ed_bdcc_ef77b68a2b98" metaid="COPASI24" name="kdegIL6Gut" value="1">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI24">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-31T13:31:28Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="mwce10678d_8197_408c_ad47_1daec8104cd8" metaid="COPASI25" name="kdistTissueToSerum" value="0.8473">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI25">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-31T13:31:31Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="mwc67e1333_079a_4bea_9b4f_0a1b15ddd7bb" metaid="_62e69a40-871d-4903-a6cf-258b9a86c95d" name="kdistSerumToTissue" value="1.2125"/>
      <parameter constant="true" id="mw5832a2dc_ee18_44df_aa59_ccb21cb74df2" metaid="_2606d4ac-091d-4cf0-ac7f-b09892c645a6" name="kRShedding" value="0.0054">
        <notes>
          <body xmlns="http://www.w3.org/1999/xhtml">1/hr

Slow receptor shedding driven by CRP. The parameter has been calculated, along with the basal sR synthesis rate, to get
sR = 1.6, when CRP = 40 (HV); and
sR = 2.8, when CRP = 2000 (CD).</body>
        </notes>
      </parameter>
      <parameter constant="true" id="mwf44f7f27_5bb1_4c7f_8964_560fa5e1743a" metaid="afea207b-5bff-4a0a-8c24-1b0a00843153" name="kintActiveR" value="0.01"/>
      <parameter constant="true" id="mwa09d6284_843e_404e_abbb_052fbb535197" metaid="COPASI26" name="kIL6RBind" value="1000">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI26">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-31T13:32:02Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="mw1c4bc9c3_52ad_4ef7_bf7f_97b0e2101ead" metaid="COPASI10" name="kIL6RUnbind" value="2.5">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI10">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-18T11:24:13Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="mwdc9e2eb7_c8f4_4026_a8d0_eff8ce1f1aea" metaid="COPASI11" name="infusionTime" value="1">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI11">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-18T11:08:30Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="mw640ca705_e089_4c64_a5f4_9562317e8c76" metaid="_6f2825e7-74ec-4166-ad69-7c91a2186a46" name="kAbSerumToLiver" value="0.0208333333333333"/>
      <parameter constant="true" id="mw43ccad8c_cabf_4eaf_90d5_e06ae43be2cb" metaid="_503f6678-9dbc-439f-8fc6-f0ae3238ae6a" name="kAbLiverToSerum" value="0.0208333333333333"/>
      <parameter constant="true" id="mw9f83bdd3_3aa1_47ff_abd6_54e5ce60704a" metaid="_226bc315-e93b-4744-b983-7ea37fd0d498" name="kAbSerumToGut" value="0.0104166666666667"/>
      <parameter constant="true" id="mwa071fdbe_d498_4620_a7a4_940aa31c8161" metaid="cea2b804-83ec-4b9f-999b-4f7eebb4fffa" name="kAbGutToSerum" value="0.0208333333333333"/>
      <parameter constant="true" id="mw2c605ff5_50f5_45f2_a70c_53fcd866d14c" metaid="_8635607f-1f0f-4b29-b182-1b8b2618664b" name="VSerum" value="2.88"/>
      <parameter constant="true" id="mwc691d0d1_8c1b_4ce4_85c6_1315c42e97b1" metaid="COPASI35" name="VLiver" value="2.88">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI35">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-08-01T12:26:51Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="mwa8283449_0e21_41a1_baac_ebf697b3555a" metaid="_98bb6fb4-6db9-496d-9e83-0e16d2df2c09" name="VGut" value="1.44"/>
      <parameter constant="true" id="mw6729db10_c577_4319_b355_2e3f11c0f942" metaid="COPASI12" name="VPeriph" value="0.576">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI12">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-18T13:02:16Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="mw434adaf5_cef0_4a33_9ad2_a4e49e1fd825" metaid="c2b0653e-a5a0-4c31-a300-c4233112b4c6" name="QSerumLiver" value="0.06"/>
      <parameter constant="true" id="mw6a5e10a9_d442_4dde_8ec3_6a26c9807374" metaid="f00b1d3b-d7f3-4d48-b3a5-f0aab5091b9e" name="QSerumGut" value="0.03"/>
      <parameter constant="true" id="mw1366c3b5_e79b_44a7_93cc_ee09d383eabf" metaid="e60d7eed-835d-47bb-92ee-4dd672f7bf49" name="QSerumPeriph" value="0.001"/>
      <parameter constant="true" id="mwf67caf9d_2f4b_4986_abf2_e6090bbb72ce" metaid="_91a456c6-4d10-4533-aa82-48012e118832" name="kAbSerumToPeriph" value="0.000347222222222222"/>
      <parameter constant="true" id="mw4aea26f6_8860_414c_97f5_40d325196f2e" metaid="_25163ec7-6064-492d-a3cf-b811479b2b4c" name="kAbPeriphToSerum" value="0.00173611111111111"/>
      <parameter constant="true" id="mwbd1d5bc3_d4b9_4aec_9b86_6f776da20a30" metaid="COPASI27" name="kdegAb" value="0.0018">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI27">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-31T13:32:07Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="Dose" metaid="COPASI13" name="Dose" value="300">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI13">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-07-18T11:08:44Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="parameter_1" metaid="COPASI31" name="DoseQ2W" value="0">
        <annotation>
          <COPASI xmlns="http://www.copasi.org/static/sbml">
            <rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
              <rdf:Description rdf:about="#COPASI31">
                <dcterms:created>
                  <rdf:Description>
                    <dcterms:W3CDTF>2014-08-01T12:08:30Z</dcterms:W3CDTF>
                  </rdf:Description>
                </dcterms:created>
              </rdf:Description>
            </rdf:RDF>
          </COPASI>
        </annotation>
            </parameter>
      <parameter constant="true" id="Metabolite_40" metaid="c6e9ae6a-4aa8-48ba-a6b3-689d980fd79e" name="Initial for CRP" value="221.06367608557">
        <annotation>
          <initialValue xmlns="http://copasi.org/initialValue" parent="mw114aa90f_5f5b_4fe8_9406_361c8489b6a1"/>
        </annotation>
            </parameter>
      <parameter constant="true" id="ModelValue_99" metaid="_31615893-c28b-4b9f-9ed6-0040fbda332d" name="Initial for DoseQ2W" value="0">
        <annotation>
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