Rendering of the source text

<?xml version="1.0"?>
<!--  FILE :  cui_2008.xml

CREATED :  12th May 2008

LAST MODIFIED : 12th May 2008

AUTHOR :  Catherine Lloyd
          Bioengineering Institute
          The University of Auckland
          
MODEL STATUS :  This model conforms to the CellML 1.1 Specification.

DESCRIPTION :  This file contains a CellML description of Cui and Kaandorp's 2008 mathematical model of the calcium-calcineurin signalling network in cardiac myocytes.

CHANGES:  
  
--><model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" cmeta:id="cui_2008" name="cui_2008">

<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
  <articleinfo>
  <title>Modelling the calcium-calcineurin signalling network in cardiac myocytes</title>
  <author>
    <firstname>Catherine</firstname>
          <surname>Lloyd</surname>
    <affiliation>
      <shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
    </affiliation>
  </author>
</articleinfo>
  <section id="sec_status">
    <title>Model Status</title>
    <para>
        This CellML model runs in both PCEnv and COR to recreate the published results.  The units have been checked and they are consistent.
          </para>
  </section>
  <sect1 id="sec_structure">
<title>Model Structure</title>

<para>
ABSTRACT: Understanding of processes in which calcium signaling is involved is of fundamental importance in systems biology and has many applications in medicine. In this paper we have studied the particular case of the complex calcium-calcineurin-MCIP-NFAT signaling network in cardiac myocytes, the understanding of which is critical for treatment of pathologic hypertrophy and heart failure. By including some most recent experimental </para>

<para>
In 2006, Shin <emphasis>et al.</emphasis> published a paper which modelled the dual role of MCIP in cardiac hypertrophy.  In the study described here, Cui and Kaandorp have extended this model to include more recent and extensive experimental data.  They used <ulink url="http://www.cellerator.org/">Cellerator</ulink>, an open source software, to automatically generate the equations, and the model was subsequently translated into CellML to facilitate future model exchange, reuse and implementation. 
</para>

<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
  <imageobject>
    <objectinfo>
      <title>model diagram</title>
    </objectinfo>
    <imagedata fileref="cui_calcium_2008.png"/>
  </imageobject>
</mediaobject>
<caption>A schematic diagram of the Ca2+-calcineurin-MCIP-NFAT signalling networks in cardiac myocytes described by the model. Abbreviations: calmodulin (CaM); calcineurin (CaN); activated calcineurin (CaN*); nuclear factor of activated T-cells (NFAT); phosphorylated NFAT (NFATP); modulatory calcineurin-interacting protein (MCIP); phosphorylated MCIP on serine 112 (MCIPP); phosphorylated MCIP on both serine 112 and serine 108 (MCIPPP); big mitogen-activated protein kinase 1 (BMK1); glycogen synthase 3</caption>
</informalfigure>

<para>
The original book chapter reference is cited below:
</para>

<para>
Simulating Complex Calcium-Calcineurin Signaling Network, Jiangjun Cui and Jaap A. Kaandorp, 2008,
            <emphasis>Lecture Notes in Computer Science</emphasis>, 5013, 110-119, <ulink url="http://www.ncbi.nlm.nih.gov/pubmed/16445978">PubMed ID: 16445978</ulink>.
</para>

</sect1>
</article>
</documentation> 

  
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  </units>
  
  <units name="micromolar">
    <unit prefix="nano" units="mole"/>
    <unit exponent="-1" units="litre"/>
  </units>

  <units name="flux">
    <unit units="micromolar"/>
    <unit exponent="-1" units="minute"/>
  </units>

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  </units>

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    <unit exponent="-1" units="minute"/>
  </units>
   

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  </component>
  

  <!-- substrates : enzymes, reactants and products -->
  
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    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
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        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">BMK1</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">big mitogen-activated protein kinase 1</dcterms:alternative>
      </rdf:Description>
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      <rdf:Description rdf:about="#MRNA">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">MRNA</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">MCIP mRNA</dcterms:alternative>
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        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">NFATc</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">cytosolic NFAT</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
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        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">NFATn</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">nuclear NFAT</dcterms:alternative>
      </rdf:Description>
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        </apply> 
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    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
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        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">NFATpc</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">cytosolic NFATp</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
    <variable cmeta:id="NFATpc_NFATpc" initial_value="4.94E-3" name="NFATpc" public_interface="out" units="micromolar"/>
    
    <variable name="v2" public_interface="in" units="flux"/>
    <variable name="v9" public_interface="in" units="flux"/>
    <variable name="v14" public_interface="in" units="flux"/> 
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            <ci>time</ci>
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      <rdf:Description rdf:about="#NFATpn">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">NFATpn</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">nuclear NFATp</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
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    <variable name="v2" public_interface="in" units="flux"/>
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    <variable name="v17" public_interface="in" units="flux"/> 
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            <ci>time</ci>
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          <ci>NFATpn</ci> 
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            <plus/>
            <ci>v2</ci>
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          </apply>
        </apply> 
      </apply> 
    </math>  
  </component>

  <component cmeta:id="GSK3betac" name="GSK3betac">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#GSK3betac">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">GSK3betac</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">cytosolic glycogen synthase 3-beta</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
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    <variable name="v3" public_interface="in" units="flux"/>
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    <variable name="v12b" public_interface="in" units="flux"/>
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    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
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          <ci>GSK3betac</ci> 
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            <plus/>
            <ci>v12b</ci>
            <ci>v15b</ci>
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            <plus/>
            <ci>v3</ci>
            <ci>v12a</ci>
            <ci>v15a</ci>
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        </apply> 
      </apply> 
    </math>  
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  <component cmeta:id="GSK3betan" name="GSK3betan">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#GSK3betan">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">GSK3betan</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">nuclear glycogen synthase 3-beta</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
    <variable cmeta:id="GSK3betan_GSK3betan" initial_value="0.339" name="GSK3betan" public_interface="out" units="micromolar"/>
    
    <variable name="v3" public_interface="in" units="flux"/>
    <variable name="v17a" public_interface="in" units="flux"/>
    <variable name="v17b" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
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            <ci>time</ci>
          </bvar> 
          <ci>GSK3betan</ci> 
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          <minus/>
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            <plus/>
            <ci>v3</ci>
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          <ci>v17a</ci>
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      </apply> 
    </math>  
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    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#CaNc">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">CaNc</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">cytosolic inactive calcineurin</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
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    <variable name="v6" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
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            <ci>time</ci>
          </bvar> 
          <ci>CaNc</ci> 
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          <minus/>
          <ci>v6</ci>
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      </apply> 
    </math>  
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    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#CaNc_star">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">CaNc_star</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">cytosolic activated calcineurin</dcterms:alternative>
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          <ci>CaNc_star</ci> 
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            <ci>v6</ci>
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            <ci>v13b</ci>
            <ci>v14b</ci>
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            <ci>v7</ci>
            <ci>v11a</ci>
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        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">CaNn_star</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">nuclear activated calcineurin</dcterms:alternative>
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        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">CaNn</dc:title>
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    <variable name="v6" public_interface="in" units="flux"/>
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      <rdf:Description rdf:about="#CaM">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">CaM</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">calmodulin</dcterms:alternative>
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        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">CaMCa</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">calcium-calmodulin complex</dcterms:alternative>
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    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
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          <bvar>
            <ci>time</ci>
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          <ci>CaMCa</ci> 
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          <minus/>
          <ci>v5</ci>
          <ci>v6</ci>
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  <component cmeta:id="MCIP" name="MCIP">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#MCIP">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">MCIP</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">modulatory calcineurin-interacting protein</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
    <variable initial_value="2.15E-4" name="MCIP" public_interface="out" units="micromolar"/>
    
    <variable name="v7" public_interface="in" units="flux"/>
    <variable name="v10" public_interface="in" units="flux"/> 
    <variable name="v11" public_interface="in" units="flux"/>
    <variable name="v19" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>MCIP</ci> 
        </apply>
        <apply>
          <minus/>
          <ci>v11</ci>
          <apply>
            <plus/>
            <ci>v7</ci>
            <ci>v10</ci>
            <ci>v19</ci>
          </apply>
        </apply> 
      </apply> 
    </math>  
  </component>

  <component cmeta:id="MCIPp" name="MCIPp">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#MCIPp">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">MCIPp</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">phosphorylated MCIP on serine 112</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
    <variable initial_value="7.76E-3" name="MCIPp" public_interface="out" units="micromolar"/>
    
    <variable name="v10" public_interface="in" units="flux"/>
    <variable name="v11" public_interface="in" units="flux"/> 
    <variable name="v12" public_interface="in" units="flux"/> 
    <variable name="v13" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>MCIPp</ci> 
        </apply>
        <apply>
          <minus/>
          <apply>
            <plus/>
            <ci>v10</ci>
            <ci>v13</ci>
          </apply>
          <apply>
            <plus/>
            <ci>v11</ci>
            <ci>v12</ci>
          </apply>
        </apply> 
      </apply> 
    </math>  
  </component>

  <component cmeta:id="MCIPpp" name="MCIPpp">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#MCIPpp">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">MCIPpp</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">phosphorylated MCIP on both serine 112 and serine 108</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
    <variable initial_value="0.0798" name="MCIPpp" public_interface="out" units="micromolar"/>
    
    <variable name="v8" public_interface="in" units="flux"/>
    <variable name="v12" public_interface="in" units="flux"/> 
    <variable name="v13" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>MCIPpp</ci> 
        </apply>
        <apply>
          <minus/>
          <ci>v12</ci>
          <apply>
            <plus/>
            <ci>v8</ci>
            <ci>v13</ci>
          </apply>
        </apply> 
      </apply> 
    </math>  
  </component>

  <component cmeta:id="Comp1" name="Comp1">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Comp1">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Comp1</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">complex formed by MCIP and calcineurin</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
    <variable cmeta:id="Comp1_Comp1" initial_value="5.21E-3" name="Comp1" public_interface="out" units="micromolar"/>
    
    <variable name="v7" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>Comp1</ci> 
        </apply>
        <ci>v7</ci>
      </apply> 
    </math>  
  </component>

  <component cmeta:id="Comp2" name="Comp2">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Comp2">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Comp2</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">complex formed by MCIPPP and 14-3-3</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
    <variable cmeta:id="Comp2_Comp2" initial_value="0.283" name="Comp2" public_interface="out" units="micromolar"/>
    
    <variable name="v8" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>Comp2</ci> 
        </apply>
        <ci>v8</ci>
      </apply> 
    </math>  
  </component>

  <component cmeta:id="Comp3" name="Comp3">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#Comp3">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Comp3</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">complex formed by NFATP and 14-3-3</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
    <variable cmeta:id="Comp3_Comp3" initial_value="0.014" name="Comp3" public_interface="out" units="micromolar"/>
    
    <variable name="v9" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>Comp3</ci> 
        </apply>
        <ci>v9</ci>
      </apply> 
    </math>  
  </component>

  <component cmeta:id="P1433" name="P1433">
    <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
      <rdf:Description rdf:about="#P1433">
        <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">P1433</dc:title>
        <dcterms:alternative xmlns:dcterms="http://purl.org/dc/terms/">14-3-3 protein</dcterms:alternative>
      </rdf:Description>
    </rdf:RDF> 
    <variable cmeta:id="P1433_P1433" initial_value="0.708" name="P1433" public_interface="out" units="micromolar"/>
    
    <variable name="v8" public_interface="in" units="flux"/>
    <variable name="v9" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>P1433</ci> 
        </apply>
        <apply>
          <minus/>
          <apply>
            <plus/>
            <ci>v8</ci>
            <ci>v9</ci>
          </apply>
        </apply>
      </apply> 
    </math>  
  </component>

  <!-- reactants-enzyme complexes -->
  
  <component name="MCIP_BMK1"> 
    <variable initial_value="2.14E-5" name="MCIP_BMK1" public_interface="out" units="micromolar"/>
    
    <variable name="v10a" public_interface="in" units="flux"/>
    <variable name="v10b" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>MCIP_BMK1</ci> 
        </apply>
        <apply>
          <minus/>
          <ci>v10a</ci>
          <ci>v10b</ci>
        </apply> 
      </apply> 
    </math>  
  </component>

  <component name="MCIPp_CaNc_star"> 
    <variable initial_value="1.07E-4" name="MCIPp_CaNc_star" public_interface="out" units="micromolar"/>
    
    <variable name="v11a" public_interface="in" units="flux"/>
    <variable name="v11b" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>MCIPp_CaNc_star</ci> 
        </apply>
        <apply>
          <minus/>
          <ci>v11a</ci>
          <ci>v11b</ci>
        </apply> 
      </apply> 
    </math>  
  </component>

  <component name="MCIPp_GSK3betac"> 
    <variable initial_value="1.1E-3" name="MCIPp_GSK3betac" public_interface="out" units="micromolar"/>
    
    <variable name="v12a" public_interface="in" units="flux"/>
    <variable name="v12b" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>MCIPp_GSK3betac</ci> 
        </apply>
        <apply>
          <minus/>
          <ci>v12a</ci>
          <ci>v12b</ci>
        </apply> 
      </apply> 
    </math>  
  </component>

  <component name="MCIPpp_CaNc_star"> 
    <variable initial_value="1.1E-3" name="MCIPpp_CaNc_star" public_interface="out" units="micromolar"/>
    
    <variable name="v13a" public_interface="in" units="flux"/>
    <variable name="v13b" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>MCIPpp_CaNc_star</ci> 
        </apply>
        <apply>
          <minus/>
          <ci>v13a</ci>
          <ci>v13b</ci>
        </apply> 
      </apply> 
    </math>  
  </component>

  <component name="NFATpc_CaNc_star"> 
    <variable initial_value="8.15E-5" name="NFATpc_CaNc_star" public_interface="out" units="micromolar"/>
    
    <variable name="v14a" public_interface="in" units="flux"/>
    <variable name="v14b" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>NFATpc_CaNc_star</ci> 
        </apply>
        <apply>
          <minus/>
          <ci>v14a</ci>
          <ci>v14b</ci>
        </apply> 
      </apply> 
    </math>  
  </component>

  <component name="NFATc_GSK3betac"> 
    <variable initial_value="1.36E-6" name="NFATc_GSK3betac" public_interface="out" units="micromolar"/>
    
    <variable name="v15a" public_interface="in" units="flux"/>
    <variable name="v15b" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>NFATc_GSK3betac</ci> 
        </apply>
        <apply>
          <minus/>
          <ci>v15a</ci>
          <ci>v15b</ci>
        </apply> 
      </apply> 
    </math>  
  </component>

  <component name="NFATpn_CaNn_star"> 
    <variable initial_value="2.27E-6" name="NFATpn_CaNn_star" public_interface="out" units="micromolar"/>
    
    <variable name="v16a" public_interface="in" units="flux"/>
    <variable name="v16b" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>NFATpn_CaNn_star</ci> 
        </apply>
        <apply>
          <minus/>
          <ci>v16a</ci>
          <ci>v16b</ci>
        </apply> 
      </apply> 
    </math>  
  </component>

  <component name="NFATn_GSK3betan"> 
    <variable initial_value="8.46E-5" name="NFATn_GSK3betan" public_interface="out" units="micromolar"/>
    
    <variable name="v17a" public_interface="in" units="flux"/>
    <variable name="v17b" public_interface="in" units="flux"/>
    <variable name="time" public_interface="in" units="minute"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML"> 
      <apply>
        <eq/> 
        <apply>
          <diff/> 
          <bvar>
            <ci>time</ci>
          </bvar> 
          <ci>NFATn_GSK3betan</ci> 
        </apply>
        <apply>
          <minus/>
          <ci>v17a</ci>
          <ci>v17b</ci>
        </apply> 
      </apply> 
    </math>  
  </component>

  <!-- Simple Irreversible Reactions -->
  
  <component name="v1">
    <variable name="v1" public_interface="out" units="flux"/>
    
    <variable name="NFATc" public_interface="in" units="micromolar"/>
    <variable name="k29" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v1 </ci>
        <apply>
          <times/>
          <ci> k29 </ci>
          <ci> NFATc </ci>
        </apply>
      </apply>    
    </math>
  </component>

  <component name="v2">
    <variable name="v2" public_interface="out" units="flux"/>
    
    <variable name="NFATpn" public_interface="in" units="micromolar"/>
    <variable name="k30" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v2 </ci>
        <apply>
          <times/>
          <ci> k30 </ci>
          <ci> NFATpn </ci>
        </apply>
      </apply>    
    </math>
  </component>

  <!-- Simple Reversible Reactions -->

  <component name="v3">
    <variable name="v3" public_interface="out" units="flux"/>
    
    <variable name="GSK3betac" public_interface="in" units="micromolar"/>
    <variable name="GSK3betan" public_interface="in" units="micromolar"/>
    <variable name="k31" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k32" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v3 </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k31 </ci>
            <ci> GSK3betac </ci>
          </apply>
          <apply>
            <times/>
            <ci> k32 </ci>
            <ci> GSK3betan </ci>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>

  <component name="v4">
    <variable name="v4" public_interface="out" units="flux"/>
    
    <variable name="CaNc_star" public_interface="in" units="micromolar"/>
    <variable name="CaNn_star" public_interface="in" units="micromolar"/>
    <variable name="k33" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k34" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v4 </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k33 </ci>
            <ci> CaNc_star </ci>
          </apply>
          <apply>
            <times/>
            <ci> k34 </ci>
            <ci> CaNn_star </ci>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>

  <!-- Reversible Binding Reactions -->

  <component name="v5">
    <variable name="v5" public_interface="out" units="flux"/>
    
    <variable name="CaM" public_interface="in" units="micromolar"/>
    <variable name="Ca" public_interface="in" units="micromolar"/>
    <variable name="CaMCa" public_interface="in" units="micromolar"/>
    <variable name="k1" public_interface="in" units="fifth_order_rate_constant"/>
    <variable name="k2" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v5 </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k1 </ci>
            <ci> CaM </ci>
            <apply>
              <power/>
	      <ci> Ca </ci>
	      <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 4 </cn>
            </apply>
          </apply>
          <apply>
            <times/>
            <ci> k2 </ci>
            <ci> CaMCa </ci>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>

  <component name="v6">
    <variable name="v6" public_interface="out" units="flux"/>
    
    <variable name="CaNc" public_interface="in" units="micromolar"/>
    <variable name="CaNc_star" public_interface="in" units="micromolar"/>
    <variable name="CaMCa" public_interface="in" units="micromolar"/>
    <variable name="k3" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k4" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v6 </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k3 </ci>
            <ci> CaMCa </ci>
            <ci> CaNc </ci>
	  </apply>
          <apply>
            <times/>
            <ci> k4 </ci>
            <ci> CaNc_star </ci>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>

  <component name="v7">
    <variable name="v7" public_interface="out" units="flux"/>
    
    <variable name="MCIP" public_interface="in" units="micromolar"/>
    <variable name="CaNc_star" public_interface="in" units="micromolar"/>
    <variable name="Comp1" public_interface="in" units="micromolar"/>
    <variable name="k5" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k6" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v7 </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k5 </ci>
            <ci> CaNc_star </ci>
            <ci> MCIP </ci>
	  </apply>
          <apply>
            <times/>
            <ci> k6 </ci>
            <ci> Comp1 </ci>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>

  <component name="v8">
    <variable name="v8" public_interface="out" units="flux"/>
    
    <variable name="MCIPpp" public_interface="in" units="micromolar"/>
    <variable name="P1433" public_interface="in" units="micromolar"/>
    <variable name="Comp2" public_interface="in" units="micromolar"/>
    <variable name="k19" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k20" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v8 </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k19 </ci>
            <ci> P1433 </ci>
            <ci> MCIPpp </ci>
	  </apply>
          <apply>
            <times/>
            <ci> k20 </ci>
            <ci> Comp2 </ci>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>

  <component name="v9">
    <variable name="v9" public_interface="out" units="flux"/>
    
    <variable name="NFATpc" public_interface="in" units="micromolar"/>
    <variable name="P1433" public_interface="in" units="micromolar"/>
    <variable name="Comp3" public_interface="in" units="micromolar"/>
    <variable name="k27" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k28" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v9 </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k27 </ci>
            <ci> NFATpc </ci>
            <ci> P1433 </ci>
	  </apply>
          <apply>
            <times/>
            <ci> k28 </ci>
            <ci> Comp3 </ci>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>

  <!-- Catalytic Binding Reactions -->

  <component name="v10">
    <variable name="v10" public_interface="out" units="flux"/>
    <variable name="v10a" public_interface="out" units="flux"/>
    <variable name="v10b" public_interface="out" units="flux"/>
    
    <variable name="BMK1" public_interface="in" units="micromolar"/>
    <variable name="MCIP_BMK1" public_interface="in" units="micromolar"/>
    <variable name="MCIP" public_interface="in" units="micromolar"/>
    <variable name="k7" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k8" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k9" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v10a </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k7 </ci>
            <ci> MCIP </ci>
            <ci> BMK1 </ci>
	  </apply>
          <apply>
            <times/>
            <ci> k8 </ci>
            <ci> MCIP_BMK1 </ci>
          </apply>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v10b </ci>
        <apply>
          <times/>
          <ci> k9 </ci>
          <ci> MCIP_BMK1 </ci>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v10 </ci>
        <apply>
          <plus/>
          <ci> v10a </ci>
          <ci> v10b </ci>
        </apply>
      </apply>     
    </math>
  </component>

  <component name="v11">
    <variable name="v11" public_interface="out" units="flux"/>
    <variable name="v11a" public_interface="out" units="flux"/>
    <variable name="v11b" public_interface="out" units="flux"/>
    
    <variable name="MCIPp_CaNc_star" public_interface="in" units="micromolar"/>
    <variable name="CaNc_star" public_interface="in" units="micromolar"/>
    <variable name="MCIPp" public_interface="in" units="micromolar"/>
    <variable name="k10" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k11" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k12" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v11a </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k10 </ci>
            <ci> MCIPp </ci>
            <ci> CaNc_star </ci>
	  </apply>
          <apply>
            <times/>
            <ci> k11 </ci>
            <ci> MCIPp_CaNc_star </ci>
          </apply>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v11b </ci>
        <apply>
          <times/>
          <ci> k12 </ci>
          <ci> MCIPp_CaNc_star </ci>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v11 </ci>
        <apply>
          <plus/>
          <ci> v11a </ci>
          <ci> v11b </ci>
        </apply>
      </apply>     
    </math>
  </component>

  <component name="v12">
    <variable name="v12" public_interface="out" units="flux"/>
    <variable name="v12a" public_interface="out" units="flux"/>
    <variable name="v12b" public_interface="out" units="flux"/>
    
    <variable name="MCIPp_GSK3betac" public_interface="in" units="micromolar"/>
    <variable name="GSK3betac" public_interface="in" units="micromolar"/>
    <variable name="MCIPp" public_interface="in" units="micromolar"/>
    <variable name="k13" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k14" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k15" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v12a </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k13 </ci>
            <ci> MCIPp </ci>
            <ci> GSK3betac </ci>
	  </apply>
          <apply>
            <times/>
            <ci> k14 </ci>
            <ci> MCIPp_GSK3betac </ci>
          </apply>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v12b </ci>
        <apply>
          <times/>
          <ci> k15 </ci>
          <ci> MCIPp_GSK3betac </ci>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v12 </ci>
        <apply>
          <plus/>
          <ci> v12a </ci>
          <ci> v12b </ci>
        </apply>
      </apply>     
    </math>
  </component>
  
  <component name="v13">
    <variable name="v13" public_interface="out" units="flux"/>
    <variable name="v13a" public_interface="out" units="flux"/>
    <variable name="v13b" public_interface="out" units="flux"/>
    
    <variable name="MCIPpp_CaNc_star" public_interface="in" units="micromolar"/>
    <variable name="CaNc_star" public_interface="in" units="micromolar"/>
    <variable name="MCIPpp" public_interface="in" units="micromolar"/>
    <variable name="k16" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k17" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k18" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v13a </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k16 </ci>
            <ci> MCIPpp </ci>
            <ci> CaNc_star </ci>
	  </apply>
          <apply>
            <times/>
            <ci> k17 </ci>
            <ci> MCIPpp_CaNc_star </ci>
          </apply>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v13b </ci>
        <apply>
          <times/>
          <ci> k18 </ci>
          <ci> MCIPpp_CaNc_star </ci>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v13 </ci>
        <apply>
          <plus/>
          <ci> v13a </ci>
          <ci> v13b </ci>
        </apply>
      </apply>     
    </math>
  </component>

  <component name="v14">
    <variable name="v14" public_interface="out" units="flux"/>
    <variable name="v14a" public_interface="out" units="flux"/>
    <variable name="v14b" public_interface="out" units="flux"/>
    
    <variable name="NFATpc_CaNc_star" public_interface="in" units="micromolar"/>
    <variable name="CaNc_star" public_interface="in" units="micromolar"/>
    <variable name="NFATpc" public_interface="in" units="micromolar"/>
    <variable name="k21" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k22" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k23" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v14a </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k21 </ci>
            <ci> NFATpc </ci>
            <ci> CaNc_star </ci>
	  </apply>
          <apply>
            <times/>
            <ci> k22 </ci>
            <ci> NFATpc_CaNc_star </ci>
          </apply>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v14b </ci>
        <apply>
          <times/>
          <ci> k23 </ci>
          <ci> NFATpc_CaNc_star </ci>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v14 </ci>
        <apply>
          <plus/>
          <ci> v14a </ci>
          <ci> v14b </ci>
        </apply>
      </apply>     
    </math>
  </component>

  <component name="v15">
    <variable name="v15" public_interface="out" units="flux"/>
    <variable name="v15a" public_interface="out" units="flux"/>
    <variable name="v15b" public_interface="out" units="flux"/>
    
    <variable name="NFATc_GSK3betac" public_interface="in" units="micromolar"/>
    <variable name="GSK3betac" public_interface="in" units="micromolar"/>
    <variable name="NFATc" public_interface="in" units="micromolar"/>
    <variable name="k24" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k25" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k26" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v15a </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k24 </ci>
            <ci> NFATc </ci>
            <ci> GSK3betac </ci>
	  </apply>
          <apply>
            <times/>
            <ci> k25 </ci>
            <ci> NFATc_GSK3betac </ci>
          </apply>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v15b </ci>
        <apply>
          <times/>
          <ci> k26 </ci>
          <ci> NFATc_GSK3betac </ci>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v15 </ci>
        <apply>
          <plus/>
          <ci> v15a </ci>
          <ci> v15b </ci>
        </apply>
      </apply>     
    </math>
  </component>

  <component name="v16">
    <variable name="v16" public_interface="out" units="flux"/>
    <variable name="v16a" public_interface="out" units="flux"/>
    <variable name="v16b" public_interface="out" units="flux"/>
    
    <variable name="NFATpn_CaNn_star" public_interface="in" units="micromolar"/>
    <variable name="CaNn_star" public_interface="in" units="micromolar"/>
    <variable name="NFATpn" public_interface="in" units="micromolar"/>
    <variable name="k35" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k36" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k37" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v16a </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k35 </ci>
            <ci> NFATpn </ci>
            <ci> CaNn_star </ci>
	  </apply>
          <apply>
            <times/>
            <ci> k36 </ci>
            <ci> NFATpn_CaNn_star </ci>
          </apply>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v16b </ci>
        <apply>
          <times/>
          <ci> k37 </ci>
          <ci> NFATpn_CaNn_star </ci>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v16 </ci>
        <apply>
          <plus/>
          <ci> v16a </ci>
          <ci> v16b </ci>
        </apply>
      </apply>     
    </math>
  </component>

  <component name="v17">
    <variable name="v17" public_interface="out" units="flux"/>
    <variable name="v17a" public_interface="out" units="flux"/>
    <variable name="v17b" public_interface="out" units="flux"/>
    
    <variable name="NFATn_GSK3betan" public_interface="in" units="micromolar"/>
    <variable name="GSK3betan" public_interface="in" units="micromolar"/>
    <variable name="NFATn" public_interface="in" units="micromolar"/>
    <variable name="k38" public_interface="in" units="second_order_rate_constant"/>
    <variable name="k39" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k40" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v17a </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k38 </ci>
            <ci> NFATn </ci>
            <ci> GSK3betan </ci>
	  </apply>
          <apply>
            <times/>
            <ci> k39 </ci>
            <ci> NFATn_GSK3betan </ci>
          </apply>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v17b </ci>
        <apply>
          <times/>
          <ci> k40 </ci>
          <ci> NFATn_GSK3betan </ci>
        </apply>
      </apply>

      <apply>
        <eq/>
        <ci> v17 </ci>
        <apply>
          <plus/>
          <ci> v17a </ci>
          <ci> v17b </ci>
        </apply>
      </apply>     
    </math>
  </component>

  <!-- transcription control process of MCIP by NFAT -->

  <component name="v18">
    <variable name="v18" public_interface="out" units="flux"/>
    
    <variable name="NFATn" public_interface="in" units="micromolar"/>
    <variable name="MRNA" public_interface="in" units="micromolar"/>
    <variable name="k41" public_interface="in" units="first_order_rate_constant"/>
    <variable name="k42" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v18 </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k41 </ci>
            <ci> NFATn </ci>
          </apply>
          <apply>
            <times/>
            <ci> k42 </ci>
            <ci> MRNA </ci>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>

  <component name="v19">
    <variable name="v19" public_interface="out" units="flux"/>
    
    <variable name="t_half" public_interface="in" units="minute"/>
    <variable name="MRNA" public_interface="in" units="micromolar"/>
    <variable name="MCIP" public_interface="in" units="micromolar"/>
    <variable name="k43" public_interface="in" units="first_order_rate_constant"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply>
        <eq/>
        <ci> v19 </ci>
        <apply>
          <minus/>
          <apply>
            <times/>
            <ci> k43 </ci>
            <ci> MRNA </ci>
          </apply>
          <apply>
            <times/>
            <apply>
              <divide/>
              <apply>
                <ln/>
                <cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless"> 2.0 </cn>
              </apply>
              <ci> t_half </ci>
            </apply>
            <ci> MCIP </ci>
          </apply>
        </apply>
      </apply>    
    </math>
  </component>
 
  <component name="model_parameters">
    <variable initial_value="5" name="k1" public_interface="out" units="fifth_order_rate_constant"/>
    <variable initial_value="100" name="k2" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="2760" name="k3" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.072" name="k4" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="50" name="k5" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.0567" name="k6" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="5" name="k7" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.1" name="k8" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.5" name="k9" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k10" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.1" name="k11" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k12" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.5" name="k13" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.5" name="k14" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k15" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k16" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.1" name="k17" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k18" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.5" name="k19" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.1" name="k20" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.15" name="k21" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.15" name="k22" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.15" name="k23" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k24" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.15" name="k25" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k26" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.4" name="k27" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.1" name="k28" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.4" name="k29" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k30" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k31" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.05" name="k32" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.114" name="k33" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.0552" name="k34" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.15" name="k35" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.1" name="k36" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.2" name="k37" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k38" public_interface="out" units="second_order_rate_constant"/>
    <variable initial_value="0.1" name="k39" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.1" name="k40" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.02" name="k41" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.03" name="k42" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="0.03" name="k43" public_interface="out" units="first_order_rate_constant"/>
    <variable initial_value="15" name="t_half" public_interface="out" units="minute"/>
    <variable initial_value="0.2" name="Ca" public_interface="out" units="micromolar"/>
  </component>

  
  <connection>
    <map_components component_1="BMK1" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="MRNA" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="NFATc" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="NFATn" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>
  
  <connection>
    <map_components component_1="NFATpc" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>
  
  <connection>
    <map_components component_1="NFATpn" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="GSK3betac" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="GSK3betan" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>
  
  <connection>
    <map_components component_1="CaNc" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="CaNn" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="CaNc_star" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="CaNn_star" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>
  
  <connection>
    <map_components component_1="CaM" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="CaMCa" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="MCIP" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="MCIPp" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="MCIPpp" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="Comp1" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="Comp2" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="Comp3" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="P1433" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>
  
  <connection>
    <map_components component_1="MCIP_BMK1" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="MCIPp_CaNc_star" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="MCIPp_GSK3betac" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="MCIPpp_CaNc_star" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="NFATpc_CaNc_star" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="NFATc_GSK3betac" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="NFATpn_CaNn_star" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="NFATn_GSK3betan" component_2="environment"/>
    <map_variables variable_1="time" variable_2="time"/>
  </connection>

  <connection>
    <map_components component_1="v10" component_2="BMK1"/>
    <map_variables variable_1="v10a" variable_2="v10a"/>
    <map_variables variable_1="v10b" variable_2="v10b"/>
    <map_variables variable_1="BMK1" variable_2="BMK1"/>
  </connection> 

  <connection>
    <map_components component_1="v18" component_2="MRNA"/>
    <map_variables variable_1="v18" variable_2="v18"/>
    <map_variables variable_1="MRNA" variable_2="MRNA"/>
  </connection>

  <connection>
    <map_components component_1="v19" component_2="MRNA"/>
    <map_variables variable_1="v19" variable_2="v19"/>
    <map_variables variable_1="MRNA" variable_2="MRNA"/>
  </connection>

  <connection>
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    <dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Simulating Complex Calcium-Calcineurin Signaling Network</dc:title>
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    <rdf:value>This CellML model runs in both PCEnv and COR to recreate the published results.  The units have been checked and they are consistent.</rdf:value>
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    <dcterms:W3CDTF xmlns:dcterms="http://purl.org/dc/terms/">2008-06-00 00:00</dcterms:W3CDTF>
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