- Author:
- Catherine Lloyd <c.lloyd@auckland.ac.nz>
- Date:
- 2010-07-05 21:45:09+12:00
- Desc:
- Updated the documentation.
- Permanent Source URI:
- https://models.cellml.org/workspace/ciliberto_petrus_tyson_sible_2003/rawfile/a0963be5f4d7710cfd1527c05a8d8654575ba0c9/ciliberto_petrus_tyson_sible_2003.cellml
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COR (0.9.31.1125)
Copyright 2002-2008 Dr Alan Garny
http://COR.physiol.ox.ac.uk/ - COR@physiol.ox.ac.uk
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http://www.CellML.org/
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<title>A Kinetic Model of the Cyclin E/Cdk2 Developmental Timer in Xenopus laevis embryos</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
</affiliation>
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<section id="sec_status">
<title>Model Status</title>
<para>
This CellML version of the model has been checked in OpenCell and the model runs to replicate the results in the original published paper. This model uses the initial conditions that recreate the results in figure 6. The model runs in COR but the duration of the model simulation is too long for the results to be properly displayed in COR. The units have been checked and they are consistent.</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
ABSTRACT: Early cell cycles of Xenopus laevis embryos are characterized by rapid oscillations in the activity of two cyclin-dependent kinases. Cdk1 activity peaks at mitosis, driven by periodic degradation of cyclins A and B. In contrast, Cdk2 activity oscillates twice per cell cycle, despite a constant level of its partner, cyclin E. Cyclin E degrades at a fixed time after fertilization, normally corresponding to the midblastula transition. Based on published data and new experiments, we constructed a mathematical model in which: (1) oscillations in Cdk2 activity depend upon changes in phosphorylation, (2) Cdk2 participates in a negative feedback loop with the inhibitory kinase Wee1; (3) cyclin E is cooperatively removed from the oscillatory system; and (4) removed cyclin E is degraded by a pathway activated by cyclin E/Cdk2 itself. The model's predictions about embryos injected with Xic1, a stoichiometric inhibitor of cyclin E/Cdk2, were experimentally validated.
</para>
<para>
The original paper reference is cited below:
</para>
<para>
A kinetic model of the cyclin E/Cdk2 developmental timer in <emphasis>Xenopus laevis</emphasis> embryos, Andrea Ciliberto, Matthew J. Petrus, John J. Tyson, and Jill C. Sible, 2003,
<emphasis>Biophysical Chemistry</emphasis>
, 104, 573-589. <ulink url="http://www.ncbi.nlm.nih.gov/pubmed/12914904">PubMed ID: 12914904</ulink>
</para>
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<caption>A theoretical molecular mechanism of the cyclin E/Cdk2 developmental timer was used to construct the mathematical model. The dashed box represents a mechanism for removing cyclin E/Cdk2 from the oscillatory subsystem, which is activated by the "removed" form of cyclin E/Cdk2. The removal step is cooperative in that the more cyclin E/Cdk2 there is bound to the dashed box, the faster is the association reaction. A kinase (Kin) is introduced between cyclin E/Cdk2 and Wee1 to create a time lag in the negative feedback loop.</caption>
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<ci>Xic_PCdk2_CycErem</ci>
</apply>
<apply>
<times/>
<ci>kwee</ci>
<ci>Wee1_a</ci>
<ci>Xic_Cdk2_CycE</ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>kdissoc</ci>
<ci>Xic_PCdk2_CycE</ci>
</apply>
<apply>
<times/>
<ci>kon</ci>
<ci>phi</ci>
<ci>Xic_PCdk2_CycE</ci>
</apply>
<apply>
<times/>
<ci>k25A</ci>
<ci>Xic_PCdk2_CycE</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="Xic_Cdk2_CycErem">
<variable initial_value="0" name="Xic_Cdk2_CycErem" public_interface="out" units="dimensionless"/>
<variable name="kedeg" public_interface="in" units="first_order_rate_constant"/>
<variable name="kon" public_interface="in" units="first_order_rate_constant"/>
<variable name="kxdeg" public_interface="in" units="first_order_rate_constant"/>
<variable name="koff" public_interface="in" units="first_order_rate_constant"/>
<variable name="kassoc" public_interface="in" units="first_order_rate_constant"/>
<variable name="kdissoc" public_interface="in" units="first_order_rate_constant"/>
<variable name="phi" public_interface="in" units="dimensionless"/>
<variable name="Deg_a" public_interface="in" units="dimensionless"/>
<variable name="Xic" public_interface="in" units="dimensionless"/>
<variable name="Cdk2_CycErem" public_interface="in" units="dimensionless"/>
<variable name="Xic_Cdk2_CycE" public_interface="in" units="dimensionless"/>
<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>Xic_Cdk2_CycErem</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci>kassoc</ci>
<ci>Xic</ci>
<ci>Cdk2_CycErem</ci>
</apply>
<apply>
<times/>
<ci>kon</ci>
<ci>phi</ci>
<ci>Xic_Cdk2_CycE</ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>kdissoc</ci>
<ci>Xic_Cdk2_CycErem</ci>
</apply>
<apply>
<times/>
<ci>koff</ci>
<ci>Xic_Cdk2_CycErem</ci>
</apply>
<apply>
<times/>
<ci>kedeg</ci>
<ci>Deg_a</ci>
<ci>Xic_Cdk2_CycErem</ci>
</apply>
<apply>
<times/>
<ci>kxdeg</ci>
<ci>Xic_Cdk2_CycErem</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="Xic_PCdk2_CycErem">
<variable initial_value="0" name="Xic_PCdk2_CycErem" public_interface="out" units="dimensionless"/>
<variable name="kedeg" public_interface="in" units="first_order_rate_constant"/>
<variable name="kon" public_interface="in" units="first_order_rate_constant"/>
<variable name="kxdeg" public_interface="in" units="first_order_rate_constant"/>
<variable name="koff" public_interface="in" units="first_order_rate_constant"/>
<variable name="kassoc" public_interface="in" units="first_order_rate_constant"/>
<variable name="kdissoc" public_interface="in" units="first_order_rate_constant"/>
<variable name="phi" public_interface="in" units="dimensionless"/>
<variable name="Deg" public_interface="in" units="dimensionless"/>
<variable name="Xic" public_interface="in" units="dimensionless"/>
<variable name="PCdk2_CycErem" public_interface="in" units="dimensionless"/>
<variable name="Xic_PCdk2_CycE" public_interface="in" units="dimensionless"/>
<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>Xic_PCdk2_CycErem</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci>kassoc</ci>
<ci>Xic</ci>
<ci>PCdk2_CycErem</ci>
</apply>
<apply>
<times/>
<ci>kon</ci>
<ci>phi</ci>
<ci>Xic_PCdk2_CycE</ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci>kdissoc</ci>
<ci>Xic_PCdk2_CycErem</ci>
</apply>
<apply>
<times/>
<ci>koff</ci>
<ci>Xic_PCdk2_CycErem</ci>
</apply>
<apply>
<times/>
<ci>kedeg</ci>
<ci>Deg</ci>
<ci>Xic_PCdk2_CycErem</ci>
</apply>
<apply>
<times/>
<ci>kxdeg</ci>
<ci>Xic_PCdk2_CycErem</ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="Xicrem">
<variable initial_value="0" name="Xicrem" public_interface="out" units="dimensionless"/>
<variable name="kedeg" public_interface="in" units="first_order_rate_constant"/>
<variable name="kxdeg" public_interface="in" units="first_order_rate_constant"/>
<variable name="Deg_a" public_interface="in" units="dimensionless"/>
<variable name="Xic_Cdk2_CycErem" public_interface="in" units="dimensionless"/>
<variable name="Xic_PCdk2_CycErem" public_interface="in" units="dimensionless"/>
<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>Xicrem</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci>kedeg</ci>
<ci>Deg_a</ci>
<ci>Xic_Cdk2_CycErem</ci>
</apply>
<apply>
<times/>
<ci>kedeg</ci>
<ci>Deg_a</ci>
<ci>Xic_PCdk2_CycErem</ci>
</apply>
</apply>
<apply>
<times/>
<ci>kxdeg</ci>
<ci>Xicrem</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="Cyc_total">
<variable name="Cyc_total" public_interface="out" units="dimensionless"/>
<variable name="Xic_PCdk2_CycE" public_interface="in" units="dimensionless"/>
<variable name="Xic_Cdk2_CycE" public_interface="in" units="dimensionless"/>
<variable name="Cdk2_CycE" public_interface="in" units="dimensionless"/>
<variable name="PCdk2_CycE" public_interface="in" units="dimensionless"/>
<variable name="Cdk2_CycErem" public_interface="in" units="dimensionless"/>
<variable name="PCdk2_CycErem" public_interface="in" units="dimensionless"/>
<variable name="Xic_PCdk2_CycErem" public_interface="in" units="dimensionless"/>
<variable name="Xic_Cdk2_CycErem" public_interface="in" units="dimensionless"/>
<variable name="time" public_interface="in" units="minute"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>Cyc_total</ci>
<apply>
<plus/>
<ci>Xic_PCdk2_CycE</ci>
<ci>Xic_Cdk2_CycE</ci>
<ci>Xic_PCdk2_CycErem</ci>
<ci>Xic_Cdk2_CycErem</ci>
<ci>PCdk2_CycErem</ci>
<ci>Cdk2_CycErem</ci>
<ci>Cdk2_CycE</ci>
<ci>PCdk2_CycE</ci>
</apply>
</apply>
</math>
</component>
<component name="Xic_total">
<variable name="Xic_total" public_interface="out" units="dimensionless"/>
<variable name="Xic" public_interface="in" units="dimensionless"/>
<variable name="Xic_PCdk2_CycE" public_interface="in" units="dimensionless"/>
<variable name="Xic_Cdk2_CycE" public_interface="in" units="dimensionless"/>
<variable name="Xic_PCdk2_CycErem" public_interface="in" units="dimensionless"/>
<variable name="Xic_Cdk2_CycErem" public_interface="in" units="dimensionless"/>
<variable name="Xicrem" public_interface="in" units="dimensionless"/>
<variable name="time" public_interface="in" units="minute"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>Xic_total</ci>
<apply>
<divide/>
<apply>
<plus/>
<ci>Xic</ci>
<ci>Xic_PCdk2_CycE</ci>
<ci>Xic_Cdk2_CycE</ci>
<ci>Xic_PCdk2_CycErem</ci>
<ci>Xic_Cdk2_CycErem</ci>
<ci>Xicrem</ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3</cn>
</apply>
</apply>
</math>
</component>
<component name="kinetic_parameters">
<variable initial_value="1.5" name="kwee" public_interface="out" units="first_order_rate_constant"/>
<variable initial_value="0.1" name="k25A" public_interface="out" units="first_order_rate_constant"/>
<variable initial_value="0.02" name="kon" public_interface="out" units="first_order_rate_constant"/>
<variable initial_value="0.0001" name="koff" public_interface="out" units="first_order_rate_constant"/>
<variable initial_value="0.1" name="kassoc" public_interface="out" units="first_order_rate_constant"/>
<variable initial_value="0.001" name="kdissoc" public_interface="out" units="first_order_rate_constant"/>
<variable initial_value="0.017" name="kedeg" public_interface="out" units="first_order_rate_constant"/>
<variable initial_value="0.01" name="kxdeg" public_interface="out" units="first_order_rate_constant"/>
<variable name="phi" public_interface="out" units="dimensionless"/>
<variable initial_value="0" name="Deg" public_interface="out" units="dimensionless"/>
<variable initial_value="0.001" name="epsilon" units="dimensionless"/>
<variable name="pool" public_interface="out" units="dimensionless"/>
<variable initial_value="4" name="n" units="dimensionless"/>
<variable initial_value="0.4" name="L" units="dimensionless"/>
<variable name="Cdk2_CycErem" public_interface="in" units="dimensionless"/>
<variable name="PCdk2_CycErem" public_interface="in" units="dimensionless"/>
<variable name="Xic_Cdk2_CycErem" public_interface="in" units="dimensionless"/>
<variable name="Xic_PCdk2_CycErem" public_interface="in" units="dimensionless"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>phi</ci>
<apply>
<divide/>
<apply>
<plus/>
<ci>epsilon</ci>
<apply>
<power/>
<ci>pool</ci>
<ci>n</ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<power/>
<ci>L</ci>
<ci>n</ci>
</apply>
<apply>
<power/>
<ci>pool</ci>
<ci>n</ci>
</apply>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>pool</ci>
<apply>
<plus/>
<ci>Cdk2_CycErem</ci>
<ci>PCdk2_CycErem</ci>
<ci>Xic_Cdk2_CycErem</ci>
<ci>Xic_PCdk2_CycErem</ci>
</apply>
</apply>
</math>
</component>
<connection>
<map_components component_1="Cdk2_CycE" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="PCdk2_CycE" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Wee1_a" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Kin_a" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Cdk2_CycErem" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="PCdk2_CycErem" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Deg_a" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Xic" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Xic_total" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Xic_Cdk2_CycE" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Xic_PCdk2_CycE" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Xic_Cdk2_CycErem" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Xic_PCdk2_CycErem" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Xicrem" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Cyc_total" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="Cdk2_CycE" component_2="Wee1_a"/>
<map_variables variable_1="Wee1_a" variable_2="Wee1_a"/>
</connection>
<connection>
<map_components component_1="Cdk2_CycE" component_2="PCdk2_CycE"/>
<map_variables variable_1="PCdk2_CycE" variable_2="PCdk2_CycE"/>
<map_variables variable_1="Cdk2_CycE" variable_2="Cdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Cdk2_CycE" component_2="Cdk2_CycErem"/>
<map_variables variable_1="Cdk2_CycErem" variable_2="Cdk2_CycErem"/>
<map_variables variable_1="Cdk2_CycE" variable_2="Cdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Cdk2_CycE" component_2="Xic"/>
<map_variables variable_1="Xic" variable_2="Xic"/>
<map_variables variable_1="Cdk2_CycE" variable_2="Cdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Cdk2_CycE" component_2="Xic_Cdk2_CycE"/>
<map_variables variable_1="Xic_Cdk2_CycE" variable_2="Xic_Cdk2_CycE"/>
<map_variables variable_1="Cdk2_CycE" variable_2="Cdk2_CycE"/>
</connection>
<connection>
<map_components component_1="PCdk2_CycE" component_2="Wee1_a"/>
<map_variables variable_1="Wee1_a" variable_2="Wee1_a"/>
</connection>
<connection>
<map_components component_1="PCdk2_CycE" component_2="PCdk2_CycErem"/>
<map_variables variable_1="PCdk2_CycErem" variable_2="PCdk2_CycErem"/>
<map_variables variable_1="PCdk2_CycE" variable_2="PCdk2_CycE"/>
</connection>
<connection>
<map_components component_1="PCdk2_CycE" component_2="Xic"/>
<map_variables variable_1="Xic" variable_2="Xic"/>
<map_variables variable_1="PCdk2_CycE" variable_2="PCdk2_CycE"/>
</connection>
<connection>
<map_components component_1="PCdk2_CycE" component_2="Xic_PCdk2_CycE"/>
<map_variables variable_1="Xic_PCdk2_CycE" variable_2="Xic_PCdk2_CycE"/>
<map_variables variable_1="PCdk2_CycE" variable_2="PCdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Kin_a" component_2="Cdk2_CycE"/>
<map_variables variable_1="Cdk2_CycE" variable_2="Cdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Cdk2_CycErem" component_2="Xic"/>
<map_variables variable_1="Xic" variable_2="Xic"/>
<map_variables variable_1="Cdk2_CycErem" variable_2="Cdk2_CycErem"/>
</connection>
<connection>
<map_components component_1="Cdk2_CycErem" component_2="Xic_Cdk2_CycErem"/>
<map_variables variable_1="Xic_Cdk2_CycErem" variable_2="Xic_Cdk2_CycErem"/>
<map_variables variable_1="Cdk2_CycErem" variable_2="Cdk2_CycErem"/>
</connection>
<connection>
<map_components component_1="PCdk2_CycErem" component_2="Xic"/>
<map_variables variable_1="Xic" variable_2="Xic"/>
<map_variables variable_1="PCdk2_CycErem" variable_2="PCdk2_CycErem"/>
</connection>
<connection>
<map_components component_1="PCdk2_CycErem" component_2="Deg_a"/>
<map_variables variable_1="Deg_a" variable_2="Deg_a"/>
</connection>
<connection>
<map_components component_1="PCdk2_CycErem" component_2="Xic_PCdk2_CycErem"/>
<map_variables variable_1="Xic_PCdk2_CycErem" variable_2="Xic_PCdk2_CycErem"/>
<map_variables variable_1="PCdk2_CycErem" variable_2="PCdk2_CycErem"/>
</connection>
<connection>
<map_components component_1="Wee1_a" component_2="Kin_a"/>
<map_variables variable_1="Kin_a" variable_2="Kin_a"/>
</connection>
<connection>
<map_components component_1="Deg_a" component_2="Cdk2_CycErem"/>
<map_variables variable_1="Cdk2_CycErem" variable_2="Cdk2_CycErem"/>
<map_variables variable_1="Deg_a" variable_2="Deg_a"/>
</connection>
<connection>
<map_components component_1="Xic" component_2="Xic_Cdk2_CycE"/>
<map_variables variable_1="Xic_Cdk2_CycE" variable_2="Xic_Cdk2_CycE"/>
<map_variables variable_1="Xic" variable_2="Xic"/>
</connection>
<connection>
<map_components component_1="Xic" component_2="Xic_PCdk2_CycE"/>
<map_variables variable_1="Xic_PCdk2_CycE" variable_2="Xic_PCdk2_CycE"/>
<map_variables variable_1="Xic" variable_2="Xic"/>
</connection>
<connection>
<map_components component_1="Cyc_total" component_2="Xic_PCdk2_CycE"/>
<map_variables variable_1="Xic_PCdk2_CycE" variable_2="Xic_PCdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Cyc_total" component_2="Xic_Cdk2_CycE"/>
<map_variables variable_1="Xic_Cdk2_CycE" variable_2="Xic_Cdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Cyc_total" component_2="Cdk2_CycE"/>
<map_variables variable_1="Cdk2_CycE" variable_2="Cdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Cyc_total" component_2="PCdk2_CycE"/>
<map_variables variable_1="PCdk2_CycE" variable_2="PCdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Cyc_total" component_2="Cdk2_CycErem"/>
<map_variables variable_1="Cdk2_CycErem" variable_2="Cdk2_CycErem"/>
</connection>
<connection>
<map_components component_1="Cyc_total" component_2="PCdk2_CycErem"/>
<map_variables variable_1="PCdk2_CycErem" variable_2="PCdk2_CycErem"/>
</connection>
<connection>
<map_components component_1="Cyc_total" component_2="Xic_PCdk2_CycErem"/>
<map_variables variable_1="Xic_PCdk2_CycErem" variable_2="Xic_PCdk2_CycErem"/>
</connection>
<connection>
<map_components component_1="Cyc_total" component_2="Xic_Cdk2_CycErem"/>
<map_variables variable_1="Xic_Cdk2_CycErem" variable_2="Xic_Cdk2_CycErem"/>
</connection>
<connection>
<map_components component_1="Xic_total" component_2="Xic"/>
<map_variables variable_1="Xic" variable_2="Xic"/>
</connection>
<connection>
<map_components component_1="Xic_total" component_2="Xic_Cdk2_CycErem"/>
<map_variables variable_1="Xic_Cdk2_CycErem" variable_2="Xic_Cdk2_CycErem"/>
</connection>
<connection>
<map_components component_1="Xic_total" component_2="Xic_PCdk2_CycE"/>
<map_variables variable_1="Xic_PCdk2_CycE" variable_2="Xic_PCdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Xic_total" component_2="Xic_Cdk2_CycE"/>
<map_variables variable_1="Xic_Cdk2_CycE" variable_2="Xic_Cdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Xic_total" component_2="Xic_PCdk2_CycErem"/>
<map_variables variable_1="Xic_PCdk2_CycErem" variable_2="Xic_PCdk2_CycErem"/>
</connection>
<connection>
<map_components component_1="Xic_total" component_2="Xicrem"/>
<map_variables variable_1="Xicrem" variable_2="Xicrem"/>
</connection>
<connection>
<map_components component_1="Xic" component_2="Xic_Cdk2_CycErem"/>
<map_variables variable_1="Xic_Cdk2_CycErem" variable_2="Xic_Cdk2_CycErem"/>
<map_variables variable_1="Xic" variable_2="Xic"/>
</connection>
<connection>
<map_components component_1="Deg_a" component_2="Xic_Cdk2_CycErem"/>
<map_variables variable_1="Deg_a" variable_2="Deg_a"/>
</connection>
<connection>
<map_components component_1="Xic" component_2="Xic_PCdk2_CycErem"/>
<map_variables variable_1="Xic_PCdk2_CycErem" variable_2="Xic_PCdk2_CycErem"/>
<map_variables variable_1="Xic" variable_2="Xic"/>
</connection>
<connection>
<map_components component_1="Xic_Cdk2_CycE" component_2="Xic_Cdk2_CycErem"/>
<map_variables variable_1="Xic_Cdk2_CycErem" variable_2="Xic_Cdk2_CycErem"/>
<map_variables variable_1="Xic_Cdk2_CycE" variable_2="Xic_Cdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Xic_Cdk2_CycE" component_2="Xic_PCdk2_CycE"/>
<map_variables variable_1="Xic_PCdk2_CycE" variable_2="Xic_PCdk2_CycE"/>
<map_variables variable_1="Xic_Cdk2_CycE" variable_2="Xic_Cdk2_CycE"/>
</connection>
<connection>
<map_components component_1="Xic_Cdk2_CycE" component_2="Wee1_a"/>
<map_variables variable_1="Wee1_a" variable_2="Wee1_a"/>
</connection>
<connection>
<map_components component_1="Xic_PCdk2_CycE" component_2="Xic_PCdk2_CycErem"/>
<map_variables variable_1="Xic_PCdk2_CycErem" variable_2="Xic_PCdk2_CycErem"/>
<map_variables variable_1="Xic_PCdk2_CycE" variable_2="Xic_PCdk2_CycE"/>
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