<?xml version='1.0' encoding='utf-8'?>
<!-- FILE : sobie_model_2002.xml
CREATED : 26th June 2002
LAST MODIFIED : 9th April 2003
AUTHOR : Catherine Lloyd
Bioengineering Institute
The University of Auckland
MODEL STATUS : This model conforms to the CellML 1.0 Specification released on
10th August 2001, and the 16/1/02 CellML Metadata 1.0 Specification.
DESCRIPTION : This file contains a CellML description of Sobie et al's
2002 model of calcium-induced calcium release in cardiac muscle.
CHANGES:
18/07/2002 - CML - Added more metadata.
09/04/2003 - AAC - Added publication date information.
--><model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" cmeta:id="sobie_dilly_dossantoscruz_lederer_jafri_2002_version01" name="sobie_dilly_dossantoscruz_lederer_jafri_2002_version01">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>Mechanism of Cardiac Ca2+ Spark Termination</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<section id="sec_status">
<title>Model Status</title>
<para>
This is the original unchecked version of the model imported from the previous
CellML model repository, 24-Jan-2006.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
The activation of Ca<superscript>2+</superscript> sparks is an essential step in cardiac excitation-contraction coupling. A Ca<superscript>2+</superscript> spark arises when voltage-gated, L-type Ca<superscript>2+</superscript> channels in the sarcolemmal (SL) membrane open. Ca<superscript>2+</superscript> diffuses into the cell, causing the concentration of intracellular calcium [Ca<superscript>2+</superscript>]<subscript>i</subscript> to rise, especially in the region close to the channel in the sub-space between the sarcolemmal and the sarcoplasmic reticulum (SR) membranes (see the figure below). This local increase in [Ca<superscript>2+</superscript>]<subscript>i</subscript> triggers the opening of SR Ca<superscript>2+</superscript>-release channels (ryanodine receptors, or RyRs) located in the sub-space. Ca<superscript>2+</superscript> from the intracellular SR store is released, causing a large further increase in [Ca<superscript>2+</superscript>]<subscript>i</subscript>, which is recognised as a Ca<superscript>2+</superscript> spark. Ca<superscript>2+</superscript> spark activation displays both high gain - a small amount of trigger Ca<superscript>2+</superscript> activates a large amount of released Ca<superscript>2+</superscript> - and positive feedback - release of Ca<superscript>2+</superscript> raises [Ca<superscript>2+</superscript>]<subscript>i</subscript> and tends to trigger more Ca<superscript>2+</superscript> release.
</para>
<para>
Despite the extensive knowledge outlined above, there is still uncertainty about the mechanisms underlying the termination of Ca<superscript>2+</superscript> sparks. In their 2002 paper, Eric A. Sobie, Keith W. Dilly, Jader dos Santos Cruz, W. Jonathan Lederer, and M. Saleet Jafri propose a new hypothesis called <emphasis>sticky cluster</emphasis>, to describe the behaviour of Ca<superscript>2+</superscript> sparks in the heart. Their mathematical model focuses on how Ca<superscript>2+</superscript> sparks are terminated, and how the variable number of RyRs in a cluster may influence spark behaviour. They suggest that spark termination is dependent on two factors: the effect of [Ca<superscript>2+</superscript>]<subscript>lumen</subscript> on RyR gating, and and coupled gating between RyRs in a cluster.
</para>
<para>
The complete original paper reference is cited below:
</para>
<para>
<ulink url="http://www.biophysj.org/cgi/content/abstract/83/1/59">Termination of Cardiac Ca<superscript>2+</superscript> Sparks: An Investigative Mathematical Model of Calcium-Induced Calcium Release</ulink>, Eric A. Sobie, Keith W. Dilly, Jader dos Santos Cruz, W. Jonathan Lederer, and M. Saleet Jafri, 2002, <ulink url="http://www.biophysj.org/">
<emphasis>Biophysical Journal</emphasis>
</ulink>, 83, 59-78. (<ulink url="http://www.biophysj.org/cgi/content/full/83/1/59">Full text</ulink> and <ulink url="http://www.biophysj.org/cgi/reprint/83/1/59.pdf">PDF versions</ulink> of the article are available to subscribers on the Biophysical Journal website.) <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12080100&dopt=Abstract">PubMed ID: 12080100</ulink>
</para>
<informalfigure float="0" id="fig_cell_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>cell_diagram</title>
</objectinfo>
<imagedata fileref="sobie_2002.png"/>
</imageobject>
</mediaobject>
<caption>Layout of the model elements.</caption>
</informalfigure>
<para>
The model is separated out into two main components: 1) Mathematical description of SR Ca<superscript>2+</superscript> release through an RyR cluster at the extracellular-sarcolemmal junction. 2) Mathematical description of the Ca<superscript>2+</superscript> spark produced by the Ca<superscript>2+</superscript> efflux. This component of the model is largely based on a previously published model of Ca<superscript>2+</superscript> diffusion, buffering and imaging processes that produce the Ca<superscript>2+</superscript> spark (Smith <emphasis>et al.</emphasis>, 1998).
</para>
</sect1>
</article>
</documentation>
<!--
Below, we define some additional units for association with variables and
constants within the model. The identifiers are fairly self-explanatory.
-->
<units name="millimolar">
<unit units="mole" prefix="milli"/>
<unit units="litre" exponent="-1"/>
</units>
<units name="micromolar">
<unit units="mole" prefix="micro"/>
<unit units="litre" exponent="-1"/>
</units>
<units name="nanomolar">
<unit units="mole" prefix="nano"/>
<unit units="litre" exponent="-1"/>
</units>
<units name="flux">
<unit units="micromolar"/>
<unit units="second" exponent="-1"/>
</units>
<units name="first_order_rate_constant">
<unit units="second" exponent="-1"/>
</units>
<units name="second_order_rate_constant">
<unit units="micromolar" exponent="-1"/>
<unit units="second" exponent="-1"/>
</units>
<units name="third_order_rate_constant">
<unit units="micromolar" exponent="-1"/>
<unit units="second" exponent="-1"/>
</units>
<units name="picoA">
<unit units="ampere" prefix="pico"/>
</units>
<units name="coulomb_per_mole">
<unit units="coulomb"/>
<unit units="mole" exponent="-1"/>
</units>
<units name="micro_litre">
<unit units="litre" prefix="micro"/>
</units>
<!--
The "environment" component is used to declare variables that are used by
all or most of the other components, in this case just "time".
-->
<component name="environment">
<variable units="second" public_interface="out" name="time"/>
</component>
<component name="subspace">
<variable units="millimolar" public_interface="out" name="Ca_SS"/>
<variable units="flux" public_interface="out" name="J_RyR"/>
<variable units="flux" public_interface="out" name="J_buf"/>
<variable units="micro_litre" public_interface="out" name="V_SS" initial_value="1.0E-13"/>
<variable units="micromolar" name="Ca_myo" initial_value="0.1"/>
<variable units="coulomb_per_mole" name="F" initial_value="96480.0"/>
<variable units="flux" name="J_release"/>
<variable units="flux" name="J_DHPR"/>
<variable units="flux" name="J_efflux"/>
<variable units="dimensionless" name="i" initial_value="0.0"/>
<variable units="dimensionless" name="N" initial_value="50.0"/>
<variable units="picoA" name="I_DHPR" initial_value="-0.5"/>
<variable units="first_order_rate_constant" name="D_RyR" initial_value="4000.0"/>
<variable units="micromolar" name="Ca_B_SR_tot" initial_value="47.0"/>
<variable units="micromolar" name="Ca_B_CaM_tot" initial_value="24.0"/>
<variable units="micromolar" name="Ca_B_SL_tot" initial_value="1124.0"/>
<variable units="micromolar" name="Ca_B_trpnC_tot" initial_value="70.0"/>
<variable units="millimolar" name="Ca_B_SR"/>
<variable units="micromolar" name="Ca_B_CaM"/>
<variable units="micromolar" name="Ca_B_SL"/>
<variable units="micromolar" name="Ca_B_trpnC"/>
<variable units="second_order_rate_constant" name="k_on_SR" initial_value="115.0"/>
<variable units="first_order_rate_constant" name="k_off_SR" initial_value="100.0"/>
<variable units="second_order_rate_constant" name="k_on_CaM" initial_value="100.0"/>
<variable units="first_order_rate_constant" name="k_off_CaM" initial_value="38.0"/>
<variable units="second_order_rate_constant" name="k_on_trpnC" initial_value="39.0"/>
<variable units="first_order_rate_constant" name="k_off_trpnC" initial_value="20.0"/>
<variable units="second_order_rate_constant" name="k_on_SL" initial_value="115.0"/>
<variable units="first_order_rate_constant" name="k_off_SL" initial_value="1000.0"/>
<variable units="second" name="tau_efflux" initial_value="7.0E-7"/>
<variable units="dimensionless" name="RyR_open" initial_value="0.0"/>
<variable units="millimolar" public_interface="in" name="Ca_lumen"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="calcium_subspace_diff_eq">
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> Ca_SS </ci>
</apply>
<apply>
<plus/>
<ci> J_release </ci>
<ci> J_DHPR </ci>
<ci> J_efflux </ci>
<ci> J_buf </ci>
</apply>
</apply>
<apply id="J_DHPR_calculation">
<eq/>
<ci> J_DHPR </ci>
<apply>
<minus/>
<apply>
<divide/>
<ci> I_DHPR </ci>
<apply>
<times/>
<cn cellml:units="dimensionless"> 2.0 </cn>
<ci> F </ci>
<ci> V_SS </ci>
</apply>
</apply>
</apply>
</apply>
<apply id="J_release_calculation">
<eq/>
<ci> J_release </ci>
<apply>
<sum/>
<bvar>
<ci> i </ci>
</bvar>
<lowlimit>
<cn cellml:units="dimensionless"> 1.0 </cn>
</lowlimit>
<highlimit>
<ci> N </ci>
</highlimit>
<apply>
<times/>
<ci> RyR_open </ci>
<ci> J_RyR </ci>
</apply>
</apply>
</apply>
<apply id="J_RyR_calculation">
<eq/>
<ci> J_RyR </ci>
<apply>
<times/>
<ci> D_RyR </ci>
<apply>
<minus/>
<ci> Ca_lumen </ci>
<ci> Ca_SS </ci>
</apply>
</apply>
</apply>
<apply id="RyR_open_calculation">
<eq/>
<ci> RyR_open </ci>
<piecewise>
<piece>
<cn cellml:units="dimensionless"> 0.0 </cn>
<apply>
<eq/>
<ci> i </ci>
<cn cellml:units="dimensionless"> 0.0 </cn>
</apply>
</piece>
<otherwise>
<cn cellml:units="dimensionless"> 1.0 </cn>
</otherwise>
</piecewise>
</apply>
<apply id="Ca_B_SR_diff_eq">
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> Ca_B_SR </ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> k_on_SR </ci>
<ci> Ca_SS </ci>
<ci> Ca_B_SR </ci>
</apply>
<apply>
<times/>
<ci> k_off_SR </ci>
<apply>
<minus/>
<ci> Ca_B_SR_tot </ci>
<ci> Ca_B_SR </ci>
</apply>
</apply>
</apply>
</apply>
<apply id="Ca_B_trpnC_diff_eq">
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> Ca_B_trpnC </ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> k_on_trpnC </ci>
<ci> Ca_SS </ci>
<ci> Ca_B_trpnC </ci>
</apply>
<apply>
<times/>
<ci> k_off_trpnC </ci>
<apply>
<minus/>
<ci> Ca_B_trpnC_tot </ci>
<ci> Ca_B_trpnC </ci>
</apply>
</apply>
</apply>
</apply>
<apply id="Ca_B_CaM_diff_eq">
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> Ca_B_CaM </ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> k_on_CaM </ci>
<ci> Ca_SS </ci>
<ci> Ca_B_CaM </ci>
</apply>
<apply>
<times/>
<ci> k_off_CaM </ci>
<apply>
<minus/>
<ci> Ca_B_CaM_tot </ci>
<ci> Ca_B_CaM </ci>
</apply>
</apply>
</apply>
</apply>
<apply id="Ca_B_SL_diff_eq">
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> Ca_B_SL </ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> k_on_SL </ci>
<ci> Ca_SS </ci>
<ci> Ca_B_SL </ci>
</apply>
<apply>
<times/>
<ci> k_off_SL </ci>
<apply>
<minus/>
<ci> Ca_B_SL_tot </ci>
<ci> Ca_B_SL </ci>
</apply>
</apply>
</apply>
</apply>
<apply id="J_buf_calculation">
<eq/>
<ci> J_buf </ci>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<times/>
<ci> k_on_CaM </ci>
<ci> Ca_SS </ci>
<ci> Ca_B_CaM </ci>
</apply>
<apply>
<times/>
<ci> k_off_CaM </ci>
<apply>
<minus/>
<ci> Ca_B_CaM_tot </ci>
<ci> Ca_B_CaM </ci>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> k_on_trpnC </ci>
<ci> Ca_SS </ci>
<ci> Ca_B_trpnC </ci>
</apply>
<apply>
<times/>
<ci> k_off_trpnC </ci>
<apply>
<minus/>
<ci> Ca_B_trpnC_tot </ci>
<ci> Ca_B_trpnC </ci>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> k_on_SR </ci>
<ci> Ca_SS </ci>
<ci> Ca_B_SR </ci>
</apply>
<apply>
<times/>
<ci> k_off_SR </ci>
<apply>
<minus/>
<ci> Ca_B_SR_tot </ci>
<ci> Ca_B_SR </ci>
</apply>
</apply>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> k_on_SL </ci>
<ci> Ca_SS </ci>
<ci> Ca_B_SL </ci>
</apply>
<apply>
<times/>
<ci> k_off_SL </ci>
<apply>
<minus/>
<ci> Ca_B_SL_tot </ci>
<ci> Ca_B_SL </ci>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply id="J_efflux_calculation">
<eq/>
<ci> J_efflux </ci>
<apply>
<divide/>
<apply>
<plus/>
<ci> Ca_myo </ci>
<ci> Ca_SS </ci>
</apply>
<ci> tau_efflux </ci>
</apply>
</apply>
</math>
</component>
<component name="lumen">
<variable units="millimolar" public_interface="out" name="Ca_lumen"/>
<variable units="flux" name="J_refill"/>
<variable units="second" name="tau_refill" initial_value="0.01"/>
<variable units="millimolar" name="Ca_NSR" initial_value="1.0"/>
<variable units="micro_litre" name="V_JSR" initial_value="1.0E-11"/>
<variable units="millimolar" name="CSQ_tot" initial_value="10.0"/>
<variable units="millimolar" name="CSQ"/>
<variable units="millimolar" name="K_CSQ" initial_value="0.8"/>
<variable units="dimensionless" name="beta_JSR"/>
<variable units="flux" public_interface="in" name="J_RyR"/>
<variable units="micro_litre" public_interface="in" name="V_SS"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="calcium_lumen_diff_eq">
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> Ca_lumen </ci>
</apply>
<apply>
<times/>
<ci> beta_JSR </ci>
<apply>
<plus/>
<apply>
<times/>
<apply>
<minus/>
<ci> J_RyR </ci>
</apply>
<apply>
<divide/>
<ci> V_SS </ci>
<ci> V_JSR </ci>
</apply>
</apply>
<ci> J_refill </ci>
</apply>
</apply>
</apply>
<apply id="J_refill_calculation">
<eq/>
<ci> J_refill </ci>
<apply>
<divide/>
<apply>
<minus/>
<ci> Ca_NSR </ci>
<ci> Ca_lumen </ci>
</apply>
<ci> tau_refill </ci>
</apply>
</apply>
<apply id="beta_JSR_calculation">
<eq/>
<ci> beta_JSR </ci>
<apply>
<power/>
<apply>
<plus/>
<cn cellml:units="dimensionless"> 1.0 </cn>
<apply>
<divide/>
<apply>
<times/>
<ci> CSQ_tot </ci>
<ci> K_CSQ </ci>
</apply>
<apply>
<power/>
<apply>
<plus/>
<ci> CSQ </ci>
<ci> K_CSQ </ci>
</apply>
<cn cellml:units="dimensionless"> 2.0 </cn>
</apply>
</apply>
</apply>
<cn cellml:units="dimensionless"> -1.0 </cn>
</apply>
</apply>
</math>
</component>
<component name="RyR_receptor_gating">
<variable units="dimensionless" name="k_coop" initial_value="1.0"/>
<variable units="first_order_rate_constant" name="k_close"/>
<variable units="first_order_rate_constant" name="k_open"/>
<variable units="dimensionless" name="CF_close"/>
<variable units="dimensionless" name="CF_open"/>
<variable units="dimensionless" name="N_closed"/>
<variable units="dimensionless" name="N_open"/>
<variable units="micromolar" name="K_m"/>
<variable units="second" public_interface="in" name="time"/>
<variable units="millimolar" public_interface="in" name="Ca_lumen"/>
<variable units="millimolar" public_interface="in" name="Ca_SS"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="k_close_calculation">
<eq/>
<ci> k_close </ci>
<apply>
<times/>
<ci> CF_close </ci>
<cn cellml:units="first_order_rate_constant"> 480.0 </cn>
</apply>
</apply>
<apply id="k_open_calculation">
<eq/>
<ci> k_open </ci>
<apply>
<times/>
<ci> CF_open </ci>
<cn cellml:units="first_order_rate_constant"> 30000.0 </cn>
<apply>
<divide/>
<apply>
<power/>
<ci> Ca_SS </ci>
<cn cellml:units="dimensionless"> 4.0 </cn>
</apply>
<apply>
<plus/>
<apply>
<power/>
<ci> Ca_SS </ci>
<cn cellml:units="dimensionless"> 4.0 </cn>
</apply>
<apply>
<power/>
<ci> K_m </ci>
<cn cellml:units="dimensionless"> 4.0 </cn>
</apply>
</apply>
</apply>
</apply>
</apply>
<apply id="K_m_calculation">
<eq/>
<ci> K_m </ci>
<apply>
<minus/>
<cn cellml:units="micromolar"> 6.0 </cn>
<apply>
<times/>
<cn cellml:units="dimensionless"> 0.0024 </cn>
<ci> Ca_lumen </ci>
</apply>
</apply>
</apply>
<apply id="CF_open_calculation">
<eq/>
<ci> CF_open </ci>
<apply>
<plus/>
<cn cellml:units="dimensionless"> 1.0 </cn>
<apply>
<divide/>
<apply>
<plus/>
<ci> N_open </ci>
<cn cellml:units="dimensionless"> 1.0 </cn>
</apply>
<apply>
<plus/>
<ci> N_open </ci>
<ci> N_closed </ci>
</apply>
</apply>
</apply>
</apply>
<apply id="CF_close_calculation">
<eq/>
<ci> CF_close </ci>
<apply>
<times/>
<ci> k_coop </ci>
<apply>
<plus/>
<cn cellml:units="dimensionless"> 1.0 </cn>
<apply>
<divide/>
<apply>
<plus/>
<ci> N_closed </ci>
<cn cellml:units="dimensionless"> 1.0 </cn>
</apply>
<apply>
<plus/>
<ci> N_open </ci>
<ci> N_closed </ci>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="spark_model">
<variable units="millimolar" name="Ca"/>
<variable units="millimolar" name="Ca_F"/>
<variable units="millimolar" name="Ca_trpnC"/>
<variable units="millimolar" name="Ca_CaM"/>
<variable units="third_order_rate_constant" name="DC" initial_value="250.0"/>
<variable units="third_order_rate_constant" name="DF" initial_value="20.0"/>
<variable units="micromolar" name="F_T" initial_value="50.0"/>
<variable units="flux" name="J_pump"/>
<variable units="flux" name="J_leak"/>
<variable units="flux" name="J_n"/>
<variable units="flux" name="J_dye"/>
<variable units="flux" name="Vmax_pump" initial_value="208.0"/>
<variable units="micromolar" name="Km_pump" initial_value="0.184"/>
<variable units="dimensionless" name="m" initial_value="3.9"/>
<variable units="nanomolar" name="C_infinity" initial_value="100.0"/>
<variable units="second_order_rate_constant" name="k_F_plus" initial_value="80.0"/>
<variable units="first_order_rate_constant" name="k_F_minus" initial_value="40.0"/>
<variable units="second" public_interface="in" name="time"/>
<variable units="flux" public_interface="in" name="J_RyR"/>
<variable units="flux" public_interface="in" name="J_buf"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="cytosolic_calcium_diff_eq">
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> Ca </ci>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci> DC </ci>
<ci> Ca </ci>
</apply>
<ci> J_dye </ci>
<ci> J_buf </ci>
<ci> J_pump </ci>
<ci> J_leak </ci>
<ci> J_RyR </ci>
</apply>
</apply>
<apply id="calcium_bound_dye_diff_eq">
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> Ca_F </ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci> DF </ci>
<ci> Ca_F </ci>
</apply>
<ci> J_dye </ci>
</apply>
</apply>
<apply id="J_dye_calculation">
<eq/>
<ci> J_dye </ci>
<apply>
<plus/>
<apply>
<times/>
<apply>
<minus/>
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<power/>
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<ci> Km_pump </ci>
<apply>
<power/>
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This is the CellML description of Sobie et al's 2002 model of
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Added publication date information.
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Termination of Cardiac Ca2+ Sparks: An Investigative Mathematical Model of Calcium-Induced Calcium Release
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Sobie et al's 2002 model of calcium-induced calcium release in cardiac
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