VanLeeuwen2009WntSwatCellCycleOdeSystem.cpp

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#include "VanLeeuwen2009WntSwatCellCycleOdeSystem.hpp"
#include "CellwiseOdeSystemInformation.hpp"
#include "IsNan.hpp"
#include "ApcOneHitCellMutationState.hpp"
#include "ApcTwoHitCellMutationState.hpp"
#include "BetaCateninOneHitCellMutationState.hpp"

VanLeeuwen2009WntSwatCellCycleOdeSystem::VanLeeuwen2009WntSwatCellCycleOdeSystem(unsigned hypothesis,
                                                                                 double wntLevel,
                                                                                 boost::shared_ptr<AbstractCellMutationState> pMutationState,
                                                                                 std::vector<double> stateVariables)
    : AbstractOdeSystem(22),
      mpMutationState(pMutationState),
      mHypothesis(hypothesis),
      mWntLevel(wntLevel)
{
    if (hypothesis!=1 && hypothesis!=2)
    {
        EXCEPTION("You must set up this cell cycle ODE system with hypothesis one or two.");
    }

    mpSystemInfo.reset(new CellwiseOdeSystemInformation<VanLeeuwen2009WntSwatCellCycleOdeSystem>);

    Init(); // set up parameter values

    double d_d_hat = mDd + mXiD*wntLevel;
    double d_d_x_hat = mDdx + mXiDx*wntLevel;
    double d_x_hat = mDx + mXiX*wntLevel;
    double p_c_hat = mPc + mXiC*wntLevel;

    double sigma_D = 0.0; // for healthy cells
    //double sigma_B = 0.0; // for healthy cells - never used!

    if (!mpMutationState)
    {
        // No mutations specified
    }
    else if (mpMutationState->IsType<ApcOneHitCellMutationState>())
    {
        sigma_D = 0.5;
    }
    else if (mpMutationState->IsType<ApcTwoHitCellMutationState>())
    {
        sigma_D = 1.0;
    }
    else if (mpMutationState->IsType<BetaCateninOneHitCellMutationState>())
    {
        //sigma_B = 0.5; // never used!
    }
    // Other mutations have no effect.

    // Cell-specific initial conditions
    double steady_D = ((1.0-sigma_D)*mSd*mSx)/((1.0-sigma_D)*mSd*d_d_hat + d_x_hat*(d_d_hat + d_d_x_hat));
    SetDefaultInitialCondition(5, steady_D); // Destruction complex (APC/Axin/GSK3B)

    double temp = (mSx*(d_d_hat+d_d_x_hat))/((1.0-sigma_D)*mSd*d_d_hat+d_x_hat*(d_d_hat+d_d_x_hat));
    SetDefaultInitialCondition(6, temp);  // Axin

    double steady_Cf = ((mSc-mDc*mKd - mPu*steady_D)+sqrt(SmallPow((mSc-mDc*mKd - mPu*steady_D),2) + (4.0*mSc*mDc*mKd)))/(2.0*mDc);
    temp = (mPu*steady_D*steady_Cf)/(mDu*(steady_Cf+mKd));
    SetDefaultInitialCondition(7, temp); // beta-catenin to be ubiquitinated

    double theta = mDc + (mPu*steady_D)/(steady_Cf + mKd);

    double steady_Co = ( mSc - p_c_hat - theta*mKc + sqrt(4.0*mSc*theta*mKc + SmallPow((mSc - p_c_hat - theta*mKc),2)) )/(2.0*theta);
    SetDefaultInitialCondition(8, steady_Co); // Open form beta-catenin

    double steady_Cc = steady_Cf - steady_Co;

    if ((steady_Cc < 0) && (steady_Cc+100*DBL_EPSILON > 0) ) // stop protein values going -ve
    {
        steady_Cc = 0.0;
    }
    SetDefaultInitialCondition(9, steady_Cc); // Closed form beta-catenin

    SetDefaultInitialCondition(12, mSa/mDa);  // 'Free' adhesion molecules

    SetDefaultInitialCondition(13, mSa*mSca*steady_Co/(mDa*mDca)); // Co-A Adhesion complex

    SetDefaultInitialCondition(15, mSt/mDt); // `Free' transcription molecules (TCF)

    SetDefaultInitialCondition(16, mSct*mSt*steady_Co/(mDt*mDct)); // Co-T open form beta-catenin/TCF

    SetDefaultInitialCondition(17, mSct*mSt*steady_Cc/(mDt*mDct)); // Cc-T closed beta-catenin/TCF

    temp = (mSct*mSt*mSy*steady_Cf)/(mDy*(mSct*mSt*steady_Cf + mDct*mDt*mKt));
    SetDefaultInitialCondition(20, temp); // Wnt target protein

    SetDefaultInitialCondition(21, wntLevel); // Wnt stimulus

    if (stateVariables != std::vector<double>())
    {
        SetStateVariables(stateVariables);
    }
}

void VanLeeuwen2009WntSwatCellCycleOdeSystem::SetMutationState(boost::shared_ptr<AbstractCellMutationState> pMutationState)
{
    mpMutationState = pMutationState;
}

VanLeeuwen2009WntSwatCellCycleOdeSystem::~VanLeeuwen2009WntSwatCellCycleOdeSystem()
{
    // Do nothing
}

void VanLeeuwen2009WntSwatCellCycleOdeSystem::Init()
{
    // Swat (2004) parameters
    double k1 = 1.0;
    double k2 = 1.6;
    double k3 = 0.05;
    double k16 = 0.4;
    double k34 = 0.04;
    double k43 = 0.01;
    double k61 = 0.3;
    double k23 = 0.3;
    double a = 0.04;
    double J11 = 0.5;
    double J12 = 5.0;
    double J61 = 5.0;
    double J62 = 8.0;
    double J13 = 0.002;
    double J63 = 2.0;
    double Km1 = 0.5;
    double Km2 = 4.0;
    double Km4 = 0.3;
    double kp = 0.05;
    double phi_pRb = 0.005;
    double phi_E2F1 = 0.1;
    double phi_CycDi = 0.023;
    double phi_CycDa = 0.03;
    double phi_pRbp = 0.06;

    // Value of the mitogenic factor to make the van Leeuwen model influence cell cycle just the same
    double mitogenic_factorF = 1.0/25.0;

    // Non-dimensionalise parameters
    mk2d = k2/(Km2*phi_E2F1);
    mk3d = k3*mitogenic_factorF/(Km4*phi_E2F1);
    mk34d = k34/phi_E2F1;
    mk43d = k43/phi_E2F1;
    mk23d = k23*Km2/(Km4*phi_E2F1);
    mad = a/Km2;
    mJ11d = J11*phi_E2F1/k1;
    mJ12d = J12*phi_E2F1/k1;
    mJ13d = J13*phi_E2F1/k1;
    mJ61d = J61*phi_E2F1/k1;
    mJ62d = J62*phi_E2F1/k1;
    mJ63d = J63*phi_E2F1/k1;
    mKm1d = Km1/Km2;
    mkpd = kp/(Km2*phi_E2F1);
    mphi_r = phi_pRb/phi_E2F1;
    mphi_i = phi_CycDi/phi_E2F1;
    mphi_j = phi_CycDa/phi_E2F1;
    mphi_p = phi_pRbp/phi_E2F1;
    mk16d = k16*Km4/phi_E2F1;
    mk61d = k61/phi_E2F1;
    mPhiE2F1 = phi_E2F1;

    // Initialize van Leeuwen model parameters
    mSa = 20;   //  nM/h
    mSca = 250; //  (nMh)^-1
    mSc = 25;   //  nM/h
    mSct = 30;  //  (nMh)^-1
    mSd = 100;  //  h^-1
    mSt = 10;   //  nM/h
    mSx = 10;   //  nM/h
    mSy = 10;   //  h^-1
    mDa = 2;    //  h^-1
    mDca = 350; //  h^-1
    mDc = 1;    //  h^-1
    mDct = 750; //  h^-1
    mDd = 5;    //  h^-1
    mDdx = 5;   //  h^-1
    mDt = 0.4;  //  h^-1
    mDu = 50;   //  h^-1
    mDx = 100;  //  h^-1
    mDy = 1;    //  h^-1
    mKc = 200;  //  nM
    mKd = 5;    //  nM
    mKt = 50;   //  nM
    mPc = 0.0;  //  h^-1
    mPu = 100;  //  h^-1
    mXiD = 5;   //  h^-1
    mXiDx = 5;  //  h^-1
    mXiX = 200; //  h^-1
    if (mHypothesis==1)
    {
        mXiC = 0.0; //  h^-1 (FOR HYPOTHESIS ONE)
    }
    else
    {
        mXiC = 5000.0;   //  h^-1 (FOR HYPOTHESIS TWO)
    }
}

void VanLeeuwen2009WntSwatCellCycleOdeSystem::EvaluateYDerivatives(double time, const std::vector<double>& rY, std::vector<double>& rDY)
{
    double r = rY[0];
    double e = rY[1];
    double i = rY[2];
    double j = rY[3];
    double p = rY[4];

    double dx1 = 0.0;
    double dx2 = 0.0;
    double dx3 = 0.0;
    double dx4 = 0.0;
    double dx5 = 0.0;

    // Bit back-to-front, but work out the Wnt section first...

    // Variables
    double D = rY[5];
    double X = rY[6];
    double Cu = rY[7];
    double Co = rY[8];
    double Cc = rY[9];
    double Mo = rY[10];
    double Mc = rY[11];
    double A = rY[12];
    double Ca = rY[13];
    double Ma = rY[14];
    double T = rY[15];
    double Cot = rY[16];
    double Cct = rY[17];
    double Mot = rY[18];
    double Mct = rY[19];
    double Y = rY[20];
    double stimulus_wnt = rY[21];

    // Totals
    double Cf = Cc+Co;
    double Ct = Cct+Cot;
    double Mf = Mc+Mo;
    double Mt = Mct+Mot;

    double d_d_hat = mDd + mXiD*stimulus_wnt;
    double d_d_x_hat = mDdx + mXiDx*stimulus_wnt;
    double d_x_hat = mDx + mXiX*stimulus_wnt;
    double p_c_hat = mPc + mXiC*stimulus_wnt;

    double sigma_D = 0.0;   // for healthy cells
    double sigma_B = 0.0;   // for healthy cells

    if (!mpMutationState)
    {
        // No mutations specified
    }
    else if (mpMutationState->IsType<ApcOneHitCellMutationState>())
    {
        sigma_D = 0.5;
    }
    else if (mpMutationState->IsType<ApcTwoHitCellMutationState>())
    {
        sigma_D = 1.0;
    }
    else if (mpMutationState->IsType<BetaCateninOneHitCellMutationState>())
    {
        sigma_B = 0.5;
    }
    // Other mutations have no effect.

    // Now the cell cycle stuff...

    // dr
    dx1 = e/(mKm1d+e)*mJ11d/(mJ11d+r)*mJ61d/(mJ61d+p) - mk16d*r*j+mk61d*p-mphi_r*r;
    // de
    dx2 = mkpd+mk2d*(mad*mad+e*e)/(1+e*e)*mJ12d/(mJ12d+r)*mJ62d/(mJ62d+p) - e;
    // di - changed to include Ct+Mt - transcriptional beta-catenin
    dx3 = mk3d*(Ct+Mt) + mk23d*e*mJ13d/(mJ13d+r)*mJ63d/(mJ63d+p) + mk43d*j - mk34d*i*j/(1+j) - mphi_i*i;
    // dj
    dx4 = mk34d*i*j/(1+j) - (mk43d+mphi_j)*j;
    // dp
    dx5 = mk16d*r*j - mk61d*p - mphi_p*p;

    double factor = mPhiE2F1*60.0;  // Convert non-dimensional d/dt s to d/dt in hours.

    rDY[0] = dx1*factor;
    rDY[1] = dx2*factor;
    rDY[2] = dx3*factor;
    rDY[3] = dx4*factor;
    rDY[4] = dx5*factor;

    // The van Leeuwen ODE system
    rDY[5] = (1.0-sigma_D)*mSd*X - (d_d_hat + d_d_x_hat)*D;
    rDY[6] = mSx - (1.0-sigma_D)*mSd*X - d_x_hat*X + d_d_x_hat*D;
    rDY[7] = (mPu*D*Cf)/(Cf+mKd) - mDu*Cu;

    rDY[8] = (1.0-sigma_B)*mSc + mDca*Ca + mDct*Cot - (mSca*A + mSct*T + mDc)*Co
             - (p_c_hat*Co)/(Co + Mo + mKc) - (mPu*D*Co)/(Cf+mKd);

    rDY[9] = (p_c_hat*Co)/(Co + Mo + mKc) + mDct*Cct - (mSct*T + mDc)*Cc
             - (mPu*D*Cc)/(Cf+mKd);

    rDY[10] = sigma_B*mSc + mDca*Ma + mDct*Mot - (mSca*A + mSct*T + mDc)*Mo
             - (p_c_hat*Mo)/(Co + Mo + mKc);

    rDY[11] = (p_c_hat*Mo)/(Co + Mo + mKc) + mDct*Mct - (mSct*T + mDc)*Mc;
    rDY[12] = mSa + mDca*(Ca+Ma) - (mSca*(Co+Mo) + mDa)*A;
    rDY[13] = mSca*Co*A - mDca*Ca;
    rDY[14] = mSca*Mo*A - mDca*Ma;
    rDY[15] = mSt + mDct*(Ct+Mt) - mSct*(Cf+Mf)*T - mDt*T;
    rDY[16] = mSct*Co*T - mDct*Cot;
    rDY[17] = mSct*Cc*T - mDct*Cct;
    rDY[18] = mSct*Mo*T - mDct*Mot;
    rDY[19] = mSct*Mc*T - mDct*Mct;
    rDY[20] = (mSy*(Ct+Mt))/(Ct + Mt + mKt) - mDy*Y;
    rDY[21] = 0.0;  // don't interfere with Wnt stimulus
}

const boost::shared_ptr<AbstractCellMutationState> VanLeeuwen2009WntSwatCellCycleOdeSystem::GetMutationState() const
{
    return mpMutationState;
}

bool VanLeeuwen2009WntSwatCellCycleOdeSystem::CalculateStoppingEvent(double time, const std::vector<double>& rY)
{
    std::vector<double> dy(rY.size());
    EvaluateYDerivatives(time, rY, dy);

    return (rY[1] > 1.0 && dy[1] > 0.0);
}

double VanLeeuwen2009WntSwatCellCycleOdeSystem::CalculateRootFunction(double time, const std::vector<double>& rY)
{
    return rY[1] - 1.0;
}

template<>
void CellwiseOdeSystemInformation<VanLeeuwen2009WntSwatCellCycleOdeSystem>::Initialise()
{
    this->mVariableNames.push_back("pRb");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(7.357000000000000e-01);

    this->mVariableNames.push_back("E2F1");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(1.713000000000000e-01);

    this->mVariableNames.push_back("CycD_i");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(6.900000000000001e-02);

    this->mVariableNames.push_back("CycD_a");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(3.333333333333334e-03);

    this->mVariableNames.push_back("pRb_p");
    this->mVariableUnits.push_back("non_dim");
    this->mInitialConditions.push_back(1.000000000000000e-04);

    this->mVariableNames.push_back("D");  // Destruction complex (APC/Axin/GSK3B)
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("X");  // Axin
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Cu"); // beta-catenin to be ubiquitinated
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Co"); // Open form beta-catenin
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Cc"); // Closed form beta-catenin
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Mo"); // Open form mutant beta-catenin
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(0.0);

    this->mVariableNames.push_back("Mc"); // Closed form mutant beta-catenin
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(0.0);

    this->mVariableNames.push_back("A");  // 'Free' adhesion molecules
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Ca"); // Co-A Adhesion complex
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Ma"); // Mo-A Mutant adhesion complex
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(0.0);

    this->mVariableNames.push_back("T"); // `Free' transcription molecules (TCF)
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Cot"); // Co-T open form beta-catenin/TCF
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Cct"); // Cc-T closed beta-catenin/TCF
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Mot"); // Mo-T open form mutant beta-catenin/TCF
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(0.0);

    this->mVariableNames.push_back("Mct"); // Mc-T closed form mutant beta-catenin/TCF
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(0.0);

    this->mVariableNames.push_back("Y"); // Wnt target protein
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mVariableNames.push_back("Sw"); // Wnt stimulus
    this->mVariableUnits.push_back("nM");
    this->mInitialConditions.push_back(NAN); // will be filled in later

    this->mInitialised = true;
}

double VanLeeuwen2009WntSwatCellCycleOdeSystem::GetWntLevel() const
{
    return mWntLevel;
}

unsigned VanLeeuwen2009WntSwatCellCycleOdeSystem::GetHypothesis() const
{
    return mHypothesis;
}

// Serialization for Boost >= 1.36
#include "SerializationExportWrapperForCpp.hpp"
CHASTE_CLASS_EXPORT(VanLeeuwen2009WntSwatCellCycleOdeSystem)