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runfile_SERCA.m
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% main runfile AL
% 10/08/2021
%
% clear workspace
clear
% close all
load('finalpars.mat')
load('newparams.mat')
%% Which Figures do you want to generate?
% From 2-7
% For figure 8, need to use bifurcation scripts
figselect = [9];
figselect = [2,3,4,5,6,7,9,10];
% figselect = [6];
getplotid
% %figselect = [2];
finalpars(105) = 3;
pars = finalpars;
%% Initial conditions
init = leung_icsource;
%% inserted to swap to fit pars
% pars = newparams(1:162);
% finalpars =pars;
% init = newparams(163:222);
% init(38) =-init(38);
%Integration options
options = odeset('InitialStep',1e-6);
% options = odeset('RelTol',1e-5, 'AbsTol',1e-8, 'MaxStep',1e-1, ...
% 'InitialStep',1e-5, 'MaxOrder',5, 'BDF','on','NonNegative',[1:37,39:60]);
t_prior = 0 ;
t_start = 10000;
pulsetime = -100;
init_baseval = init;
kHYD = pars(4);
[t0, y_ss]= ode15s(@leung2022_SERCA,[t_prior t_start],init,...
options,pars, kHYD,pulsetime);
for fig_index = figselect
%% Initialization of Runtime Parameters
pulsetime = 0;
kHYD = pars(4);
glutconc = 50; % muM
disp(['Simulating for Figure ' num2str(fig_index)])
%% Figure 2 : Steady State System
if fig_index == 2
%% Simulation Engine for Steady State
% initialization run
% or load premade initialization data
% initcond = y_ss(end,:);
%
% %% Sensitivity Analysis
% [t, y]= ode15s(@leung2022_SERCA,[0,500],initcond,...
% options,co_pars, kHYD,pulsetime);
t = t0;
y = y_ss;
plotfigure2
end
%% Figure 3 Simple stimulus
if fig_index == 3
%% Simulation Engine
% initialization run
% or load premade initialization data
initcond = y_ss(end,:);
stimstart =0;
y = [y_ss(end,:)];
t = [0];
stim_dur =50;
pulsetime = 0;
frequency = 1; %Hz
intervals = 1/frequency;%s
timevec = (stimstart:intervals:stimstart+stim_dur);
for i = 1:(size(timevec,2)-1) %simulate stimulus section
startpoint = timevec(i)+0.001;
endpoint = timevec(i+1);
initcond = y(end,:);
initcond(12) = glutconc;
pulsetime = startpoint;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[startpoint endpoint],initcond,...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
end
recov_dur = 5000;
recovtime = timevec(end)+1:1:timevec(end) +recov_dur;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[recovtime],y(end,:),...
options,pars, kHYD,pulsetime); % simulate steady state
y = [y;x_temp];
t = [t;t_temp];
stimstart=recovtime(end)+0.001;
t_auc = t;
y_auc = y;
t = [t0(1:end)-t_start;t];
y = [y_ss(1:end,:);y];
%compute metrics
[~,t200] = min(abs(t_auc-200));
[~,t400] = min(abs(t_auc-400));
[~,t600] = min(abs(t_auc-600));
% compute AUC
% compute baseline AUC
AMPK_base = trapz(t_auc(t400:t600),y_auc(t400:t600,pAMPK));
mTORC1_base = trapz(t_auc(t400:t600),y_auc(t400:t600,pmTORC1));
mTORC2_base = trapz(t_auc(t400:t600),y_auc(t400:t600,pmTORC2));
CaC_base = trapz(t_auc(t400:t600),y_auc(t400:t600,Ca_C));
% compute AUC for time period
AMPK_AUC = trapz(t_auc(1:t200),y_auc(1:t200,pAMPK));
mTORC1_AUC = trapz(t_auc(1:t200),y_auc(1:t200,pmTORC1));
mTORC2_AUC = trapz(t_auc(1:t200),y_auc(1:t200,pmTORC2));
CaC_AUC = trapz(t_auc(1:t200),y_auc(1:t200,Ca_C));
% % compute baseline AUC
% AMPK_base(inttime_ind,fscan_ind) = trapz(t(t400:t600),y(t400:basetime(inttime_ind),pAMPK));
% mTORC1_base(inttime_ind,fscan_ind) = trapz(t(t400:t600),y(t400:basetime(inttime_ind),pmTORC1));
% mTORC2_base(inttime_ind,fscan_ind) = trapz(t(t400:t600),y(t400:basetime(inttime_ind),pmTORC2));
% CaC_base(inttime_ind,fscan_ind) = trapz(t(t400:t600),y(t400:basetime(inttime_ind),Ca_C));
% % compute AUC for time period
% AMPK_AUC(inttime_ind,fscan_ind) = trapz(t(1:t200),y(1:inttime(inttime_ind),pAMPK));
% mTORC1_AUC(inttime_ind,fscan_ind) = trapz(t(1:t200),y(1:inttime(inttime_ind),pmTORC1));
% mTORC2_AUC(inttime_ind,fscan_ind) = trapz(t(1:t200),y(1:inttime(inttime_ind),pmTORC2));
% CaC_AUC(inttime_ind,fscan_ind) = trapz(t(1:t200),y(1:inttime(inttime_ind),Ca_C));
% normalize to baseline
normAMPK = AMPK_AUC./AMPK_base ;
normmTOR1 = mTORC1_AUC./mTORC1_base ;
normmTOR2 = mTORC2_AUC./mTORC2_base ;
normCa = CaC_AUC./CaC_base ;
t_TC = t_auc;
ampk_TC = y_auc(:,pAMPK) ;
mTORC1_TC = y_auc(:,pmTORC1) ;
mTORC2_TC = y_auc(:,pmTORC2) ;
% time to peak
%Period
ampk_based = ampk_TC - mean(ampk_TC(floor(7*end/8):end));
m1_based = mTORC1_TC - mean(mTORC1_TC(floor(7*end/8):end));
m2_based = mTORC2_TC - mean(mTORC2_TC(floor(7*end/8):end));
[peakheight_a,tmaxes_a] = findpeaks(ampk_based,t_TC,'MinPeakWidth',2);
[mins_a,tmins_a] = findpeaks(-ampk_based,t_TC,'MinPeakWidth',2);
[peakheight_m1,tmaxes_m1] =findpeaks(m1_based,t_TC,'MinPeakWidth',2);
[ mins_m1,tmins_m1] = findpeaks(-m1_based,t_TC,'MinPeakWidth',2);
[peakheight_m2,tmaxes_m2] = findpeaks(m2_based,t_TC,'MinPeakWidth',2);
[mins_m2,tmins_m2] = findpeaks(-m2_based,t_TC,'MinPeakWidth',2);
dtmaxes_a =diff(tmaxes_a) ;
dtmaxes_m1=diff(tmaxes_m1) ;
dtmaxes_m2=diff(tmaxes_m2) ;
period_a= mean(dtmaxes_a(dtmaxes_a>3));
period_m1= mean(dtmaxes_m1(dtmaxes_m1>3));
period_m2 = mean(dtmaxes_m2(dtmaxes_m2>3));
%maximum amplitude
%first compute mean peak values
maxamp_a= max(peakheight_a);
maxamp_m1= max(peakheight_m1) ;
maxamp_m2= max(peakheight_m2) ;
%% Plots
plotfigure3
end
%% Figure 4 Frequency Scan
if fig_index == 4
%% Simulation Engine
% initialization run
% or load premade initialization data
%for freq_ind = 1:size(freq_vec,2)
% freq_scan = [0.1,1,10,100];
freq_scan = [0.1,1,10,50];
for fscan_ind = 1:numel(freq_scan)
j=freq_scan(fscan_ind);
initcond = y_ss(end,:);
stimstart =0;
y = [y_ss(end,:)];
t = [0];
stim_dur =5;
frequency = j; %Hz
intervals = 1/frequency;%s
timevec = (stimstart:intervals:stimstart+stim_dur);
if j==0.1
timevec = [0,10];
end
for i = 1:(size(timevec,2)-1)
startpoint = timevec(i)+0.00001;
endpoint = timevec(i+1);
initcond = y(end,:);
initcond(12) = glutconc;
pulsetime = startpoint;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[startpoint endpoint],initcond,...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
end
recov_dur = 5000;
recovtime = timevec(end)+0.000001:0.1:timevec(end) +recov_dur;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[recovtime],y(end,:),...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
stimstart=recovtime(end)+0.001;
t = [t0(1:end)-t_start;t];
y = [y_ss(1:end,:);y];
%% Plots
plotfigure4
end
end
%% Figure 5
if fig_index == 5
%% Simulation Engine
% initialization run
% or load premade initialization data
%for freq_ind = 1:size(freq_vec,2)
freq_scan = [0.1,1,10,50];
for fscan_ind = 1:numel(freq_scan)
j=freq_scan(fscan_ind);
initcond = y_ss(end,:);
stimstart =0;
y = [y_ss(end,:)];
t = [0];
stim_dur =5;
frequency = j; %Hz
intervals = 1/frequency;%s
timevec = (stimstart:intervals:stimstart+stim_dur);
if j==0.1
timevec = [0,10];
end
for i = 1:(size(timevec,2)-1)
startpoint = timevec(i)+0.00001;
endpoint = timevec(i+1);
initcond = y(end,:);
initcond(12) = glutconc;
pulsetime = startpoint;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[startpoint endpoint],initcond,...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
end
recov_dur = 5000;
recovtime = timevec(end)+1e-9:0.1:timevec(end) +recov_dur;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[recovtime],y(end,:),...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
stimstart=recovtime(end)+0.001;
% find indexes for simulation time
[~,t5] = min(abs(t-5));
[~,t100] = min(abs(t-50));
[~,t200] = min(abs(t-200));
[~,t400] = min(abs(t-400));
[~,t500] = min(abs(t-500));
[~,t700] = min(abs(t-700));
[~,t800] = min(abs(t-750));
% compute AUC
inttime = [t100,t200,t400];
basetime = t800;
% compute baseline AUC
AMPK_base(1,fscan_ind) = trapz(t(t700:t800),y(t700:t800,pAMPK));
mTORC1_base(1,fscan_ind) = trapz(t(t700:t800),y(t700:t800,pmTORC1));
mTORC2_base(1,fscan_ind) = trapz(t(t700:t800),y(t700:t800,pmTORC2));
CaC_base(1,fscan_ind) = trapz(t(t700:t800),y(t700:t800,Ca_C));
% compute AUC for time period
AMPK_AUC(1,fscan_ind) = trapz(t(1:t100),y(1:t100,pAMPK));
mTORC1_AUC(1,fscan_ind) = trapz(t(1:t100),y(1:t100,pmTORC1));
mTORC2_AUC(1,fscan_ind) = trapz(t(1:t100),y(1:t100,pmTORC2));
CaC_AUC(1,fscan_ind) = trapz(t(1:t100),y(1:t100,Ca_C));
% normalize to baseline
normAMPK = AMPK_AUC./AMPK_base ;
normmTOR1 = mTORC1_AUC./mTORC1_base ;
normmTOR2 = mTORC2_AUC./mTORC2_base ;
normCa = CaC_AUC./CaC_base ;
t_TC = t;
ampk_TC = y(:,pAMPK) ;
mTORC1_TC = y(:,pmTORC1) ;
mTORC2_TC = y(:,pmTORC2) ;
% time to peak
%Decay time
%Period
ampk_ss = mean(ampk_TC(floor(95*end/100):end));
m1_ss =mean(mTORC1_TC(floor(95*end/100):end));
m2_ss =mean(mTORC2_TC(floor(95*end/100):end));
ampk_based = ampk_TC - ampk_ss;
m1_based = mTORC1_TC - m1_ss;
m2_based = mTORC2_TC - m2_ss;
[peakheight_a,tmaxes_a] = findpeaks(ampk_based,t_TC,'MinPeakWidth',2);
[mins_a,tmins_a] = findpeaks(-ampk_based,t_TC,'MinPeakWidth',2);
[peakheight_m1,tmaxes_m1] =findpeaks(m1_based,t_TC,'MinPeakWidth',2);
[ mins_m1,tmins_m1] = findpeaks(-m1_based,t_TC,'MinPeakWidth',2);
[peakheight_m2,tmaxes_m2] = findpeaks(m2_based,t_TC,'MinPeakWidth',2);
[mins_m2,tmins_m2] = findpeaks(-m2_based,t_TC,'MinPeakWidth',2);
%Algorithm to find point when it timecourse returns to baseline
%values
% take abs value of ss subtracted values
ab_ampktc = abs(ampk_based);
ab_m1tc = abs(m1_based);
ab_m2tc = abs(m2_based);
% moving window mean of time course with a step size of 30 seconds
windowstart = t5;
ampk_movmean = movmean(ab_ampktc(windowstart:end), 60);
m1_movmean = movmean(ab_m1tc(windowstart:end), 60);
m2_movmean = movmean(ab_m2tc(windowstart:end), 60);
% < some threshold value
eq_thresh = 1e-8;
% find closest peak value
roc_AMPK = abs(diff(ampk_TC)./diff(t_TC));
roc_m1 = abs(diff(mTORC1_TC)./diff(t_TC));
roc_m2 = abs(diff(mTORC2_TC)./diff(t_TC));
ampkdiff_movmean = movmean(roc_AMPK(windowstart:end), 10);
m1diff_movmean = movmean(roc_m1(windowstart:end), 10);
m2diff_movmean = movmean(roc_m2(windowstart:end), 10);
threshind_a = find(ampkdiff_movmean-eq_thresh<0);
threshind_m1 = find(m1diff_movmean-eq_thresh<0);
threshind_m2 = find(m2diff_movmean-eq_thresh<0);
%
tte_a(fscan_ind)= t_TC (windowstart + threshind_a(1));
tte_m1(fscan_ind)= t_TC (windowstart + threshind_m1(1)) ;
tte_m2(fscan_ind) =t_TC (windowstart + threshind_m2(1)) ;
dtmaxes_a =diff(tmaxes_a) ;
dtmaxes_m1=diff(tmaxes_m1) ;
dtmaxes_m2=diff(tmaxes_m2) ;
%maximum amplitude
%first compute mean values
maxamp_a(fscan_ind)= max(peakheight_a)/ampk_ss;
maxamp_m1(fscan_ind)= max(peakheight_m1)/m1_ss;
maxamp_m2(fscan_ind)= max(peakheight_m2)/m2_ss;
%
%% Plots
% plotfigure4
%figure(411)
%plotfigure4_fft
end
% barlabel = categorical({'Calcium','pAMPK','pmTORC1','pmTORC2'});
%bar(barlabel,[CaC_AUC./max(CaC_AUC);AMPK_AUC./max(AMPK_AUC);mTORC1_AUC./max(mTORC1_AUC);mTORC2_AUC./max(mTORC2_AUC)])
%ylabel('Normalized Area Under Curve')
%legend('0.1 Hz','1','10','100')
plotfigure5_metrics
end
%% Figure 6
if fig_index == 6
clear AMPK_AUC mTORC1_AUC CaC_AUC mTORC2_AUC
%% Simulation Engine
% initialization run
% or load premade initialization data
%for freq_ind = 1:size(freq_vec,2)
parscan = [0.1,1,2,3];
kHYDbasal = kHYD;
for j = 1:numel(parscan)
h = parscan(j);
kHYD = kHYDbasal * h;
initcond = y_ss(end,:);
stimstart =0;
y = [y_ss(end,:)];
t = [0];
stim_dur =5;
frequency = 10; %Hz
intervals = 1/frequency;%s
timevec = (stimstart:intervals:stimstart+stim_dur);
for i = 1:(size(timevec,2)-1)
startpoint = timevec(i)+0.001;
endpoint = timevec(i+1);
initcond = y(end,:);
initcond(12) = glutconc;
pulsetime = startpoint;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[startpoint endpoint],initcond,...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
end
recov_dur = 1500;
recovtime = timevec(end)+1:1:timevec(end) +recov_dur;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[recovtime],y(end,:),...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
t_auc = t;
y_auc = y;
t = [t0(1:end)-t_start;t];
y = [y_ss(1:end,:);y];
%% Plots
[~,t50] = min(abs(t_auc-50));
[~,t200] = min(abs(t_auc-200));
[~,t400] = min(abs(t_auc-400));
[~,t600] = min(abs(t_auc-600));
% compute AUC
% compute baseline AUC
AMPK_base(j) = trapz(t_auc(t400:t600),y_auc(t400:t600,pAMPK));
mTORC1_base(j) = trapz(t_auc(t400:t600),y_auc(t400:t600,pmTORC1));
mTORC2_base(j) = trapz(t_auc(t400:t600),y_auc(t400:t600,pmTORC2));
CaC_base(j) = trapz(t_auc(t400:t600),y_auc(t400:t600,Ca_C));
% compute AUC for time period
AMPK_AUC(j) = trapz(t_auc(1:t200),y_auc(1:t200,pAMPK));
mTORC1_AUC(j) = trapz(t_auc(1:t200),y_auc(1:t200,pmTORC1));
mTORC2_AUC(j) = trapz(t_auc(1:t200),y_auc(1:t200,pmTORC2));
CaC_AUC(j) = trapz(t_auc(1:t200),y_auc(1:t200,Ca_C));
% % compute baseline AUC
% AMPK_base(inttime_ind,fscan_ind) = trapz(t(t400:t600),y(t400:basetime(inttime_ind),pAMPK));
% mTORC1_base(inttime_ind,fscan_ind) = trapz(t(t400:t600),y(t400:basetime(inttime_ind),pmTORC1));
% mTORC2_base(inttime_ind,fscan_ind) = trapz(t(t400:t600),y(t400:basetime(inttime_ind),pmTORC2));
% CaC_base(inttime_ind,fscan_ind) = trapz(t(t400:t600),y(t400:basetime(inttime_ind),Ca_C));
% % compute AUC for time period
% AMPK_AUC(inttime_ind,fscan_ind) = trapz(t(1:t200),y(1:inttime(inttime_ind),pAMPK));
% mTORC1_AUC(inttime_ind,fscan_ind) = trapz(t(1:t200),y(1:inttime(inttime_ind),pmTORC1));
% mTORC2_AUC(inttime_ind,fscan_ind) = trapz(t(1:t200),y(1:inttime(inttime_ind),pmTORC2));
% CaC_AUC(inttime_ind,fscan_ind) = trapz(t(1:t200),y(1:inttime(inttime_ind),Ca_C));
% normalize to baseline
t_TC = t_auc;
% normAMPK = AMPK_AUC./AMPK_base ;
% normmTOR1 = mTORC1_AUC./mTORC1_base ;
% normmTOR2 = mTORC2_AUC./mTORC2_base ;
% normCa = CaC_AUC./CaC_base ;
ampk_TC = y_auc(:,pAMPK) ;
mTORC1_TC = y_auc(:,pmTORC1) ;
mTORC2_TC = y_auc(:,pmTORC2) ;
% time to peak
%Decay time
%Period
ampk_ss = mean(ampk_TC(floor(90*end/100):end));
m1_ss =mean(mTORC1_TC(floor(90*end/100):end));
m2_ss =mean(mTORC2_TC(floor(90*end/100):end));
ampk_based = ampk_TC - ampk_ss;
m1_based = mTORC1_TC - m1_ss;
m2_based = mTORC2_TC - m2_ss;
[peakheight_a,tmaxes_a] = findpeaks(ampk_based,t_TC,'MinPeakWidth',2);
[mins_a,tmins_a] = findpeaks(-ampk_based,t_TC,'MinPeakWidth',2);
[peakheight_m1,tmaxes_m1] =findpeaks(m1_based,t_TC,'MinPeakWidth',2);
[ mins_m1,tmins_m1] = findpeaks(-m1_based,t_TC,'MinPeakWidth',2);
[peakheight_m2,tmaxes_m2] = findpeaks(m2_based,t_TC,'MinPeakWidth',2);
[mins_m2,tmins_m2] = findpeaks(-m2_based,t_TC,'MinPeakWidth',2);
windowstart = t50;
roc_AMPK = abs(diff(ampk_TC)./diff(t_TC));
roc_m1 = abs(diff(mTORC1_TC)./diff(t_TC));
roc_m2 = abs(diff(mTORC2_TC)./diff(t_TC));
ampkdiff_movmean = movmean(roc_AMPK(windowstart:end), 10);
m1diff_movmean = movmean(roc_m1(windowstart:end), 10);
m2diff_movmean = movmean(roc_m2(windowstart:end), 10);
eq_thresh = 1e-6;
threshind_a = find(ampkdiff_movmean-eq_thresh<0);
threshind_m1 = find(m1diff_movmean-eq_thresh<0);
threshind_m2 = find(m2diff_movmean-eq_thresh<0);
% %Algorithm to find point when it timecourse returns to baseline
% %values
%
% % take abs value of ss subtracted values
% ab_ampktc = abs(ampk_based);
% ab_m1tc = abs(m1_based);
% ab_m2tc = abs(m2_based);
% % moving window mean of time course with a step size of 30 seconds
% windowstart = t50;
% ampk_movmean = movmean(ab_ampktc(windowstart:end), 30);
% m1_movmean = movmean(ab_m1tc(windowstart:end), 30);
% m2_movmean = movmean(ab_m2tc(windowstart:end), 30);
% % < some threshold value
% eq_thresh = 1e-6;
% % find closest peak value
% threshind_a = find(ampk_movmean-eq_thresh<0);
% threshind_m1 = find(m1_movmean-eq_thresh<0);
% threshind_m2 = find(m2_movmean-eq_thresh<0);
% % put into period for quick plotting, change in plotfigure5_metrics
% % later
%
tte_a(j)= t_TC (windowstart + threshind_a(1));
tte_m1(j)= t_TC (windowstart + threshind_m1(1)) ;
tte_m2(j) =t_TC (windowstart + threshind_m2(1)) ;
% if isempty(tte_a)
% tte_a(fscan_ind) = 1;
% end
dtmaxes_a =diff(tmaxes_a) ;
dtmaxes_m1=diff(tmaxes_m1) ;
dtmaxes_m2=diff(tmaxes_m2) ;
% period_a= mean(dtmaxes_a(dtmaxes_a>3));
% period_m1= mean(dtmaxes_m1(dtmaxes_m1>3));
% period_m2 = mean(dtmaxes_m2(dtmaxes_m2>3));
%maximum amplitude
%first compute mean peak values
% [freq_a,zeta_a] = damp(t_TC,ampk_TC);
% tau_a = decayTime(zeta_a,freq_a);
% period_a(fscan_ind) = mean(dtmaxes_a(dtmaxes_a>3));
% period_m1(fscan_ind) = mean(dtmaxes_m1(dtmaxes_m1>3));
% period_m2(fscan_ind) = mean(dtmaxes_m2(dtmaxes_m2>3));
%maximum amplitude
%first compute mean values
maxamp_a(j)= max(peakheight_a)/ampk_ss;
maxamp_m1(j)= max(peakheight_m1)/m1_ss;
maxamp_m2(j)= max(peakheight_m2)/m2_ss;
plotfigure6
AMPK_SS(j) = ampk_ss;
mTOR1_SS(j) = m1_ss;
mTOR2_SS(j) =m2_ss;
end %end parscan
AMPK_SS = AMPK_SS./AMPK_SS(2) ;
mTOR1_SS = mTOR1_SS./mTOR1_SS(2) ;
mTOR2_SS = mTOR2_SS./mTOR2_SS(2) ;
maxamp_a = maxamp_a./maxamp_a(2)/100;
maxamp_m1 = maxamp_m1./maxamp_m1(2)/100;
maxamp_m2 = maxamp_m2./maxamp_m2(2)/100;
normAMPK = AMPK_AUC./AMPK_AUC(2) ;
normmTOR1 = mTORC1_AUC./mTORC1_AUC(2) ;
normmTOR2 = mTORC2_AUC./mTORC2_AUC(2) ;
normCa = CaC_AUC./CaC_base(2) ;
plotfigure6_metrics
end
%% Figure 7: VIR
if fig_index == 7
clear AMPK_AUC mTORC1_AUC CaC_AUC mTORC2_AUC
parscan = [0.1,1,2,10];
khyd_vary = [0.1,1,2,10];
pulsetime =0;
%% Simulation Engine
% initialization run
% or load premade initialization data
[~,y_ss]= ode15s(@leung2022_SERCA,[0:1:1000],init,options,pars, kHYD,pulsetime);
initcond = y_ss(end,:);
[tbaseline,ybaseline]= ode15s(@leung2022_SERCA,[0:1:200],initcond,options,pars, kHYD,pulsetime);
AMPK_base = trapz(tbaseline,ybaseline);
mTORC1_base= trapz(tbaseline,ybaseline);
mTORC2_base = trapz(tbaseline,ybaseline);
CaC_base= trapz(tbaseline,ybaseline);
%for freq_ind = 1:size(freq_vec,2)
colorvector = ['#0072BD';'#D95319';'#EDB120'; '#7E2F8E'];
markervector = {'-';'--';':';'-.'};
kHYDbasal = kHYD;
VIRbasal = pars(104);
for VIR_ind = 1:numel(parscan)
for khyd_ind = 1:numel(khyd_vary)
pulsetime =0;
h = khyd_vary(khyd_ind);
kHYD = kHYDbasal * h;
VIR = parscan(VIR_ind)*VIRbasal;
pars(4) = kHYD;
pars(105) = VIR;
[t0,y_ss]= ode15s(@leung2022_SERCA,[0:1:1000],init,options,pars, kHYD,pulsetime);
initcond = y_ss(end,:);
stimstart =0;
y = [y_ss(end,:)];
t = [0];
stim_dur =5;
frequency = 10; %Hz
intervals = 1/frequency;%s
timevec = (stimstart:intervals:stimstart+stim_dur);
for i = 1:(size(timevec,2)-1)
startpoint = timevec(i)+0.001;
endpoint = timevec(i+1);
initcond = y(end,:);
initcond(12) = glutconc;
pulsetime = startpoint;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[startpoint endpoint],initcond,...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
end
recov_dur = 500;
recovtime = timevec(end)+1:1:timevec(end) +recov_dur;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[recovtime],y(end,:),...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
stimstart=recovtime(end)+0.001;
figure(8)
hold on
[~,t200] = min(abs(t-200));
[~,t400] = min(abs(t-400));
[~,t600] = min(abs(t-600));
AMPK_AUC(VIR_ind,khyd_ind) = trapz(t(1:t200),y(1:t200,pAMPK));
mTORC1_AUC(VIR_ind,khyd_ind) = trapz(t(1:t200),y(1:t200,pmTORC1));
mTORC2_AUC(VIR_ind,khyd_ind) = trapz(t(1:t200),y(1:t200,pmTORC2));
CaC_AUC(VIR_ind,khyd_ind) = trapz(t(1:t200),y(1:t200,Ca_C));
% AMPK_AUC = AMPK_AUC ./ AMPK_base;
% mTORC1_AUC = mTORC1_AUC ./ mTORC1_base;
% mTORC2_AUC = mTORC2_AUC ./ mTORC2_base;
% CaC_AUC = CaC_AUC ./ CaC_base;
t = [t0(1:end)-t_start;t];
y = [y_ss(1:end,:);y];
plotfigure7
%% Plots
end
end
end
if (fig_index == 9 )
% Frequency vs VIR
clear AMPK_AUC mTORC1_AUC CaC_AUC mTORC2_AUC
%% Simulation Engine
% initialization run
% or load premade initialization data
basepars = finalpars;
pars = basepars;
pulsetime =0;
kHYD = pars(4);
VIR = pars(105);
tstart = 1000;
[t0,y_ss]= ode15s(@leung2022_SERCA,[0:1:tstart],init,options,pars, kHYD,pulsetime);
initcond = y_ss(end,:);
[tbaseline,ybaseline]= ode15s(@leung2022_SERCA,[0:1:200],init,options,pars, kHYD,pulsetime);
AMPK_base = trapz(tbaseline,ybaseline);
mTORC1_base= trapz(tbaseline,ybaseline);
mTORC2_base = trapz(tbaseline,ybaseline);
CaC_base= trapz(tbaseline,ybaseline);
%for freq_ind = 1:size(freq_vec,2)
parscan = [0.5,1,2,5];
freq_vary = [0.1,1,10,50];
colorvector = ['#0072BD';'#D95319';'#EDB120'; '#7E2F8E'];
markervector = {'-';'--';':';'-.'};
for VIR_ind = 1:numel(parscan)
for freq_ind = 1:numel(freq_vary)
pulsetime =0;
h = freq_vary(freq_ind); %vary frequency in nested for loop
freepar = parscan(VIR_ind);
pars(105) = freepar*VIR; % vary VIR in nested for loop
%initializes the simulation for new parameter set
[t0_temp,y_ss_temp]= ode15s(@leung2022_SERCA,[0:1:tstart],init,options,pars, kHYD,pulsetime);
initcond = y_ss(end,:);
stimstart =0;
y = [y_ss(end,:)];
t = [0];
stim_dur =5;
frequency = h; %Hz
intervals = 1/frequency;%s
timevec = (stimstart:intervals:stimstart+stim_dur);
for i = 1:(size(timevec,2)-1)
startpoint = timevec(i)+0.001;
endpoint = timevec(i+1);
initcond = y(end,:);
initcond(12) = glutconc;
pulsetime = startpoint;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[startpoint endpoint],initcond,...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
end
recov_dur = 500;
recovtime = timevec(end)+1:1:timevec(end) +recov_dur;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[recovtime],y(end,:),...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
stimstart=recovtime(end)+0.001;
recov_dur = 500;
recovtime = recovtime(end)+1:recovtime(end) +recov_dur;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[recovtime],y(end,:),...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
% find timepoint where t=200, etc
[~,t200] = min(abs(t-200));
[~,t400] = min(abs(t-400));
[~,t600] = min(abs(t-600));
%compute AUC's and assign to matrix
AMPK_AUC(VIR_ind,freq_ind) = trapz(t(1:t200),y(1:t200,pAMPK));
mTORC1_AUC(VIR_ind,freq_ind) = trapz(t(1:t200),y(1:t200,pmTORC1));
mTORC2_AUC(VIR_ind,freq_ind) = trapz(t(1:t200),y(1:t200,pmTORC2));
CaC_AUC(VIR_ind,freq_ind) = trapz(t(1:t200),y(1:t200,Ca_C));
% AMPK_AUC = AMPK_AUC ./ AMPK_base;
% mTORC1_AUC = mTORC1_AUC ./ mTORC1_base;
% mTORC2_AUC = mTORC2_AUC ./ mTORC2_base;
% CaC_AUC = CaC_AUC ./ CaC_base;
t = [t0(1:end)-tstart;t]; % add the initialization
y = [y_ss(1:end,:);y];
plotfigure9
%% Plots
end
end
subplot(3,2,5)
legend('0.5,0.1','0.5,1','0.5,10','0.5,50','1,0.1','1,1','1,10','1,50','2,0.1','2,1','2,5','2,50','5,0.1','5,1','5,10','5,50')
end
if (fig_index == 10 )
% Frequency vs kHYD
clear AMPK_AUC mTORC1_AUC CaC_AUC mTORC2_AUC
%% Simulation Engine
% initialization run
% or load premade initialization data
basepars = finalpars;
pars = basepars;
pulsetime =0;
kHYD = pars(4);
VIR = pars(105);
tstart = 1000;
freq_vary = [0.1,1,10,50];
khyd_vary = [0.5,1,2,5];
[~,y_ss]= ode15s(@leung2022_SERCA,[0:1:tstart],init,options,pars, kHYD,pulsetime);
initcond = y_ss(end,:);
[tbaseline,ybaseline]= ode15s(@leung2022_SERCA,[0:1:200],init,options,pars, kHYD,pulsetime);
AMPK_base = trapz(tbaseline,ybaseline);
mTORC1_base= trapz(tbaseline,ybaseline);
mTORC2_base = trapz(tbaseline,ybaseline);
CaC_base= trapz(tbaseline,ybaseline);
%for freq_ind = 1:size(freq_vec,2)
colorvector = ['#0072BD';'#D95319';'#EDB120'; '#7E2F8E'];
markervector = {'-';'--';':';'-.'};
kHYDbasal = kHYD;
for freq_ind = 1:numel(freq_vary)
for khyd_ind = 1:numel(khyd_vary)
pulsetime = 0;
h = khyd_vary(khyd_ind);
kHYD = kHYDbasal * h;
frequency = freq_vary(freq_ind);
[t0,y_ss]= ode15s(@leung2022_SERCA,[0:1:tstart],init,options,pars, kHYD,pulsetime);
initcond = y_ss(end,:);
stimstart =0;
y = [y_ss(end,:)];
t = [0];
stim_dur =5;
intervals = 1/frequency;%s
timevec = (stimstart:intervals:stimstart+stim_dur);
for i = 1:(size(timevec,2)-1)
startpoint = timevec(i)+0.001;
endpoint = timevec(i+1);
initcond = y(end,:);
initcond(12) = glutconc;
pulsetime = startpoint;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[startpoint endpoint],initcond,...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
end
recov_dur = 500;
recovtime = timevec(end)+1:1:timevec(end) +recov_dur;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[recovtime],y(end,:),...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
stimstart=recovtime(end)+0.001;
recov_dur = 500;
recovtime = recovtime(end)+1:recovtime(end) +recov_dur;
[t_temp,x_temp]= ode15s(@leung2022_SERCA,[recovtime],y(end,:),...
options,pars, kHYD,pulsetime);
y = [y;x_temp];
t = [t;t_temp];
hold on
[~,t200] = min(abs(t-200));
[~,t400] = min(abs(t-400));
[~,t600] = min(abs(t-600));
AMPK_AUC(freq_ind,khyd_ind) = trapz(t(1:t200),y(1:t200,pAMPK));
mTORC1_AUC(freq_ind,khyd_ind) = trapz(t(1:t200),y(1:t200,pmTORC1));
mTORC2_AUC(freq_ind,khyd_ind) = trapz(t(1:t200),y(1:t200,pmTORC2));
CaC_AUC(freq_ind,khyd_ind) = trapz(t(1:t200),y(1:t200,Ca_C));
t = [t0(1:end)-tstart;t];
y = [y_ss(1:end,:);y];
plotfigure10
%% Plots
end
end
subplot(3,2,5)
freq_vary = [0.1,1,10,50];
khyd_vary = [0.5,1,2,5];
legend('0.1,0.5','0.1,1','0.1,2','0.1,5','1,0.5','1,1','1,2','1,5','10,0.1','10,1','10,2','10,5','50,0.1','50,1','50,2','50,5')
end
% legend('1','2','3','4','5','6','7')
end