ROS effects

using ModelingToolkit
using OrdinaryDiffEq, DiffEqCallbacks
using Plots
using CSV
using DataFrames
using Dates
using CaMKIIModel
using CaMKIIModel: second, μM
Plots.default(lw=1.5)

Setup model

sys = build_neonatal_ecc_sys(simplify=true, reduce_iso=true, reduce_camk=true)
tend = 205second
prob = ODEProblem(sys, [], tend)
stimstart = 30second
stimend = 120second
@unpack Istim = sys
callback = build_stim_callbacks(Istim, stimend; period=1second, starttime=stimstart)
alg = KenCarp47()

KenCarp47(; linsolve = nothing, nlsolve = OrdinaryDiffEqNonlinearSolve.NLNewton{Rational{Int64}, Rational{Int64}, Rational{Int64}, Rational{Int64}}(1//100, 10, 1//5, 1//5, false, true, 0//1), precs = DEFAULT_PRECS, smooth_est = true, extrapolant = linear, controller = PI, autodiff = ADTypes.AutoForwardDiff(),)

Comparisons

@time sol = solve(prob, alg; callback)

  3.634825 seconds (7.42 M allocations: 566.133 MiB, 3.72% gc time, 71.27% compilation time)

retcode: Success
Interpolation: 3rd order Hermite
t: 4071-element Vector{Float64}:
      0.0
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      0.09098129546757994
      0.20735582943983855
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      1.0472562928406122
      2.0342667657223696
      3.451776641148454
      6.733792423912806
     12.450117081023194
      ⋮
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 191258.90946281631
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u: 4071-element Vector{Vector{Float64}}:
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 ⋮
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ROS 0.1uM

prob2 = remake(prob, p=[sys.ROS => 0.1μM])
@time sol2 = solve(prob2, alg; callback)

  1.024565 seconds (65.99 k allocations: 212.910 MiB, 5.64% gc time)

retcode: Success
Interpolation: 3rd order Hermite
t: 4072-element Vector{Float64}:
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      ⋮
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u: 4072-element Vector{Vector{Float64}}:
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 ⋮
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 [0.001782168115163597, 781.1337975600096, 781.4471592386413, 0.006502300080339709, 0.9997190010675766, 0.9997209724198294, 0.0016231436816816081, 0.0025179413961018103, 0.0016266580320545324, 0.001205357338220176  …  0.13367276227687255, 0.13367246719126905, 0.13367217323132796, 0.13367188031448698, 0.13367158836145496, 0.13367129729605173, 0.13367100704505722, -69.93267010157932, 13341.90220076345, 151451.8186038869]
 [0.00176476913605272, 780.8305763558983, 781.1407513244353, 0.0065167190202319895, 0.999717020458502, 0.9997189839270085, 0.0016307550440619973, 0.0025240432778758115, 0.0016305998246819008, 0.0012114327900439692  …  0.13346390373438016, 0.13346361208661045, 0.1334633215899223, 0.13346303216196684, 0.13346274372365854, 0.13346245619901542, 0.13346216951500847, -69.90008938888167, 13324.926015454637, 151468.84470879182]

ROS 0.5uM

prob3 = remake(prob, p=[sys.ROS => 0.5μM])
@time sol3 = solve(prob3, alg; callback)

  1.008109 seconds (65.96 k allocations: 212.775 MiB, 3.88% gc time)

retcode: Success
Interpolation: 3rd order Hermite
t: 4070-element Vector{Float64}:
      0.0
      0.01933312328485172
      0.09098129546759129
      0.20735582943986441
      0.4561191027686822
      1.047256292840743
      2.0342667657226237
      3.451776641148885
      6.7337924239136475
     12.45011708102475
      ⋮
 148407.71053766683
 152963.08286658817
 157518.4551955095
 163268.1543188535
 169694.74092358912
 177941.12476481107
 186187.50860603302
 195845.67458090663
 205000.0
u: 4070-element Vector{Vector{Float64}}:
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 [0.002598565959029538, 829.9994975880693, 829.9999654017583, 0.007020208561323646, 0.9660018276402699, 0.2215639938807744, 0.09242766669618695, 0.001879826176081169, 0.009769882842069916, 0.2608055799112056  …  0.12113000000000405, 0.12113000000038378, 0.12113000001389383, 0.12113000037367234, 0.12113000811850358, 0.1211301421535992, 0.1211319185255175, -68.79732946186226, 13838.375711519551, 150952.7504077194]
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 [0.0023106557277343207, 829.8589858006806, 829.9689941817725, 0.006355039713677761, 0.966628695781256, 0.22294828828976596, 0.09161908329520757, 0.001685589909492206, 0.009786689200123865, 0.2604150766754201  …  0.12150439833798583, 0.12154722283384219, 0.12159304920072066, 0.12164180995533604, 0.12169340184086011, 0.12174768443532405, 0.1218044794888063, -70.35063788657448, 13838.2694938995, 150952.77598869594]
 [0.0022289950402245053, 829.7704141396295, 829.923524981244, 0.0059261500856759575, 0.967155451223036, 0.2241256030327346, 0.09093422465365371, 0.0015688568862425737, 0.009873892913308362, 0.2610441780460306  …  0.12171274673876394, 0.12175152667167392, 0.12179171693004433, 0.12183318573340762, 0.12187579038290368, 0.12191937753328352, 0.12196378364408192, -71.35304509818098, 13838.18882346682, 150952.80529264064]
 ⋮
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 [0.0020439940696006086, 784.5385372411694, 784.9027633010024, 0.006282881542686192, 0.9997479938239393, 0.9995887201790881, 0.0015093993782631398, 0.0024252317386472527, 0.001566742152498455, 0.0011146010144969364  …  0.13698085088117393, 0.13698085638263988, 0.13698085696606255, 0.13698085272638427, 0.13698084375476877, 0.13698083013878587, 0.13698081196258624, -70.4375201658923, 13611.229537457635, 151181.82102815836]
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Comparisons

i = (sys.t / 1000, sys.CaMKAct * 100)
plot(sol, idxs=i, lab="ROS (-)")
plot!(sol2, idxs=i, lab="ROS 0.1uM")
plot!(sol3, idxs=i, lab="ROS 0.5uM")
plot!(xlabel="Time (s)", ylabel="Active fraction (%)", title="Simulation")

savefig("ros-camkii.pdf")
savefig("ros-camkii.png")

"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/ros-camkii.png"

Oxidized fraction

i = (sys.t / 1000, 100 * (sys.CaMKBOX + sys.CaMKPOX + sys.CaMKAOX + sys.CaMKOX ))
plot(sol, idxs=i, lab="ROS (-)")
plot!(sol2, idxs=i, lab="ROS 0.1uM")
plot!(sol3, idxs=i, lab="ROS 0.5uM")
plot!(xlabel="Time (s)", ylabel="Oxidized fraction (%)", title="Simulation")

savefig("ros-camkiiox.pdf")
savefig("ros-camkiiox.png")

"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/ros-camkiiox.png"

Autophosphorylated fraction

i = (sys.t / 1000, 100 * (sys.CaMKP + sys.CaMKA + sys.CaMKA2))
plot(sol, idxs=i, lab="ROS (-)")
plot!(sol2, idxs=i, lab="ROS 0.1uM")
plot!(sol3, idxs=i, lab="ROS 0.5uM")
plot!(xlabel="Time (s)", ylabel="Phosphorylated fraction (%)", title="Simulation")

savefig("ros-camkiip.pdf")
savefig("ros-camkiip.png")

"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/ros-camkiip.png"

Experimental data

chemicaldf = CSV.read(joinpath(@__DIR__, "data/CaMKAR-chemical.csv"), DataFrame)
ts = Dates.value.(chemicaldf[!, "Time"]) ./ 10^9
ctl = chemicaldf[!, "Ctrl Mean"]
ctl_error = chemicaldf[!, "Ctrl SD"] ./ sqrt.(chemicaldf[!, "Ctrl N"])

ros50 = chemicaldf[!, "H2O2 50uM Mean"]
ros50_error = chemicaldf[!, "H2O2 50uM SD"] ./ sqrt.(chemicaldf[!, "H2O2 50uM N"])
ros200 = chemicaldf[!, "H2O2 200uM Mean"]
ros200_error = chemicaldf[!, "H2O2 200uM SD"] ./ sqrt.(chemicaldf[!, "H2O2 200uM N"])

plot(ts, ctl, yerr=ctl_error, lab="Control", color=:blue, markerstrokecolor=:blue)
plot!(ts, ros50, yerr=ros50_error, lab="H2O2 50uM", color=:red, markerstrokecolor=:red)
plot!(ts, ros200, yerr=ros200_error, lab="H2O2 200uM", color=:green, markerstrokecolor=:green)
plot!(xlabel="Time (s)", ylabel="CaMKII activity (A.U.)", title="Experiment")

savefig("ros-exp.pdf")
savefig("ros-exp.png")

"/home/runner/work/camkii-cardiomyocyte-model/camkii-cardiomyocyte-model/.cache/docs/ros-exp.png"

---

This notebook was generated using Literate.jl.