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}, Nothing}(1//100, 10, 1//5, 1//5, false, true, nothing), precs = DEFAULT_PRECS, smooth_est = true, extrapolant = linear, controller = PI, autodiff = ADTypes.AutoForwardDiff(),)
Comparisons#
@time sol = solve(prob, alg; callback)
3.640331 seconds (5.21 M allocations: 479.147 MiB, 3.93% gc time, 76.48% compilation time)
retcode: Success
Interpolation: 3rd order Hermite
t: 4019-element Vector{Float64}:
0.0
0.019333123284849308
0.09098129546757994
0.20735582943983855
0.45611910276862533
1.0472562928406122
2.0342667657223696
3.451776641148454
6.733792423912806
12.450117081023194
⋮
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199430.11235309625
205000.0
u: 4019-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)
0.855354 seconds (61.80 k allocations: 208.122 MiB, 9.38% gc time)
retcode: Success
Interpolation: 3rd order Hermite
t: 4019-element Vector{Float64}:
0.0
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⋮
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u: 4019-element Vector{Vector{Float64}}:
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⋮
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[151469.10067707088, 13324.671131839817, -69.89959923376037, 0.13345904066622533, 0.1334593272945481, 0.13345961476385224, 0.133459903147163, 0.13346019252045807, 0.13346048296281876, 0.1334607745565895 … 0.0012115246802243246, 0.0016306592157390057, 0.0025241351889792015, 0.0016308698145448917, 0.999718953897033, 0.9997169905556449, 0.006516936186128647, 781.1361237429879, 780.8259964225541, 0.0017645088785524865]
ROS 0.5uM
prob3 = remake(prob, p=[sys.ROS => 0.5μM])
@time sol3 = solve(prob3, alg; callback)
0.808285 seconds (61.75 k allocations: 207.727 MiB, 4.30% gc time)
retcode: Success
Interpolation: 3rd order Hermite
t: 4018-element Vector{Float64}:
0.0
0.01933312328485172
0.09098129546759129
0.20735582943986441
0.4561191027686822
1.047256292840743
2.0342667657226237
3.451776641148885
6.7337924239136475
12.45011708102475
⋮
148408.62966738208
152964.20825143054
157519.786835479
163269.67214080694
169696.5522318492
177943.5318763309
186190.5115208126
195849.19866415721
205000.0
u: 4018-element Vector{Vector{Float64}}:
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[150952.80529264064, 13838.18882346682, -71.35304509818098, 0.12196378364408189, 0.12191937753328351, 0.12187579038290368, 0.12183318573340765, 0.12179171693004436, 0.12175152667167395, 0.12171274673876395 … 0.2610441780460306, 0.009873892913308362, 0.0015688568862425737, 0.09093422465365371, 0.2241256030327346, 0.967155451223036, 0.005926150085675958, 829.923524981244, 829.7704141396295, 0.002228995040224502]
⋮
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[151182.15208010815, 13610.899797610118, -70.4369300285762, 0.13697641060713323, 0.13697642863092263, 0.13697644209372742, 0.13697645091135224, 0.13697645499618064, 0.13697645425700034, 0.13697644859881866 … 0.0011147027405978803, 0.001566810884089907, 0.0024253381159187615, 0.001509527467664393, 0.9995887341354597, 0.999747961767255, 0.006283133684319197, 784.8971824855273, 784.5330280928397, 0.0020435991107827394]
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[151469.08953901724, 13324.682038433735, -69.89961947391694, 0.13345918129130233, 0.1334594679213355, 0.13345975539163135, 0.1334600437751818, 0.13346033314793065, 0.13346062358892408, 0.13346091518047068 … 0.0012115349086659478, 0.0016306577856468286, 0.002524131409657626, 0.0016308651724549815, 0.9997189548650912, 0.9997169918568639, 0.006516927100471058, 781.136278294349, 780.8261486472999, 0.0017645190645695233]
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/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/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/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/docs/ros-exp.png"
This notebook was generated using Literate.jl.