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)

[ Info: Precompiling GRIJuliaExt [84369c5d-ffb2-5a92-8288-3470980d96d0] 



SYSTEM: caught exception of type :MethodError while trying to print a failed Task notice; giving up

[ Info: Precompiling IJuliaExt [2f4121a4-3b3a-5ce6-9c5e-1f2673ce168a] 



SYSTEM: caught exception of type :MethodError while trying to print a failed Task notice; giving up

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 = 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)

  9.667808 seconds (23.26 M allocations: 1.224 GiB, 1.78% gc time, 91.99% compilation time)

retcode: Success
Interpolation: 3rd order Hermite
t: 4019-element Vector{Float64}:
      0.0
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      0.09098129546758026
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      ⋮
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u: 4019-element Vector{Vector{Float64}}:
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 ⋮
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ROS (H2O2) 0.1uM

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

  0.764156 seconds (63.27 k allocations: 208.038 MiB, 5.04% gc time)

retcode: Success
Interpolation: 3rd order Hermite
t: 4019-element Vector{Float64}:
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      ⋮
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 ⋮
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ROS (H2O2) 0.5uM

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

  1.068357 seconds (63.31 k allocations: 208.344 MiB, 25.86% gc time)

retcode: Success
Interpolation: 3rd order Hermite
t: 4019-element Vector{Float64}:
      0.0
      0.019333123284852018
      0.09098129546759268
      0.20735582943986758
      0.45611910276868917
      1.047256292840759
      2.0342667657226547
      3.4517766411489377
      6.73379242391375
     12.450117081024938
     21.597356188113203
     34.569649574425604
     51.605564656858704
      ⋮
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 148124.08993327222
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 162137.25596277026
 168220.05331925137
 175684.1621984258
 183498.26432090864
 192274.69276273437
 202819.53195738627
 205000.0
u: 4019-element Vector{Vector{Float64}}:
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 [151273.38014925693, 13519.83660060375, -70.26673060448068, 0.13590575282411668, 0.1359060466591627, 0.13590634049202574, 0.13590663438057854, 0.13590692838503254, 0.1359072225680569, 0.13590751699490503  …  0.0011446175865424775, 0.0015867698139153759, 0.0024562111763589776, 0.001547065222903169, 0.9997377628053505, 0.999738527307958, 0.006356274292265905, 784.3927065966819, 784.0445517984231, 0.0019703233318542376]
 [151315.77134176026, 13477.559244346041, -70.18840368846465, 0.135370977186642, 0.1353712846656086, 0.13537159255940198, 0.13537190093669693, 0.13537220986894483, 0.1353725194305149, 0.1353728296988452  …  0.001158583046956617, 0.0015960350944804226, 0.0024705494336962354, 0.0015645910354672567, 0.9997357184902989, 0.9997340736983188, 0.006390217698571022, 783.766552666038, 783.4267996141033, 0.0019255951046944892]
 [151358.64479065445, 13434.806583900372, -70.10864235465442, 0.13483019080754022, 0.1348304971719481, 0.13483080414700724, 0.1348311118050347, 0.13483142022127134, 0.13483172947403124, 0.1348320396448599  …  0.0011729615039235304, 0.001605524198424298, 0.002485235283769405, 0.0015826299918433584, 0.9997314266114357, 0.9997294613744953, 0.006424967786165937, 783.0678150068961, 782.7365344295841, 0.001879771124786155]
 [151405.02848957514, 13388.55639834317, -70.02152279359439, 0.13424982550943057, 0.13425012489997895, 0.13425042502099663, 0.13425072594579876, 0.13425102775066472, 0.13425133051498897, 0.13425163432144174  …  0.0011889215329374308, 0.0016159528187012896, 0.0025013741994336946, 0.0016025625757090372, 0.9997263208770492, 0.9997243321237556, 0.006463138217085289, 782.2740844758519, 781.951822520619, 0.0018307061608736127]
 [151458.3825053809, 13335.357949703744, -69.92012537858326, 0.1335903877500261, 0.13359067665137986, 0.13359096637702256, 0.1335912570001016, 0.1335915485967215, 0.1335918412460949, 0.1335921350307026  …  0.0012076873871477635, 0.0016281752477336564, 0.0025202892519309485, 0.0016260702019856997, 0.9997202085156728, 0.9997182401820821, 0.006507848139661528, 781.3293671124205, 781.0172372163945, 0.0017754417709190664]
 [151469.10198081317, 13324.66992190788, -69.8995972454628, 0.13345902635863294, 0.13345931297234132, 0.1334596004270282, 0.13345988879572335, 0.1334601781544088, 0.13346046858216956, 0.13346076016135341  …  0.0012115058325956128, 0.0016306584080682813, 0.0025241355329057896, 0.0016308705866934518, 0.999718953841047, 0.999716990422487, 0.006516937056444002, 781.1361067314109, 780.8259796394238, 0.0017645071047812154]

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")

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

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")

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

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")

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

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"])

42-element Vector{Float64}:
 0.02305850621757014
 0.023225557529411765
 0.023536003837902393
 0.022995786588235295
 0.023056161133316953
 0.02236794743822152
 0.02448575734900888
 0.02631837493460871
 0.029628792824062226
 0.0306227531696316
 0.03440544933688571
 0.03638835689675227
 0.03637182395488222
 ⋮
 0.028657939696241287
 0.02769675888235294
 0.027350470452150753
 0.02665056333747046
 0.02525893438851731
 0.024749347823716496
 0.024158682609370527
 0.023572491294117648
 0.0240760416039372
 0.023230166
 0.023759599761907887
 0.02369791084482974

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"])

42-element Vector{Float64}:
 0.01579193843196981
 0.015098907892605207
 0.01579878654371588
 0.015408311367567479
 0.01575464714359121
 0.015563615686070896
 0.015839325542753135
 0.01815890968670797
 0.022420341690296358
 0.026401360928455686
 0.029427224511157125
 0.03136683817775766
 0.03287974611049711
 ⋮
 0.02345856047323667
 0.021230514099692135
 0.021140506988645197
 0.01970504059747541
 0.018928610243134615
 0.018308801083333333
 0.017872510075561544
 0.017135324764712814
 0.016622042234321177
 0.01699837223508933
 0.01644948545788867
 0.016236308371972322

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")

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