BCR-CD40-integration Model

"A molecular network model reveals non-monotonic integration of BCR and CD40 signals for controlling B-cell proliferation"

A combination of Receptor, NFkB, Proliferation, and Apoptosis modules. We recommend running the model on a server with at least 32 threads. To run the model, one can run the main2.jl file. There are a few options one can set:

• -v for the type of multi-thread parallelization, where the option are: "nonthread", "thread", "spawn". "nonthread" will run the model linearly and does not parallelize it, while "thread" will parallelize the model on static schedule, and "spawn" on dynamic schedule.
• -o for the destination of output .txt cell lineage file
• -c for the destination of output .jld signaling dynamics file (include output of nuclear RelA and cRel)
• -i for the destination of output steady state file. In the case it is combined with -r, the path will be used to reload from previous steady states, if the parameter distribution & pre-stimulation was already done. This can be used when you would like to rerun a simulation from a .jld file generated previously.
• -r for reloading from previous steady states

Example:

export JULIA_NUM_THREADS=64 # set number of threads to be used
home_dir="/path/to/dir/BCR-CD40-integration/"
modifier="lineages_125_CD40A_H62" # set the file name for outputs
julia $home_dir'Simulation_scripts/main3.jl' -v "spawn" -o $home_dir'results/'$modifier'.txt' -i $home_dir'data/steady_'$modifier'.jld' -c $home_dir'data/cells_'$modifier'.jld' >> $home_dir'job-logs/'$modifier'.out'

Simulation Scripts:

• main3.jl: function for running the simulations and saving results
• ConstantParams2.jl: constant parameters, including stimulus doses, stimulus delay, simulation time, scaling factors, etc.
• ReactionRates3.jl: reaction rate parameters for all module
• ODE_Receptor5.jl: ODE equations for BCR and CD40 receptor modules
• ODE_NFkB3.jl: ODE equations for NFkB module
• ODE_Apoptosis2.jl: ODE equations for Apoptosis module
• ODE_Differentiation.jl: ODE equations for Differentiation module
• ODE_Proliferation.jl: ODE equations for Cell Cycle module
• SimulateFunctions4+.jl: pre-simulation and simulation functions
• HelperFunctions.jl: helper functions for Michaelis-Menten and Hill functions, as well as parameter distributions

Plotting scripts for each figure:

Figure 1:

Panel C,D: NFkB trajectories (dose response + composition).ipynb

Panel E,G: NFkB trajectories (ignore cell fates).ipynb to plot NFkB trajectories from intermediate .jld files

Figure 2:

Panel B: calcModelFit.R to plot the population dynamics by generation

Panel C: Excel sheets

Panel F: calcModelFit.R to calculate RMSD between model vs. experiment, then RMSDheatmap.R to plot from the tabulated results

Figure 3:

Panel A,C: calcModelFit.R to plot the population dynamics by generation

Panel B,D: Excel sheets

Panel E: calcModelFit.R to calculate RMSD between model vs. experiment, then used Excel to tabulate the results and plot

Panel F,G,I,J: Excel sheets

Panel H,K: calcReproducibility.R to calculate RMSD between experimental replicates, then used Excel to tabulate the results and plot

Figure 4:

Panel B,D: calcModelFit.R to plot the population dynamics by generation

Panel C,E: Excel sheets

Panel F: calcModelFit.R to calculate RMSD between model vs. experiment, then used Excel to tabulate the results and plot

Panel G-J: NFkB trajectories (cell fates low vs high).ipynb to plot NFkB trajectories from intermediate .jld files

Figure 5:

Panel A: calcModelFit.R to plot the population dynamics by generation

Panel B,C,D: plotTd2.R for both Kaplan-Meier curve for each CD40 and BCR dose (B,C) and the bar graph of # survived cells at 24hrs (D)

Panel E-J: plotFateLandscape.R for the fate map. Need to adjust the code to specify with or without AICD

Panel K-M: plotFateLandscapeDiff.R to plot the difference between 2 fate maps from E-J

Figure 6:

Panel B: plotPopulationSize2.R to plot the relative population size over time

Panel C: Excel sheets

Figure 7:

Panel B: BclXL trajectories (colored line).ipynb to plot single-cell Bcl-xL trajectories, colored with caspase 8 level

Panel C: BclXL trajectories (colored line).ipynb to plot single-cell Bcl-xL trajectories, colored with NFkB level

Panel D: BclXL trajectories (heatmap).ipynb (last 8 blocks) to plot the violin plot of RelA, cRel, and Bcl-xL peak activity between dead and live cells

Panel E-I: plotFateLandscape.R for the fate map. Need to adjust the code to specify for with AICD

Panel G-J: plotFateLandscapeDiff.R to plot the difference between 2 fate maps from E-I