Examples of Tissue Forge modeling features.

A: Five superimposed snapshots of a double pendulum implemented in Tissue Forge. Bonded interactions (represented as green cylinders) explicitly describe the interaction between a particular pair of particles, while a constant force acts on the blue particles in the downward direction. The red particle is fixed. B: Four Tissue Forge clusters representing biological cells, each consisting of ten particles whose color demonstrates cluster membership. Potentials describe particle interactions by whether they are in the same cluster (i.e., intracellular) or different clusters i.e., intercellular. C: Tissue Forge simulation of chemical flux during fluid droplet collision. Each particle represents a portion of fluid that carries an amount of a diffusive chemical, the amount of which varies from zero (blue) to one (red). When two droplets carrying different initial chemical amounts collide, resulting droplets tend towards homogeneous chemical distributions.</p

Standalone simulation of sub-cellular model.

<p>Results of the standalone run of the sub-cellular model using parameter set <b>REFSIM</b> and an initial concentration of APAP of 0.1mM (15<i>μ</i>g/ml).</p

Plasma concentrations versus time for APAP and metabolites for REFSIM.

<p>Plasma concentrations versus time for APAP and metabolites simulated with the complete multiscale model using parameter set <b>REFSIM</b> (lines). Open symbols are <i>in</i> <i>vivo</i> average values from nine Caucasian subjects given a 1.4g oral dose of APAP [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162428#pone.0162428.ref058" target="_blank">58</a>].</p

Sensitivity comparisons for formation of NAPQI-GSH.

<p>Comparison of the sensitivities for the formation of NAPQI-GSH (NAPQIGSH_Sum) versus the average parameter sensitivities about the fixed point <b>REFSIM</b>. Axis are as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162428#pone.0162428.g013" target="_blank">Fig 13</a>.</p

PBPK Parameter Set REFSIM.

<p>PBPK Parameter Set REFSIM.</p

Subcellular concentration of APAP and Phase I metabolites in REFSIM simulation.

<p>Four cells were monitored in each of the three regions; (A), periportal (PP), midzonal (MZ) and perivenous (PV), and the average concentration in each group is plotted. (B) APAP, (C) GSH, (D) NAPQI, (E) NAPQI-GSH, (E) APAP-Glucuronide, and (E) APAP-Sulfate. Error bars are the standard deviation of the four cells in a region.</p

Time course of a standalone simulation of the sinusoid model in CC3D using the parameters set REFSIM.

<p>A simulated 3 second square pulse of APAP was pushed into the left end of the vessel lumen for three seconds starting one second into the simulation. The concentration of APAP in the blood and hepatocytes is given by the heat map scale at left and time progresses from top to bottom. Blood components are created at the periportal (left) end and a constant force is exerted on the blood components to induce blood flow through the simulated sinusoid. The temporal scales was adjusted so that the blood speed in the simulation was equivalent to 200 <i>μ</i>m/s, giving a transit time of a blood component through the sinusoid of one second.</p

The diffusion model for the multicell scale sinusoid model.

<p>Transfer between each of the three cell, or pseudo-cell, <i>types</i> is described by this transfer map. Subscripts indicate that there are multiple cells of each of the types and transfer is calculated between all pairs of cells that are in contact at a particular instant. The paired arrows represent passive transport that equilibrates across pairs of cell types if they are in contact. Looped arrows represent passive transport between adjacent cells of the same type. The single arrow labeled “Active Transport” represents the Michaelis-Menten modeled import of APAP from the serum into hepatocytes.</p

Plasma concentrations calculated using parameter set LNsim23.

<p>This parameter set represents a hypothetical chemical species with ADME behavior significantly different than APAP or the hypothetical species in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162428#pone.0162428.g009" target="_blank">Fig 9</a>. Symbols are as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162428#pone.0162428.g007" target="_blank">Fig 7</a> and the APAP <i>in</i> <i>vivo</i> data is included for comparison.</p

CC3D Parameters.

<p>CC3D Parameters.</p