Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms
Fig 1
Component organization and model mechanism features.
(A) A virtual Mouse, detailed in Methods, is a concretized, coarse-grain software analogy of an actual mouse. Shading within a cross-section of a hepatic lobule illustrates idealized PP-to-PC gradients. (B) A portion (16%) of one vLobule is illustrated. A Monte-Carlo specified interconnected directed graph, which can be different (within constraints) for each vExperiment, specifies flow paths for APAP and other Compounds (see Methods). (C) A multi-layered, quasi-3D Sinusoid Segment (SS) maps to a portion of hepatic tissue. One is placed at each graph node. An SS functions during execution analogous to sinusoid components and features averaged across many actual lobules; SS dimensions are Monte Carlo-sampled to mimic lobular variability. An SS comprises a Core surrounded concentrically by five 2D grids. One space contains virtual Endothelial Cells (vECs) and another contains vHPCs. (D) Mobile Compound objects move within and between the grids in C. They enter and exit an SS via Core and Interface, percolate stochastically through accessible spaces influenced by flow parameters. Compounds that exit to the CV are returned to Mouse Body. vHPCs and vECs control Compound entry from, and exit to, adjacent spaces, and the fate of Compounds within. Each vHPC contains a variety of components needed to enable the cause-effect events. All of the preceding components are parameterized the same as in Smith et al. [8].