High-content imaging: Cell state trajectories & tipping points

Presented at WC9/Pragu

Modelling The Biological Complexity Of Our Environment

Presentation at the Douglas Connect Environmental Health and Protection Modeling Knowledge Cafe meeting May 201

Toxicological Tipping Points & Cell Stress

Presented at the <table><tr> <td>Society of Toxicology Annual Meeting<br> </td></tr></table

Predictive Toxicology: Current Status and Future Outlook

Presented at EBI-EMBL Industry Programme Workshop Predictive Toxicolog

Using High-Content Imaging to Analyze Toxicological Tipping Points

Presented at the International Conference on Toxicological Alternatives & Translational Toxicolog

Toxicological Tipping Points

Presented at the <table><tr> <td>National Toxicology Program <br> Laboratory Seminar Series<br> </td></tr></table

A physiologic lobule is a three-dimensional polyhedron with a volume between 0.1 and 0.9 µL [8].

<p>Our (quasi-)two-dimensional simulated lobule is assumed to have a thickness equal to a sinusoidal diameter (23.5 µm <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000756#pcbi.1000756-Rani1" target="_blank">[29]</a>). Therefore many identical simulated lobules in parallel are needed to fill the volume of one physiologic lobule. Blood flow to the simulated lobules is divided by R_liv∶lob, the ratio of the volume of the whole liver to the volume of single lobule.</p

The virtual lobule morphology is constructed iteratively.

<p>First, sinusoids outward from the central vein (i). In addition to small random variations in the direction of propagation, the sinusoids branch into two sinusoids pointed away from the central vein with probability P_br (ii). Multiple sinusoids are started from the central vein in an attempt to fill space (iii). Portal “triads” consisting of arterioles and venules through which blood enters the lobule are added to the perimeter of the lobule and connected to the vasculature (iv). Finally, the sinusoids are lined with hepatocytes as space allows (v).</p

Similar nodes were aggregated to reduce the complexity of the sinusoid connectivity graph.

<p>Similar nodes were aggregated to reduce the complexity of the sinusoid connectivity graph.</p

Hepatic lobules receive nutrient-rich blood from the gut through the portal venule and oxygen-rich blood from the lungs through arterioles.

<p>Blood flows past sheets of hepatocytes through the sinusoids and into the central vein. Image adapted from an original by Amber Goetz, first published in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000756#pcbi.1000756-Rockett1" target="_blank">[42]</a>.</p