Commit 1bc6a267 authored by Vincent Noël's avatar Vincent Noël
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<h2 id="about"><strong>COVID19 tissue simulator</strong></h2>
<p>This model simulates viral dynamics of SARS-CoV-2 (coronavirus / COVID19) in a layer of epithelium
and an immune response. It is being rapidly prototyped and refined with community support
(<a href="#model_details">see below</a>). </p>
<p><b>Please note that this is a stochastic model: for some simulation runs, you may see the immune system fail to respond. Users are encouraged to try the simulation multiple times.</b></p>
<p>This multiscale simulator combines several model components:</p>
<ul>
<li><strong>Tissue:</strong> Virus, cell debris, and chemokines diffuse within the extracellular space.
They may also “decay” to reflect removal by interstitial flow into nearby blood vessels or airways. </li>
<li><strong>ACE2 receptor dynamics:</strong> Virions bind to ACE2 receptors on the surface, which
are internalized (endocytosed) into cells. After virions are released from internalized receptors, they
can return to the surface. </li>
<li><strong>Viral replication:</strong> Internalized virus is uncoated to expose viral RNA, which synthesizes
viral proteins that are assembled into virions. Assembled virions are transported to the cell surface to be exported
to the tissue (exocytosed). </li>
<li><strong>Single-cell response:</strong> Infected cells secrete a chemokine that may attract immune cells. In a simple
pharmacodynamics response (to assembled virions), infected cells can undergo apoptosis. Apoptosed cells release some or
all of their internal contents, notably including virions. </li>
<li><strong><span style="background-color: red; color: white; padding-left: 0.1in; padding-right: 0.1in">
<strong>Immune response (new in version 3)</strong></span>:</strong> </li>
<ul>
<li><strong>Resident (and recruited) macrophages</strong> seek apoptotic cells. They phagocytose (ingest) dead cells
upon contact and activate. They also break down ("digest") ingested materials. </li>
<li><strong>Activated macrophages</strong> release a pro-inflammatory cytokine to recruit other immune cells, while
seeking both apoptotic and infected cells by chemotaxis. Activated macrophages can “wear out” and apoptose after phagocytosing
too much material.</li>
<li><strong>Neutrophils</strong> are recruited by accumulated pro-inflammatory cytokine. They seek apoptotic cells,
phagocytose them, and activate. Activated neutrophils seek both apoptotic and infected cells. Neutrophils also capture
extracellular virions. </li>
<li><strong>CD8<sup>+</sup> T cells</strong> are recruited by accumulated pro-inflammatory cytokine.
They seek and adhere to infected cells. After sufficient contact time with one or more CD8<sup>+</sup> T cells, infected cells undergo apoptosis. </li>
</ul>
</ul>
<p>
Please cite this project via the preprint:
</p>
<p style="text-align: center;">
Y. Wang et al., Rapid community-driven development of a SARS-CoV-2 tissue simulator.
<i>bioRxiv</i> 2020.04.02.019075, 2020, <b>(Preprint)</b>.
doi: <a href="https://dx.doi.org/10.1101/2020.04.02.019075" target="_blank">10.1101/2020.04.02.019075</a>.
</p>
<p><strong>Legend:</strong></b>
<ul>
<li><strong>lung epithelium:</strong> are colored by their (assembled) virion loads in four colors </li>
<ul style="font-family: courier;">
<!--
<li><span style="font-weight: strong; background-color: rgb(0,0,255)" >dark blue----:</span> Cells with 0 assembled virions. </li>
<li><span style="font-weight: strong; background-color: rgb(64,64,199)" >pale blue----:</span> Cells with 1-9 assembled virions. </li>
<li><span style="font-weight: strong; background-color: rgb(128,128,128)">grey---------:</span> Cells with 10-99 assembled virions. </li>
<li><span style="font-weight: strong; background-color: rgb(199,199,64)" >light yellow-:</span> Cells with 100-999 assembled virions. </li>
<li><span style="font-weight: strong; background-color: rgb(255,255,0)" >bright yellow:</span> Cells with 1000+ assembled virions. </li>
-->
<li><span style="height: 25px; width: 25px; background-color: rgb(0,0,255); display: inline-block; border-radius: 50%; border: 1px solid black;"></span> Cells with 0 assembled virions. </li>
<li><span style="height: 25px; width: 25px; background-color: rgb(64,64,199); display: inline-block; border-radius: 50%; border: 1px solid black;"></span> Cells with 1-9 assembled virions. </li>
<li><span style="height: 25px; width: 25px; background-color: rgb(128,128,128); display: inline-block; border-radius: 50%; border: 1px solid black;"></span> Cells with 10-99 assembled virions. </li>
<li><span style="height: 25px; width: 25px; background-color: rgb(199,199,64); display: inline-block; border-radius: 50%; border: 1px solid black;"></span> Cells with 100-999 assembled virions. </li>
<li><span style="height: 25px; width: 25px; background-color: rgb(255,255,0); display: inline-block; border-radius: 50%; border: 1px solid black;"></span> Cells with 1000+ assembled virions. </li>
<li><span style="height: 25px; width: 25px; background-color: rgb(0,0,0); display: inline-block; border-radius: 50%; border: 1px solid black;"></span> Apoptotic (dead from viral load) </li>
</ul>
<br/>
<li><strong>CD8<sup>+</sup> T cells:</strong> are colored by their cell cycle status </li>
<ul style="font-family: courier;">
<li><span style="height: 25px; width: 25px; background-color: red; display: inline-block; border-radius: 50%; border: 1px solid black;"></span> G0G1, S, G2, M cycle</li>
<li><span style="height: 25px; width: 25px; background-color: rosybrown; display: inline-block; border-radius: 50%; border: 1px solid black;"></span> Apoptotic</li>
</ul>
<br/>
<li><strong>macrophage:</strong> are colored by their cell cycle status </li>
<ul style="font-family: courier;">
<li><span style="height: 25px; width: 25px; background-color: lime; display: inline-block; border-radius: 50%; border: 1px solid black;"></span> G0G1, S, G2, M cycle</li>
<li><span style="height: 25px; width: 25px; background-color: fuchsia; display: inline-block; border-radius: 50%; border: 1px solid black;"></span> Flag of activated_immune_cell &gt; 0.5 </li>
<li><span style="height: 25px; width: 25px; background-color: rosybrown; display: inline-block; border-radius: 50%; border: 1px solid black;"></span> Apoptotic</li>
</ul>
<br/>
<li><strong>neutrophil:</strong> are colored by their cell cycle status </li>
<ul style="font-family: courier;">
<li><span style="height: 25px; width: 25px; background-color: cyan; display: inline-block; border-radius: 50%; border: 1px solid black;"></span> G0G1, S, G2, M cycle</li>
<li><span style="height: 25px; width: 25px; background-color: rosybrown; display: inline-block; border-radius: 50%; border: 1px solid black;"></span> Apoptotic</li>
</ul>
<br/>
<li><strong>Background:</strong> Contour plot of released virus that is diffusing in and above the tissue.
</li>
</ul>
<h3 style="color: red; font-weight: strong">Caveats and disclaimers</h3>
<strong>This model is under active development using rapid prototyping:</strong>
<ul>
<li>It has not been peer reviewed. </li>
<li>It is intended to drive basic scientific research and public education at this stage.</li>
<li><strong>It cannot be used for public policy decisions. </strong></li>
<li><strong>It cannot be used for individual medical decisions.</strong></li>
</ul>
<p><strong>
This model will be continually refined with input from the community, particularly experts
in infectious diseases. The validation state will be updated as this progresses.</strong></p>
<h2 id="GUI_overview"><strong>GUI Overview</strong></h2>
<ul>
<li><b>Config Basics</b> tab:&nbsp;&nbsp;&nbsp; input parameters common to all models (e.g., domain grid, simulation time, choice/frequency of outputs)</li>
<li><b>Microenvironment</b> tab:&nbsp;&nbsp; microenvironment parameters that are model-specific</li>
<li><b>User Params</b> tab:&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; user parameters that are model-specific</li>
<li><b>Cell Types</b> tab:&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; parameters for cell types that are model-specific</li>
<li><b>Out: Plots</b> tab:&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; output display of cells and substrates</li>
<li><b>Out: PhysiBoSS</b> tab:&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; output display of cells intracellular states</li>
<li><b>Animate</b> tab:&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; generate an animation of cells</li>
<li><b>Config Basics</b> tab:&nbsp;&nbsp;&nbsp; input parameters common to all models (e.g., domain grid, simulation time, choice/frequency of outputs)</li>
<li><b>Microenvironment</b> tab:&nbsp;&nbsp; microenvironment parameters that are model-specific</li>
<li><b>User Params</b> tab:&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; user parameters that are model-specific</li>
<li><b>Cell Types</b> tab:&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; parameters for cell types that are model-specific</li>
<li><b>Out: Plots</b> tab:&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; output display of cells and substrates</li>
<li><b>Animate</b> tab:&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; generate an animation of cells</li>
</ul>
Clicking the 'Run' button will use the specified parameters and start a simulation. When clicked, it creates an "Output" widget
that can be clicked/expanded to reveal the progress (text) of the simulation. When the simulation generates output files,
that can be clicked/expanded to reveal the progress of the simulation. When the simulation generates output files,
they can be visualized in the "Out: Plots" tab. The "# cell frames" will be dynamically updated
as those output files are generated by the running simulation. When the "Run" button is clicked, it toggles to a "Cancel" button
that will terminate (not pause) the simulation.
<h2><strong>Introduction</strong></h2>
<p>
This app demonstrates ...
</p>
<h2 id="model_details"><strong>Model details</strong></h2>
<p>This model is being rapidly prototyped. Biological and mathematical detail can be found at:</p>
<ul>
<li>
<b>Project website:</b> <a href="http://covid19.physicell.org" target="_blank">http://covid19.physicell.org</a> (opens in new tab)
</li>
<li>
<b>Model feedback:</b> <a href="https://forms.gle/12vmLR7aiMTHoD5YA" target="_blank">Google feedback form</a> (opens in new tab)
</li>
<li>
<b>Preprint:</b> <a href="https://dx.doi.org/10.1101/2020.04.02.019075" target="_blank">Wang et al. (2020)</a> (opens in new tab)
</li>
<p>This model and cloud-hosted demo are part of a course on computational multicellular systems biology created and taught by
Dr. Paul Macklin in the Department of Intelligent Systems Engineering at Indiana University. It is also part of the education
<li>
<b>GitHub codes:</b> <a href="https://github.com/pc4covid19" target="_blank">pc4covid19 GitHub organization</a> (opens in new tab)
</li>
</ul>
<p><strong>We request community help in estimating parameters and improving model assumptions at the link above. </strong>
</p>
<p>This model and cloud-hosted demo are part of the education
and outreach for the IU Engineered nanoBIO Node and the NCI-funded cancer systems biology grant U01CA232137.
The models are built using <a href="https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1005991" target="_blank">PhysiCell</a>:
a C++ framework for multicellular systems biology [1].</p>
a C++ framework for multicellular systems biology.</p>
<h2><a id="instructions" name="instructions">Basic instructions</a></h2>
<p>Modify parameters in the &quot;Config Basics&quot;, &quot;Microenvironment&quot;, or &quot;User Params&quot; tabs. Click the &quot;Run&quot; button once you are ready.</p>
<p>Modify parameters in the &quot;Config Basics&quot;, &quot;Microenvironment&quot;, &quot;User Params&quot;, or &quot;Cell Types&quot; tabs. Click the &quot;Run&quot; button once you are ready.</p>
<p>To view the output results, click the &quot;Out: Plots&quot; tab, and move the slider bar to advance through simulation frames.
Note that as the simulation runs, the &quot;# cell frames&quot; field will increase, so you can view more simulation frames.</p>
......@@ -53,3 +194,4 @@ This model and cloud-hosted demo are part of the education and outreach
<a href="https://joss.theoj.org/papers/10.21105/joss.01408">R. Heiland, D. Mishler, T. Zhang, E. Bower, and P. Macklin. xml2jupyter: Mapping parameters between XML and Jupyter widgets. Journal of Open Source Software 4(39):1408, 2019. DOI: 10.21105/joss.01408.
</li>
</ol>
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