Applications of Transport/Reaction Codes to Problems in Cell Modeling

We demonstrate two specific examples that show how our exiting capabilities in solving large systems of partial differential equations associated with transport/reaction systems can be easily applied to outstanding problems in computational biology. First, we examine a three-dimensional model for calcium wave propagation in a Xenopus Laevis frog egg and verify that a proposed model for the distribution of calcium release sites agrees with experimental results as a function of both space and time. Next, we create a model of the neuron's terminus based on experimental observations and show that the sodium-calcium exchanger is not the route of sodium's modulation of neurotransmitter release. These state-of-the-art simulations were performed on massively parallel platforms and required almost no modification of existing Sandia codes

Participatory development of a target policy profile to support soil-transmitted helminth elimination

IntroductionSoil-transmitted helminths (STH) are parasitic worms that infect nearly a quarter of the world's population, particularly those living in communities without access to adequate water, sanitation, and housing. Emerging evidence suggests that it may be possible to interrupt transmission of STH by deworming individuals of all ages via community-wide MDA (cMDA), as opposed to only treating children and other focal populations. Transitioning from a policy of STH control to STH elimination in targeted areas would require a fundamental shift in STH policy and programming. This policy change would require updated guidance to support countries as they adapt their current approaches for STH surveillance, supply chain management, community mobilization, and core programmatic activities in pursuit of STH elimination. There is an opportunity to engage with key stakeholders, such as program implementers and implementation partners, to understand what evidence they need to confidently adopt a new policy guideline and to deliver guideline adherent management at scale.MethodsWe aimed to engage with STH stakeholders to develop a Target Policy Profile (TPoP), a single document that describes optimal characteristics and evidence requirements that STH stakeholders prioritized in future potential STH transmission interruption efforts. Steps in TPoP development included a scoping review and key informant interviews (KIIs), which were used to design a two-stage Delphi technique to identify and verify TPoP components.ResultsThe scoping review resulted in 25 articles, and 8 experts participated in KII's. Twenty respondents completed the first Delphi survey and 10 respondents completed the second. This systematic effort resulted in a net of 3 key information domains (background/context, clinical considerations, and implementation considerations) encompassing 24 evidence categories (examples include evidence regarding safety and adverse events, implementation feasibility, or evidence dissemination). For each evidence category, STH stakeholders reviewed, endorsed, or revised a range of options for how the evidence could be presented.DiscussionThis information can be used by guideline committees or global policy makers prior to convening guideline advisory groups. The TPoP tool may also speed the process of stakeholder consensus building around guidelines, accelerating progress towards implementing evidence-based policy at scale

A permutation method for network assembly.

We present a method for assembling directed networks given a prescribed bi-degree (in- and out-degree) sequence. This method utilises permutations of initial adjacency matrix assemblies that conform to the prescribed in-degree sequence, yet violate the given out-degree sequence. It combines directed edge-swapping and constrained Monte-Carlo edge-mixing for improving approximations to the given out-degree sequence until it is exactly matched. Our method permits inclusion or exclusion of 'multi-edges', allowing assembly of weighted or binary networks. It further allows prescribing the overall percentage of such multiple connections-permitting exploration of a weighted synthetic network space unlike any other method currently available for comparison of real-world networks with controlled multi-edge proportion null spaces. The graph space is sampled by the method non-uniformly, yet the algorithm provides weightings for the sample space across all possible realisations allowing computation of statistical averages of network metrics as if they were sampled uniformly. Given a sequence of in- and out- degrees, the method can also produce simple graphs for sequences that satisfy conditions of graphicality. Our method successfully builds networks with order O(107) edges on the scale of minutes with a laptop running Matlab. We provide our implementation of the method on the GitHub repository for immediate use by the research community, and demonstrate its application to three real-world networks for null-space comparisons as well as the study of dynamics of neuronal networks

A Multi-Scale Spatial Model of Hepatitis-B Viral Dynamics

<p>Dataset related to an accepted manuscript:</p> <p>A Multi-Scale Spatial Model of Hepatitis-B Viral Dynamic. Cangelosi  Q., Means S., Ho H. PLOS One</p> <p>Dataset documented in a ReadMe file.</p

Table of notations.

<p>Table of notations.</p

Evolution of hepatitis B infection homogenous case.

<p>With <i>n</i> = 5 simulations of agent-based stochastic model, we averaged results and present for sinusoidal viral particles (Panel A) and intracellular particles for hepatocytes (Panel B). Panel C plots percentage of infection across all hepatocytes where we define infected as at least one HBV or cccDNA copy. Results presented include extra-hepatic HBV replication and no cccDNA persistence in new replenishment hepatocytes. Note, scaling translates from the model values of, say, 7.5 HBV copies in our simulated liver to an entire liver at 10⁶ HBV copies/mL on the graph. Simulated inoculum of 2.10⁹ HBV copies/mL at t = 0, Δ<i>t</i> = <i>τ</i>/30 = 1min, <i>N</i> = 150 cells, <i>κ</i> = 0.3. Immune response activation at day 40 with CYL strength <i>δ</i> = 0.6 and Non-CYL strength <i>u</i> = 0.25. Note negative logarithmic values occur (Panels A and B) since the average number of copies/cell fall under 1, e.g., sums of HBV particles across all cells in our model translates into 1 particle per the population of 150 or log(1/150).</p

Table of parameters.

<p>Table of parameters.</p

Spatial heterogeneities effects on HBV infection and clearance.

<p>(Panel A) Results are in percentage of cells; averaged over <i>n</i> = 5 simulations of agent-based stochastic model. Inoculum of 2.10⁹ HBV copies per mL at day 0 and immune responses activation at day 40 (<i>δ</i> = 0.3, <i>u</i> = 0.75). Legend: Solid lines represent percentage of cells in the liver with at least 1 HBV copy (<i>V</i>_Φ<i>k</i>+<i>R</i>_Φ<i>k</i>) and dotted lines percentage of cells in the liver with at least 1 cccDNA copy (<i>C</i>_Φ<i>k</i>). cccDNA survival to replenishment hepatocytes was set to zero probability. (1) Homogeneous base line case; (2) Gradients of HBV replication cycle efficiency (parameters Γ and <i>κ</i>) (3) Gradients of <i>δ</i>, (4) Gradients of both (Γ, <i>κ</i>) and <i>δ</i>. (Panels B & C) Ribbon plots before immune activation (<i>t</i> = 1–30 days) showing intracellular viral particles (<i>V</i>_Φ) for each hepatocyte (sinusoid 5). Hepatocyte number order reflects proximity to sinusoidal periportal entrance, i.e., #1 at entry point, and #30 at pericentral exit. Panel B shows particle counts over sinusoid with homogeneous spatial distribution of HBV replication rates (Γ) and uptake (<i>κ</i>) whereas Panel C shows distribution with linear gradient of same parameters. Peak parameter values situated at periportal hepatocyte #1 and minimal at pericentral #30. Note linear distribution of <i>V</i>_Φ corresponding to distribution of parameters with variance of 0.8; see section (3.2) for details.</p

Reinfection of transected or transplanted liver with solo cccDNA copy.

<p>Results here with increased hepatocyte population than in other results: 50 sinusoids of 300 hepatocytes or 15,000 total cells, all homogeneously distributed (no spatial gradients of any parameters). This corresponds to 0.006% of cell population with 1 cccDNA. cccDNA survival probability to replenishment hepatocytes here set to zero. (1) Evolution of HBV from only 0.006% cells infected with 1 cccDNA without any immune response (2)(1) Evolution of HBV from only 0.006% cells infected with 1 cccDNA with activation of a weak immune response at day 10 (<i>δ</i> = 0.3, <i>u</i> = 0.25) Legend: Plain lines represent percentage of cells in the liver with at least 1 HBV copy (<i>V</i>_Φ<i>k</i>+<i>R</i>_Φ<i>k</i>). Dotted lines represent percentage of cells in the liver with at least 1 cccDNA copy.</p