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Domenic P. J. Germano

Publications and source records attributed to Domenic P. J. Germano.

5 recordsLinked to original sources

Multiscale Modelling of Birth-Death Processes

Many biological systems exhibit multiscale dynamics, where some species occur in high copy numbers while others remain rare. This heterogeneity necessitates hybrid modelling approaches: deterministic models are computationally efficient but inaccurate for low-count species, while fully stochastic simulations are accurate but prohibitively expensive. Threshold-based hybrid methods, such as the Jump--Switch--Flow (JSF) algorithm, address this by simulating low-count species stochastically and high-count species deterministically, switching at a user-chosen threshold $Ω$. In such methods, the choice of $Ω$ controls the trade-off between computational cost and accuracy, but is typically made by trial-and-error: there is no principled way to choose $Ω$ a priori for a given observable of interest. We close this gap for extinction probability. Our contribution is a computable, method-agnostic error bound that quantifies the discrepancy introduced by the threshold and yields an explicit rule for selecting $Ω$ to meet a user-specified error tolerance. We formalise JSF as a piecewise-deterministic Markov process and derive backward equations for extinction under exact and hybrid dynamics. Near extinction boundaries, the complex nonlinear dynamics reduce to tractable time-inhomogeneous linear birth--death processes; this structure yields a rigorous error decomposition into early and late excursions, whose dominant term becomes a fast, actionable heuristic requiring only the solution of a scalar Riccati equation. Monte Carlo studies on a stochastic Lotka--Volterra model confirm that the heuristic reliably upper-bounds the empirical error in extinction probability across a wide parameter range. The framework depends only on the birth and death rates near extinction, not on the specific simulation method, and therefore applies beyond JSF to any threshold-based hybrid scheme.

q-bio.PE↗

Spatial dynamic modelling to understand how dendritic cell clustering affects T cell activation

The coordination of the immune system and its components is essential for the body to maintain a healthy status. Recent clinical studies show that breast cancer patients with high Dendritic cell clustering in tumour draining lymph nodes have improved survival outcomes, compared to those with a lower degree of clustering. These results suggest that a specific form of Dendritic cell clustering promotes T cell activation. However, the mechanistic effects of this spatial organisation is unclear. We develop a spatially dynamic model of T cells interacting with Dendritic cells within the lymph node. We present a novel probabilistic agent-based model (ABM) of T cells, and use it to derive the deterministic, phenotypically structured partial differential equation (PS-PDE) of T cell activation and motion. Using the PS-PDE, we derive analytic approximations of the expected T cell stimulation distribution, based on the topology and level of clustering of a given Dendritic cell population. Our analytic approximation enables us to identify T cell characteristics that benefit most from Dendritic cell clustering, to result in an enhanced stimulation distribution. We also perform a sensitivity analysis with our models to identify T cell characteristics that result in desirable T cell activation characteristics, such as rapid T cell activation, and robust heterogeneous T cell activation. Our key findings show that T cells with an intermediate level of stimulation uptake benefit most from higher levels of Dendritic cell clustering, activating with a comparable or greater abundance, and greater heterogeneity, when compared to T cells of a similar characteristic but with a lower level of Dendritic cell clustering.

q-bio.CB↗

A hybrid framework for compartmental models enabling simulation-based inference

Multi-scale systems often exhibit a combination of stochastic and deterministic dynamics. In compartmental models, low occupancy compartments tend to exhibit stochastic dynamics while high occupancy compartments tend to follow deterministic dynamics. Representing both dynamics with existing methods is challenging. Failing to account for stochasticity in small populations can produce ``atto-foxes'', for example in the Lotka-Volterra ordinary differential equation (ODE) model. This limitation becomes problematic when studying the extinction of species or the clearance of infection, but it can be overcome by using discrete stochastic models, such as continuous time Markov chains (CTMCs). Unfortunately, simulating CTMCs is impractical for many realistic models, where discrete events have very high frequencies. In this work, we develop a novel mathematical framework to couple continuous ODEs and discrete CTMCs: ``Jump-Switch-Flow'' (JSF). In this framework, compartments can reach extinct states (``absorbing states''), thereby resolving atto-fox-type problems. JSF has the desired behaviours of exact CTMC simulation, but is substantially computationally faster than existing alternatives, by at least one order of magnitude, and can even obtain constant scaling, irrespective of compartment occupancy. We demonstrate JSF's utility for simulation-based inference, particularly multi-scale problems, with several case-studies. In a simulation study, we demonstrate how JSF can enable a more nuanced analysis of the efficacy of public health interventions. We also carry out a novel analysis of longitudinal within-host data from SARS-CoV-2 infections to quantify the timing of viral clearance. In this work, we show how JSF offers a novel approach to compartmental model simulation.

q-bio.PE↗

Modelling realistic 3D deformations of simple epithelia in dynamic homeostasis

The maintenance of tissue and organ structures during dynamic homeostasis is often not well understood. In order for a system to be stable, cell renewal, cell migration and cell death must be finely balanced. Moreover, a tissue's shape must remain relatively unchanged. Simple epithelial tissues occur in various structures throughout the body, such as the endothelium, mesothelium, linings of the lungs, saliva and thyroid glands, and gastrointestinal tract. Despite the prevalence of simple epithelial tissues, there are few models which accurately describe how these tissues maintain a stable structure. Here, we present a novel, 3D, deformable, multilayer, cell-centre model of a simple epithelium. Cell movement is governed by the minimisation of a bending potential across the epithelium, cell-cell adhesion, and viscous effects. We show that the model is capable of maintaining a consistent tissue structure while undergoing self renewal. We also demonstrate the model's robustness under tissue renewal, cell migration and cell removal. The model presented here is a valuable advancement towards the modelling of tissues and organs with complex and generalised structures.

q-bio.TO↗

A mathematical model of cell fate selection on a dynamic tissue

Multicellular tissues are the building blocks of many biological systems and organs. These tissues are not static, but dynamically change over time. Even if the overall structure remains the same there is a turnover of cells within the tissue. This dynamic homeostasis is maintained by numerous governing mechanisms which are finely tuned in such a way that the tissue remains in a homeostatic state, even across large timescales. Some of these governing mechanisms include cell motion, and cell fate selection through inter cellular signalling. However, it is not yet clear how to link these two processes, or how they may affect one another across the tissue. In this paper, we present a multicellular, multiscale model, which brings together the two phenomena of cell motility, and inter cellular signalling, to describe cell fate selection on a dynamic tissue. We find that the affinity for cellular signalling to occur greatly influences a cells ability to differentiate. We also find that our results support claims that cell differentiation is a finely tuned process within dynamic tissues at homeostasis, with excessive cell turnover rates leading to unhealthy (undifferentiated and unpatterned) tissues.

q-bio.TO↗