# Mathematical Biology

## On the average least negative Hecke eigenvalue

The least quadratic non-residue has been a central problem in number theory for centuries. The average least quadratic non-residue was explored by Erdős in the 1960s, and many extensions of this problem such as to the average least character non-residue (Martin, Pollack) have been explored. In this talk, we look in to the average first sign change of Fourier coefficients of newforms (equivalently Hecke eigenvalues). We discuss the distribution of Hecke eigenvalues through the so-called 'horizontal' and 'vertical' Sato-Tate distributions, and we also discuss large sieve inequalities for cusp forms that are uniform in both the weight and the level.

## Skeletal muscle: modeling and computation

Skeletal muscle is composed of cells collectively referred to as fibers, which themselves contain contractile proteins arranged longtitudinally into sarcomeres. These latter respond to signals from the nervous system, and contract; unlike cardiac muscle, skeletal muscles can respond to voluntary control. Muscles react to mechanical forces - they contain connective tissue and fluid, and are linked via tendons to the skeletal system - but they also are capable of activation via stimulation (and hence, contraction) of the sacromeres. The restorative along-fibre force introduce strong mechanical anisotropy, and depend on departures from a characteristic length of the sarcomeres; diseases such as cerebral palsy cause this characteristic length to change, thereby impacting muscle force. In the 1910s, A.V. Hill [1] posited a mathematical description of skeletal muscles which approximated muscle as a 1-dimensional nonlinear and massless spring. This has been a remarkably successful model, and remains in wide use. Yet skeletal muscle is three dimensional, has mass, and a fairly complicated structure. Are these features important? What insights are gained if we include some of this complexity in our models? Many mathematical questions of interest in skeletal muscle mechanics arise: how to model this system, how to discretize it, and what theoretical properties does it have? In this talk, we survey recent work on the modeling, parameter estimation, simulation and validation of a fully 3-D continuum elasticity approach for skeletal muscle dynamics. This is joint work based on a long-standing collaboration with James Wakeling (Dept. of Biomedical Physiology and Kinesiology, SFU).

## Computational Modeling for Medical Devices

The Food and Drug Administration (FDA) is responsible for ensuring the safety and effectiveness of medical devices marketed in the US. For several decades, in a handful of niche applications, medical device industry has used computational modeling to provide evidence for safety or effectiveness, complementing bench, animal, or clinical testing. In recent years, the use of computational modeling in medical device regulatory submissions has grown significantly. FDA’s medical device Center is now tasked with evaluating a wide range of computational models of medical devices, as well as computational models implemented in medical device software (for example, patient-specific model-based software devices, closely related to the concept of a digital twin), and in silico clinical trials. This talk will discuss how computational models are relevant to medical devices, and then delve in model credibility assessment. We will discuss key activities involved in evaluating computational models for medical devices, overview recent FDA-led Standards and Guidances, and summarize recent work expanding these methods to the new frontiers of patient-specific models and in silico clinical trials.

## Environmental feedback maintains cooperation in phage $\Phi_6$

The evolution and maintenance of cooperation is a fundamental problem in evolutionary biology. Because cooperative behaviors impose a cost, Cooperators are vulnerable to exploitation by Defectors that do not pay the cost to cooperate but still benefit from the cooperation of others. The bacteriophage $\Phi_6$ exhibits cooperative and defective phenotypes in infection: during replication, phages produce essential proteins in the host cell cytoplasm. Coinfection between multiple phages is possible. A given phage cannot guarantee exclusive access to its own proteins, so Cooperators contribute to the common pool of proteins while Defectors contribute less and instead appropriate proteins from Cooperators. Previous experimental work found that $\Phi_6$ was trapped in a prisoner's dilemma, predicting that the cooperative phenotype should disappear. Here we propose that environmental feedback, or interplay between phage and host densities, can maintain cooperation in $\Phi_6$ populations by modulating the rate of co-infection and shifting the advantages of cooperation vs. defection. We build and analyze an ODE model and find that for a wide range of parameter values, environmental feedback allows Cooperation to survive.

## Mathematical modeling applied to women's health

Several years ago, Dr Kathryn Isaac, a UBC professor and clinical surgeon contacted me with an intriguing problem. In her work on cosmetic reconstructive for post-breast-cancer-surgery patients, she encounters cases of failure that result (weeks or months later) in "capsular contraction" (CC). This painful condition arises when the healing tissue (the "capsule") that forms surrounding a breast implant undergoes pathological contraction and deformation - necessitating a new rounds of surgery. In this talk, I describe work in our team to help understand the root causes of CC, the risk factors, and possible preventative treatments. We use mathematical modeling to depict and investigate hypotheses for cell-level mechanisms involved in initiating CC. I will describe two rounds of modeling, the earliest joint with Cheryl Dyck MacDonald, and the latest joint with Ms Yuqi Xiao (UBC MSc student) and Prof. Alain Goriely (Oxford).

## Introduction to agent-based evolutionary game theory

Evolutionary game theory is a discipline devoted to studying populations of individuals that are subject to evolutionary pressures, and whose success generally depends on the composition of the population. In biological contexts, individuals could be molecules, simple organisms or animals, and evolutionary pressures often take the form of natural selection and mutations. In socioeconomic contexts, individuals could be humans, firms or other institutions, and evolutionary pressures often derive from competition for scarce resources and experimentation.

In this talk I will give a very basic introduction to agent-based evolutionary game theory, a bottom-up approach to modelling and analyzing these systems. The defining feature of this modelling approach is that the individual units of the system and their interactions are explicitly and individually represented in the model. The models thus defined can be usefully formalized as stochastic processes, whose dynamics can be explored using computer simulation and approximated using various mathematical theories.

## Reproductive value, prevalence, and perturbation theory of Perron vectors

In a linear population model that has a unique “largest” eigenvalue and is suitably irreducible, the corresponding left and right (Perron) eigenvectors determine the long-term relative prevalence and reproductive value of different types of individuals, as described by the Perron-Frobenius theorem and generalizations. It is therefore of interest to study how the Perron vectors depend on the generator of the model. Even when the generator is a finite-dimensional matrix, there are several approaches to the corresponding perturbation theory. We explore an approach that hinges on stochasticization (re-weighting the space of types to make the generator stochastic) and interprets formulas in terms of the corresponding Markov chain. The resulting expressions have a simple form that can also be obtained by differentiating the renewal-theoretic formula for the Perron vectors. The theory appears well-suited to the study of infection spread that persists in a population at a relatively low prevalence over an extended period of time, via a fast-slow decomposition with the fast/slow variables corresponding to infected/non-infected compartments, respectively. This is joint work with MSc student Tareque Hossain.

## Phase dynamics of cyclic reptilian tooth replacement

For over a century, scientists have studied striking spatiotemporal patterns during the continual tooth replacement of reptiles. Aside from the compelling aesthetics of this phenomenon, it is thought that understanding the underlying mechanisms may provide the insight required to trigger adult tooth replacement in humans. Theoretical frameworks have long been proposed to understand the rules behind the observed spatiotemporal order, but have only been analyzed mathematically more recently. Starting from Edmund's observations in crocodiles and proposed theory of replacement waves, we show how a simple model consisting of a row of non-interacting phase oscillators predicts several experimental observations. Next, inspired by the hypothesis put forth by Osborn, we consider a variation of the phase model with ODEs that account for mutual inhibition between tooth sites, and use continuation methods to thoroughly search parameter space for experimentally validated solutions. We then extend the model to a PDE that explicitly accounts for the diffusion of inhibitory signals between teeth, yielding some novel solution types. Using continuation methods once again, we delineate parameter regimes with solutions that closely resemble experimental observations in leopard geckos.

## Self-organization and pattern selection in run-and-tumble processes

I will report on a simple model for collective self-organization in colonies of myxobacteria. Mechanisms include only running, to the left or to the right at fixed speed, and tumbling, with a rate depending on head-on collisions. We show that variations in the tumbling rate only can lead to the observed qualitatively different behaviors: equidistribution, rippling, and formation of aggregates. In a second part, I will discuss in somewhat more detail questions pertaining to the selection of wavenumbers in the case where ripples are formed, in particular in connection with recent progress on the marginal stability conjecture for front invasion.

## A simple stochastic model for cell population dynamics in colonic crypts

The questions of how healthy colonic crypts maintain their size under the rapid cell turnover in intestinal epithelium, and how homeostasis is disrupted by driver mutations, are central to understanding colorectal tumorigenesis. We propose a three-type stochastic branching process, which accounts for stem, transit-amplifying (TA) and fully differentiated (FD) cells, to model the dynamics of cell populations residing in colonic crypts. Our model is simple in its formulation, allowing us to estimate all but one of the model parameters from the literature. Fitting the single remaining parameter, we find that model results agree well with data from healthy human colonic crypts, capturing the considerable variance in population sizes observed experimentally. Importantly, our model predicts a steady-state population in healthy colonic crypts for relevant parameter values. We show that APC and KRAS mutations, the most significant early alterations leading to colorectal cancer, result in increased steady-state populations in mutated crypts, in agreement with experimental results. Finally, our model predicts a simple condition for unbounded growth of cells in a crypt, corresponding to colorectal malignancy. This is predicted to occur when the division rate of TA cells exceeds their differentiation rate, with implications for therapeutic cancer prevention strategies.