L2

In this talk I discuss how we can simulate stochastic chemical kinetics when there is a memory component. This can occur when there is spatial crowding within a cell or part of a cell, which acts to constrain the motion of the molecules which then in turn changes the dynamics of the chemistry. The counterpart of the Law of Mass Action in this setting is through replacing the first derivative in the ODE description of the Law of Mass Action by a time-­fractional derivative, where the time-­fractional index is between 0 and 1. There has been much discussion in the literature, some of it wrong, as to how we model and simulate stochastic chemical kinetics in the setting of a spatially-­constrained domain – this is sometimes called anomalous diffusion kinetics.

In this presentation, I discuss some of these issues and then present two (equivalent) ways of simulating fractional stochastic chemical kinetics. The key here is to either replace the exponential waiting time used in Gillespie’s SSA by Mittag-­Leffler waiting times (MacNamara et al. [2]), which have longer tails than in the exponential case. The other approach is to use some theory developed by Jahnke and Huisinga [1] who are able towrite down the underlying probability density function for any set of mono-­molecular chemical reactions (under the standard Law of Mass Action) as a convolution of either binomial probability density functions or binomial and Poisson probability density functions). We can then extend the Jahnke and Huisinga formulation through the concept of iterated Brownian Motion paths to produce exact simulations of the underlying fractional stochastic chemical process. We demonstrate the equivalence of these two approaches through simulations and also by computing the probability density function of the underlying fractional stochastic process, as described by the fractional chemical master equation whose solution is the Mittag-­Lefflermatrix function. This is computed based on a clever algorithm for computing matrix functions by Cauchy contours (Weideman and Trefethen [3]).

This is joint work with Manuel Barrio (University of Vallodolid, Spain), Kevin Burrage (QUT), Andre Leier (University of Alabama), Shev MacNamara(University of Technology Sydney)and T. Marquez-­Lago (University of Alabama).

[1]T. Jahnke and W. Huisinga, 2007, Solving the chemical master equation for monomolecular reaction systems analytically, J. Math. Biology 54, 1, 1—26.[2]S. MacNamara, B. Henry and W. McLean, 2017, Fractional Euler limits and their applications, SIAM J. Appl. Math. 77, 2, 447—469.[3]J.A.C. Weideman and L.N. Trefethen, 2007, Parabolic and hyperbolic contours for computing the Bromwich integral, Math. Comp. 76, 1341—1356.

ACORN generators represents an approach to generating uniformly distributed pseudo-random numbers which is straightforward to implement for arbitrarily large order $k$ and modulus $M=2^{30t}$ (integer $t$). They give long period sequences which can be proven theoretically to approximate to uniformity in up to $k$ dimensions, while empirical statistical testing demonstrates that (with a few very simple constraints on the choice of parameters and the initialisation) the resulting sequences can be expected to pass all the current standard tests .

The standard TestU01 Crush and BigCrush Statistical Test Suites are used to demonstrate for ACORN generators with order $8≤k≤25$ that the statistical performance improves as the modulus increases from $2^{60}$ to $2^{120}$. With $M=2^{120}$ and $k≥9$, it appears that ACORN generators pass all the current TestU01 tests over a wide range of initialisations; results are presented that demonstrate the remarkable consistency of these results, and explore the limits of this behaviour.

This contrasts with corresponding results obtained for the widely-used Mersenne Twister MT19937 generator, which consistently failed on two of the tests in both the Crush and BigCrush test suites.

There are other pseudo-random number generators available which will also pass all the TestU01 tests. However, for the ACORN generators it is possible to go further: we assert that an ACORN generator might also be expected to pass any more demanding tests for $p$-dimensional uniformity that may be required in the future, simply by choosing the order $k>p$, the modulus $M=2^{30t}$ for sufficiently large $t$, together with any odd value for the seed and an arbitrary set of initial values. We note that there will be $M/2$ possible odd values for the seed, with each such choice of seed giving rise to a different $k$-th order ACORN sequence satisfying all the required tests.

This talk builds on and extends results presented at the recent discussion meeting on “Numerical algorithms for high-performance computational science” at the Royal Society London, 8-9 April 2019, see download link at bottom of web page http://acorn.wikramaratna.org/references.html.

This meeting is being held in celebration of Prof Philip Maini's 60th birthday. Prof Maini has been an internationally leading researcher in mathematical biology for decades. He is currently the Director of the Wolfson Centre for Mathematical Biology, a position he has held since 1998. In the past 20 years he has grown the group significantly. He has established countless interdisciplinary collaborations, has over 400 publications in numerous areas of mathematical biology, with major contributions in mathematical modelling of tumours, wound healing and embryonic pattern formation. He has been elected Fellow of the Royal Society (FRS), Fellow of the Academy of Medical Sciences (FMedSci), and Foreign Fellow of the Indian National Science Academy (FNA). He has served or is serving on editorial board of a large number of journals, and was Editor-in-Chief of the Bulletin of Mathematical Biology [2002-15]. And yet his service to the community cannot be captured just by numbers and titles. Anyone who has met him and worked with him cannot but notice and be touched by his unfailing generosity and the many sacrifices he has made and continues to make day in and day out to help students, early career researchers, and fellow faculty alike.

This meeting provides an opportunity to celebrate Prof Maini's many accomplishments; to thank him for all of his sacrifices; and to bring together the large number of researchers – mathematicians, biologists, physiologists, and clinicians – that he has worked with and interacted with over the years. More broadly, the meeting provides a unique opportunity to reflect on mathematical biology, to provide perspectives on the trajectory of a field that was scarcely recognised and had very few dedicated researchers in the days of Prof Maini's own DPhil; yet a field that has grown tremendously since then. Much of this growth is attributable to the work of Prof Maini, so that today the value of mathematics in biology is increasingly recognized by biologists and clinicians, and with theoretical predictions of mathematical models having cemented a role in advancing biological understanding. 

Speakers

David Sumpter, Uppsala University (Public lecture), Derek Moulton, University of Oxford, Hans Othmer, Minnesota University, Jen Flegg, University of Melbourne, Jim Murray, University of Washington, Jonathan Sherratt, Heriot-Watt University, Kevin Painter, Heriot-Watt University, Linus Schumacher, University of Edinburgh, Lucy Hutchinson, Roche, Mark Chaplain, University of St Andrews, Mark Lewis, University of Alberta, Mary Myerscough, University of Sydney, Natasha Martin, University of Bristol, Noemi Picco, Swansea University, Paul Kulesa, Stowers Institute for Medical Research, Ruth Baker, University of Oxford, Santiago Schnell, University of Michigan, Tim Pedley, University of Cambridge

Organising committee

Ruth Baker (University of Oxford)

Derek Moulton (University of Oxford)

Helen Byrne (University of Oxford)

Santiago Schnell (University of Michigan)

Mark Chaplain (University of St Andrews)

The disruptive drone activity at airports requires an early warning system and Aveillant make a radar system that can do the job. The main problem is telling the difference between birds and drones where there may be one or two drones and 10s or 100s of birds. There is plenty of data including time series for how the targets move and the aim is to improve the discrimination capability of tracker using machine learning.

Specifically, the challenge is to understand whether there can be sufficient separability between birds and drones based on different features, such as flight profiles, length of the track, their states, and their dominance/correlation in the overall discrimination. Along with conventional machine learning techniques, the challenge is to consider how different techniques, such as deep neural networks, may perform in the discrimination task.

Mitral regurgitation is one of the most common valve diseases in the UK and contributes to 50% of the transcatheter mitral valve replacement (TMVR) procedures with bioprosthetic valves. TMVR is generally performed in frailer, older patients unlikely to tolerate open-heart surgery or further interventions. One of the side effects of implanting a bioprosthetic valve is a condition known as left ventricular outflow obstruction, whereby the implanted device can partially obstruct the outflow of blood from the left ventricle causing high flow resistance. The ventricle has then to pump more vigorously to provide adequate blood supply to the circulatory system and becomes hypertrophic. This ultimately results in poor contractility and heart failure.
We developed personalised image-based models to characterise the complex relationship between anatomy, blood flow, and ventricular function both before and after TMVR. The model prediction provides key information to match individual patient and device size, such as postoperative changes in intraventricular pressure gradients and blood residence time. Our pilot data from a cohort of 7 TMVR patients identified a correlation between the degree of outflow obstruction and the deterioration of ventricular function: when approximately one third of the outflow was obstructed as a result of the device implantation, significant increases in the flow resistance and the average time spent by the blood inside the ventricle were observed, which are in turn associated with hypertrophic ventricular remodelling and blood stagnation, respectively. Currently, preprocedural planning for TMVR relies largely on anecdotal experience and standard anatomical evaluations. The haemodynamic knowledge derived from the models has the potential to enhance significantly pre procedural planning and, in the long term, help develop a personalised risk scoring system specifically designed for TMVR patients.
 

Cellular migration can be affected by short-range interactions between cells such as volume exclusion, long-range forces such as chemotaxis, or reactions such as phenotypic switching. In this talk I will discuss how to incorporate these processes into a discrete or continuum modelling frameworks. In particular, we consider a system with two types of diffusing hard spheres that can react (switch type) upon colliding. We use the method of matched asymptotic expansions to obtain a systematic model reduction, consisting of a nonlinear reaction-diffusion system of equations. Finally, we demonstrate how this approach can be used to study the effects of excluded volume on cellular chemotaxis. This is joint work with Dan Wilson and Helen Byrne.
 

Our aim is to construct high order approximation schemes for general 
semigroups of linear operators $P_{t},t \ge 0$. In order to do it, we fix a time 
horizon $T$ and the discretization steps $h_{l}=\frac{T}{n^{l}},l\in N$ and we suppose
that we have at hand some short time approximation operators $Q_{l}$ such
that $P_{h_{l}}=Q_{l}+O(h_{l}^{1+\alpha })$ for some $\alpha >0$. Then, we
consider random time grids $\Pi (\omega )=\{t_0(\omega )=0<t_{1}(\omega 
)<...<t_{m}(\omega )=T\}$ such that for all $1\le k\le m$, $t_{k}(\omega 
)-t_{k-1}(\omega )=h_{l_{k}}$ for some $l_{k}\in N$, and we associate the approximation discrete 
semigroup $P_{T}^{\Pi (\omega )}=Q_{l_{n}}...Q_{l_{1}}.$ Our main result is the 
following: for any approximation order $\nu $, we can construct random grids $\Pi_{i}(\omega )$ and coefficients 
$c_{i}$, with $i=1,...,r$ such that $P_{t}f=\sum_{i=1}^{r}c_{i} E(P_{t}^{\Pi _{i}(\omega )}f(x))+O(n^{-\nu})$
with the expectation concerning the random grids $\Pi _{i}(\omega ).$ 
Besides, $Card(\Pi _{i}(\omega ))=O(n)$ and the complexity of the algorithm is of order $n$, for any order
of approximation $\nu$. The standard example concerns diffusion 
processes, using the Euler approximation for $Q_l$.
In this particular case and under suitable conditions, we are able to gather the terms in order to produce an estimator of $P_tf$ with 
finite variance.
However, an important feature of our approach is its universality in the sense that
it works for every general semigroup $P_{t}$ and approximations.  Besides, approximation schemes sharing the same $\alpha$ lead to
the same random grids $\Pi_{i}$ and coefficients $c_{i}$. Numerical illustrations are given for ordinary differential equations, piecewise 
deterministic Markov processes and diffusions.

The mechanisms underlying the initiation and perpetuation of cardiac arrhythmias are inherently multi-scale: whereas arrhythmias are intrinsically tissue-level phenomena, they have a significant dependence cellular electrophysiological factors. Spontaneous sub-cellular calcium release events (SCRE), such as calcium waves, are a exemplars of the multi-scale nature of cardiac arrhythmias: stochastic dynamics at the nanometre-scale can influence tissue excitation  patterns at the centimetre scale, as triggered action potentials may elicit focal excitations. This latter mechanism has been long proposed to underlie, in particular, the initiation of rapid arrhythmias such as tachycardia and fibrillation, yet systematic analysis of this mechanism has yet to be fully explored. Moreover, potential bi-directional coupling has been seldom explored even in concept.

A major challenge of dissecting the role and importance of SCRE in cardiac arrhythmias is that of simultaneously exploring sub-cellular and tissue function experimentally. Computational modelling provides a potential approach to perform such analysis, but requires new techniques to be employed to practically simulate sub-cellular stochastic events in tissue-scale models comprising thousands or millions of coupled cells.

This presentation will outline the novel techniques developed to achieve this aim, and explore preliminary studies investigating the mechanisms and importance of SCRE in tissue-scale arrhythmia: How do independent, small-scale sub-cellular events overcome electrotonic load and manifest as a focal excitation? How can SCRE focal (and non-focal) dynamics lead to re-entrant excitation? How does long-term re-entrant excitation interact with SCRE to perpetuate and degenerate arrhythmia?