Past Mathematical Biology and Ecology Seminar

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.
 

Mechanobiology is a field of science that aims to understand how mechanics regulate biology. It focuses on how mechanical forces and alterations in mechanical properties of cell or tissues regulate biological processes in development, physiology and disease. In fact, all these processes occur in our body, which presents a clear structural and hierarchical organization that goes from the organism to the cellular level. To advance in the understanding of all these processes at different scales requires the use of simplified representations of our body, which is normally known as modelling or equivalently the creation of a model. Different types of models can be found in the literature: in-vitro, in-vivo and in-silico models.

Here, I will present our modelling strategy in which we integrate different mathematical models and experiments in order to tackle relevant mechanical-based mechanisms in wound healing and cancer metastasis progression [1,2]. In fact, we have focused our research on individual [3] and collective cell migration [4], because it is a crucial event in all these mechanisms. Therefore, unravelling the intrinsic mechanisms that cells use to define their migration is an essential element for advancing the development of new technologies in regenerative medicine and cancer.

Due to the complexity of all these mechanisms, mathematical modelling is a relevant tool for providing deeper insight and quantitative predictions of the mechanical interplay between cells and extracellular matrix during cell migration. To assess the predictive capacity of these models, we will compare our numerical results with microfluidic-based experiments [2], which provide experimental information to test and refine the main assumptions of our models.

Actually, we design and fabricate multi-channel 3D microfluidics cell culture chips, which allow recreating the physiology and disease of one organ or any biological process with a precise control of the micro environmental factors [5]. Therefore, this kind of organ-on-a-chip experiments constitutes a novel modelling strategy of in vitro multicellular human systems that in combination with mathematical simulations provide a relevant tool for research in mechanobiology.

References

Escribano J, Chen M, Moeendarbary E, Cao X, Shenoy V, Garcia-Aznar JM, Kamm RD, Spill F.  Balance of Mechanical Forces Drives Endothelial Gap Formation and May Facilitate Cancer and Immune-Cell Extravasation. PLOS Computational Biology, in press.

Cardiac fibrosis plays a significant role in the disruption of healthy electrical signalling in the heart, creating structural heterogeneities that induce and stabilise arrhythmia.  However, a proper understanding of the consequences of cardiac fibrosis must take into account the complex and highly variable patterns of its spatial localisation in the heart, which significantly affects the extent and manner of its impacts on cardiac wave propagation. In this work we present a methodology for the algorithmic generation of fibrotic patterns via Perlin noise, a technique for computationally efficient generation of textures in computer graphics.

Our approach works directly from image data to create populations of pattern realisations that all resemble the target image under a set of metrics. Our technique thus serves as a type of data enrichment, enabling analysis of how variability in the precise placement of fibrotic structures modulates their electrophysiological impact. We demonstrate our method, and the types of analysis it can enable, using a widely referenced histological image of four different types of microfibrotic structure. Our generator and Bayesian tuning method prove flexible enough to successfully capture each of these very distinct patterns.

We demonstrate the importance of this tool, by presenting 2D simulations overlayed on the generated images that highlight the effects of microscopic variability on the electrophysiological impact of fibrosis. Finally, we discuss the application of our methodology to the increasingly available imaging data of fibrotic patterning on a more macroscopic scale, and indeed to other areas of science underpinned by image based modelling and simulation.    

PLEASE NOTE THAT THIS SEMINAR IS CANCELLED DUE TO UNFORESEEN CIRCUMSTANCES.

Competition between peptides for binding and presentation by MHC class I molecules decides the immune response to foreign or tumor antigens. Many previous studies have attempted to classify the immunogenicity of a peptide using machine learning algorithms to predict the affinity, or half-life, of the peptide binding to MHC. However immunopeptidome analyses have shown a poor correlation between sequence based predictions and the abundance on the cell surface of the experimentally identified peptides. Such metrics are, for instance, only comparable when the abundance of competing peptides can be accurately quantified. We have developed a model for predicting the relative presentation of competing peptides that takes into account off-rate, source protein abundance and turnover and cofactor-assisted MHC assembly with peptides. This model is mechanism based so that it can accommodate complex biology phenomena such as inflammation, up or downregulation of peptide loading complex chaperones, appearance of a mutanome. We have used aspects of the model to drive an investigation of the precise molecular mechanism of peptide selection by MHC I and its associated intracellular cofactors.

PLEASE NOTE THAT THIS SEMINAR IS CANCELLED DUE TO UNFORSEEN CIRCUMSTANCES.

Despite their tiny size, microorganisms play a huge role in many biological, medical, and engineering phenomena. For example, massive plankton blooms are an integral part of the oceanic ecosystem. Algal cells incorporate carbon dioxide, which affects global warming. In industry, microorganisms are used in bioreactors to produce food and medicines and to treat sewage. The human body hosts hundreds of microorganism species, and the number of microorganisms in the human body is roughly double the number of cells in the body. In the intestine, approximately 1 kg of enterobacteria form a unique ecosystem, called the gut flora, which plays important roles in digestion and in relation to infection. Because of the considerable influence that microorganisms have on human life, the study of their behavior and function is important.

Recent research has demonstrated the importance of biomechanics in understanding the behavior and functions of microorganisms. For example, red tides can be induced by the interplay between the background flow and swimming cells. A dense suspension of bacteria can generate a coherent structure, which strongly enhances mass transport in a suspension. These phenomena show that the physical environments around cells alter their behavior and biological functions. Such a biomechanical understanding is still lacking in microbiology, and we believe that biomechanics can provide new perspectives on future microbiology.

In this talk, we first introduce some of our studies of the behavior of individual swimming microorganisms near surfaces. We show that hydrodynamic forces can trap cells at liquid–air or liquid–solid interfaces. We then introduce interactions between a pair of swimming microorganisms, because a two-body interaction is the simplest many-body interaction. We show that our mathematical models can describe the interactions between two nearby swimming microorganisms. Collective motions formed by a group of swimming microorganisms are also introduced. We show that some collective motions of microorganisms, such as coherent structures of bacterial suspensions, can be understood in terms of fluid mechanics. We then discuss how cellular-level phenomena can change the rheological and diffusion properties of a suspension. The macroscopic properties of a suspension are strongly affected by mesoscale flow structures, which in turn are strongly affected by the interactions between cells. Hence, a bottom-up strategy, i.e., from a cellular level to a continuum suspension level, represents a natural approach to the study of a suspension of swimming microorganisms. Finally, we discuss whether our understanding of biological functions can be strengthened by the application of biomechanics, and how we can contribute to the future of microbiology.

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?

Computational nucleic acid devices show great potential for enabling a broad range of biotechnology applications, including smart probes for molecular biology research, in vitro assembly of complex compounds, high-precision in vitro disease diagnosis and, ultimately, computational therapeutics inside living cells. This diversity of applications is supported by a range of implementation strategies, including nucleic acid strand displacement, localisation to substrates, and the use of enzymes with polymerase, nickase and exonuclease functionality. However, existing computational design tools are unable to account for these different strategies in a unified manner. This talk presents a programming language that allows a broad range of computational nucleic acid systems to be designed and analysed. We also demonstrate how similar approaches can be incorporated into a programming language for designing genetic devices that are inserted into cells to reprogram their behaviour. The language is used to characterise the genetic components for programming populations of cells that communicate and self-organise into spatial patterns. More generally, we anticipate that languages and software for programming molecular and genetic devices will accelerate the development of future biotechnology applications.

There is great interest in the molecular characterisation of intestinal metaplasia, such as Barrett’s esophagus (BE), to understand the basic biology of metaplastic development from a tissue of origin. BE is asymptomatic, so it is not generally known how long a patient has lived with this precursor of esophageal adenocarcinoma (EAC) when initially diagnosed in the clinic. We previously constructed a BE clock model using patient-specific methylation data to estimate BE onset times using Bayesian inference techniques, and thus obtain the biological age of BE tissue (Curtius et al. 2016). We find such epigenetic drift to be widely evident in BE tissue (Luebeck et al. 2017) and the corresponding tissue ages show large inter-individual heterogeneity in two patient populations.               

From a basic biological mechanism standpoint, it is not fully understood how the Barrett’s tissue first forms in the human esophagus because this process is never observed in vivo, yet such information is critical to inform biomarkers of risk based on temporal features (e.g., growth rates, tissue age) reflecting the evolution toward cancer. We analysed multi-region samples from 17 BE patients to

1) measure the spatial heterogeneity in biological tissue ages, and 2) use these ages to calibrate mathematical models (agent-based and continuum) of the mechanisms for formation of the segment itself. Most importantly, we found that tissue must be regenerated nearer to the stomach, perhaps driven by wound healing caused by exposure to reflux, implying a gastric tissue of origin for the lesions observed in BE. Combining bioinformatics and mechanistic modelling allowed us to infer evolutionary processes that cannot be clinically observed and we believe there is great translational promise to develop such hybrid methods to better understand multiscale cancer data.

References:

Curtius K, Wong C, Hazelton WD, Kaz AM, Chak A, et al. (2016) A Molecular Clock Infers Heterogeneous Tissue Age Among Patients with Barrett's Esophagus. PLoS Comput Biol 12(5): e1004919

Luebeck EG, Curtius K, Hazelton WD, Made S, Yu M, et al. (2017) Identification of a key role of epigenetic drift in Barrett’s esophagus and esophageal adenocarcinoma. J Clin Epigenet 9:113

Genome replication is a stochastic process whereby each cell exhibits different patterns of origin activation and replication fork movement.  Despite this heterogeneity, replication is a remarkably stable process that works quickly and correctly over hundreds of thousands of iterations. Existing methods for measuring replication dynamics largely focus on how a population of cells behave on average, which precludes the detection of low probability errors that may have occurred in individual cells.  These errors can have a severe impact on genome integrity, yet existing single-molecule methods, such as DNA combing, are too costly, low-throughput, and low-resolution to effectively detect them.  We have created a method that uses Oxford Nanopore sequencing to create high-throughput genome-wide maps of DNA replication dynamics in single molecules.  I will discuss the informatics approach that our software uses, our use of mathematical modelling to explain the patterns that we observe, and questions in DNA replication and genome stability that our method is uniquely positioned to answer.

In this work we will attempt, via virtual models, to interpret how structure and body positioning impact upon the outcomes of Multi-Breath-Washout tests. 

By extrapolating data from CT images, a virtual reduced dimensional airway/vascualr network will be constructed. Using this network both airway and blood flow profiles will be calculated. These profiles will then be used to model gas transport within the lungs. The models will allow us to investigate the role of airway restriction, body position during testing and washout gas choice have on MBW measures. 
 

In this talk I will show the nature, the properties and the features of the Pareto Optimality in a diverse set of phenomena modeled as complex networks.
I will present a composite design methodology for multi-objective modeling and optimization of complex networks.  The method is based on the synergy of different algorithms and computational techniques for the analysis and modeling of natural systems (e.g., metabolic pathways in prokaryotic and eukaryotic cells) and artificial systems (e.g., traffic networks, analog circuits and solar cells).

“Pareto Optimality in Multilayer Network Growth”
G. Nicosia et al, Phys. Rev. Lett., 2018

Switch-like and oscillatory dynamical systems are widely observed in biology. We investigate the simplest biological switch that is composed of a single molecule that can be autocatalytically converted between two opposing activity forms. We test how this simple network can keep its switching behaviour under perturbations in the system. We show that this molecule can work as a robust bistable system, even for alterations in the reactions that drive the switching between various conformations. We propose that this single molecule system could work as a primitive biological sensor and show by steady state analysis of a mathematical model of the system that it could switch between possible states for changes in environmental signals. Particularly, we show that a single molecule phosphorylation-dephosphorylation switch could work as a nucleotide or energy sensor. We also notice that a given set of reductions in the reaction network can lead to the emergence of oscillatory behaviour. We propose that evolution could have converted this switch into a single molecule oscillator, which could have been used as a primitive timekeeper. I will discuss how the structure of the simplest known circadian clock regulatory system, found in cyanobacteria, resembles the proposed single molecule oscillator. Besides, we speculate if such minimal systems could have existed in an RNA world. I will also present how the regulatory network of the cell cycle could have emerged from this system and what are the consequences of this possible evolution from a single antagonistic kinase-phosphatase network.

Despite progress in understanding many aspects of malignancy, resistance to therapy is still a frequent occurrence. Recognised causes of this resistance include 1) intra-tumour heterogeneity resulting in selection of resistant clones, 2) redundancy and adaptability of gene signalling networks, and 3) a dynamic and protective microenvironment. I will discuss how these aspects influence each other, and then focus on the tumour microenvironment.

The tumour microenvironment comprises a heterogeneous, dynamic and highly interactive system of cancer and stromal cells. One of the key physiological and micro-environmental differences between tumour and normal tissues is the presence of hypoxia, which not only alters cell metabolism but also affects DNA damage repair and induces genomic instability. Moreover, emerging evidence is uncovering the potential role of multiple stroma cell types in protecting the tumour primary niche.

I will discuss our work on in silico cancer models, which is using genomic data from large clinical cohorts of individuals to provide new insights into the role of the tumour microenvironment in cancer progression and response to treatment. I will then discuss how this information can help to improve patient stratification and develop novel therapeutic strategies.

Computer vision approaches have made huge advances with deep learning research. These algorithms can be employed as a basis for phenotyping of biological traits from imaging modalities. This can be employed, for example, in the context of facial photographs of rare diseases as a means of aiding diagnostic pathways, or as means to large scale phenotyping in histological imaging. With any data set, inherent biases and problems in the data available for training can have a detrimental impact on your models. I will describe some examples of such data set problems and outline how to build models that are not confounded – despite biases in the training data. 

Atherosclerosis is a manifestation of cardiovascular disease consisting of the buildup of inflamed arterial plaques. Because most heart attacks are caused by the rupture of unstable "vulnerable" plaque, the characterization of plaques and their vulnerability remains an outstanding problem in medicine.

Morphoelasticity is a mathematical framework commonly employed to describe tissue growth.

Its central premise is the decomposition of the deformation gradient into the product of an elastic tensor and a growth tensor.

In this talk, I will present some recent efforts to simulate intimal thickening -- the precursor to atherosclerosis -- using morphoelasticity theory.

The arterial wall is composed of three layers: the intima, media and adventitia. 

The intima is allowed to grow isotropically while the area of the media and adventitia is approximately conserved. 

All three layers are modeled as anisotropic hyperelastic materials, reinforced by collagen fibers.

We explore idealized axisymmetric arteries as well as more general geometries that are solved using the finite element method.

Results are discussed in the context of balloon-injury experiments on animals and Glagovian remodeling in humans.

Transdifferentiation, the process of converting from one cell type to another without going through a pluripotent state, has great promise for regenerative medicine. The identification of key transcription factors for reprogramming is limited by the cost of exhaustive experimental testing of plausible sets of factors, an approach that is inefficient and unscalable. We developed a predictive system (Mogrify) that combines gene expression data with regulatory network information to predict the reprogramming factors necessary to induce cell conversion. We have applied Mogrify to 173 human cell types and 134 tissues, defining an atlas of cellular reprogramming. Mogrify correctly predicts the transcription factors used in known transdifferentiations. Furthermore, we validated several new transdifferentiations predicted by Mogrify, including both into and out of the same cell type (keratinocytes). We provide a practical and efficient mechanism for systematically implementing novel cell conversions, facilitating the generalization of reprogramming of human cells. Predictions are made available via http://mogrify.net to help rapidly further the field of cell conversion.

Ultrasound (US) imaging is one of the first steps in a continuum of pregnancy care. During the fetal period, the brain undergoes dramatic structural changes, many of which are informative of healthy maturation. The resolution of modern US machines enables us to observe and measure brain structures, as well as detect cerebral abnormalities in fetuses from as early as 18 weeks. Recent breakthroughs in machine learning techniques for image analysis introduce opportunities to  develop bespoke methods to track spatial and temporal patterns of fetal brain development. My work focuses on the design of appropriate data-driven techniques to extract developmental information from standard clinical US images of the brain.

In this talk I will discuss how computational algebraic geometry and topology can be useful for studying questions arising in systems biology. In particular I will focus on the problem of comparing models and data through the lens of computational algebraic geometry and statistics. I will provide concrete examples of biological signalling systems that are better understood with the developed methods.

Please note that this will be held at Tsuzuki Lecture Theatre, St Annes College, Oxford.

Please note that you will need to register for this event via https://www.eventbrite.co.uk/e/qbiox-colloquium-trinity-term-2018-ticke…

Cancer causing mutations must become permanently fixed within tissues. 

Please note that this will be held at Tsuzuki Lecture Theatre, St Annes College, Oxford.

Please note that you will need to register for this event via https://www.eventbrite.co.uk/e/qbiox-colloquium-trinity-term-2018-ticke…

In this talk, I will review a number of interdisciplinary collaborations in which I have been involved over the years that have coupled mathematical
modelling with experimental studies to try to advance our understanding of processes in biology and medicine. Examples will include somatic evolution in
tumours, collective cell movement in epithelial sheets, cell invasion in neural crest, and pattern formation in slime mold. These are examples where
verbal reasoning models are misleading and insufficient, while mathematical models can enhance our intuition.

Please note that this will be held at Tsuzuki Lecture Theatre, St Annes College, Oxford.

Please note that you will need to register for this event via https://www.eventbrite.co.uk/e/qbiox-colloquium-trinity-term-2018-ticke…

ATP-sensitive potassium (KATP) channels are critical for coupling changes in blood glucose to insulin secretion. Gain-of-function mutations in KATP channels cause a rare inherited form of diabetes that manifest soon after birth (neonatal diabetes). This talk shows how understanding KATP channel function has enabled many neonatal diabetes patients to switch from insulin injections to sulphonylurea drugs that block KATP channel activity, with considerable improvement in their clinical condition and quality of life.   Using a mouse model of neonatal diabetes, we also found that as little as 2 weeks of diabetes led to dramatic changes in gene expression, protein levels and metabolite concentrations. This reduced glucose-stimulated ATP production and insulin release. It also caused substantial glycogen storage and β-cell apoptosis. This may help explain why older neonatal diabetes patients with find it more difficult to transfer to drug therapy, and why the drug dose decreases with time in many patients. It also suggests that altered metabolism may underlie both the progressive impairment of insulin secretion and reduced β-cell mass in type 2 diabetes.

I will discuss some properties of delay differential equations in which the delay is not prescribed a-priori but is determined from a threshold condition. Sometimes the delay depends on the solution of the differential equation and its history. A scenario giving rise to a threshold type delay is that larval insects sometimes experience halting or slowing down of development, known as diapause, perhaps as a consequence of intra-specific competition among larvae at higher densities. Threshold delays can result in population dynamical models having some unusual properties, for example, if the model has an Allee effect then diapause may cause extinction in some parameter regimes even where the initial population is high.

Please  note that this talk is only suitable for Mathematicians.

Since the invention of the microscope, scientists have known that pond-dwelling algae can actually swim – powering their way through the fluid using tiny limbs called cilia and flagella. Only recently has it become clear that the very same structure drives important physiological and developmental processes within the human body. Motivated by this connection, we explore flagella-mediated swimming gaits and stereotyped behaviours in diverse species of algae, revealing the extent to which control of motility is driven intracellularly. These insights suggest that the capacity for fast transduction of signal to peripheral appendages may have evolved far earlier than previously thought.

DNA computing is emerging as a versatile technology that promises a vast range of applications, including biosensing, drug delivery and synthetic biology. DNA logic circuits can be achieved in solution using strand displacement reactions, or by decision-making molecular robots-so called 'walkers'-that traverse tracks placed on DNA 'origami' tiles.

 Similarly to conventional silicon technologies, ensuring fault-free DNA circuit designs is challenging, with the difficulty compounded by the inherent unreliability of the DNA technology and lack of scientific understanding. This lecture will give an overview of computational models that capture DNA walker computation and demonstrate the role of quantitative verification and synthesis in ensuring the reliability of such systems. Future research challenges will also be discussed.

Classical work of Jeffery from 1922 established how at low Reynolds number, ellipsoids in steady shear flow undergo periodic motion with non-uniform rotation rate, termed 'Jeffery orbits'.  I will present two problems where Jeffery orbits play a critical role in understanding the transport and aggregation of rod-shaped organisms.  I will discuss the trapping of motile chemotactic bacteria in high shear, and the sedimentation rate of negatively buoyant plankton. 

Many symptoms of Parkinson’s disease are connected with abnormally high levels of synchrony in neural activity. A successful and established treatment for a drug-resistant form of the disease involves electrical stimulation of brain areas affected by the disease, which has been shown to desynchronize neural activity. Recently, a closed-loop deep brain stimulation has been developed, in which the provided stimulation depends on the amplitude or phase of oscillations that are monitored in patient’s brain. The aim of this work was to develop a mathematical model that can capture experimentally observed effects of closed-loop deep brain stimulation, and suggest how the stimulation should be delivered on the basis of the ongoing activity to best desynchronize the neurons. We studied a simple model, in which individual neurons were described as coupled oscillators. Analysis of the model reveals how the therapeutic effect of the stimulation should depend on the current level of synchrony in the network. Predictions of the model are compared with experimental data.

The derivation of so-called `effective descriptions' that explicitly incorporate microscale physics into a macroscopic model has garnered much attention, with popular applications in poroelasticity, and models of the subsurface in particular. More recently, such approaches have been applied to describe the physics of biological tissue. In such applications, a key feature is that the material is active, undergoing both elastic deformation and growth in response to local biophysical/chemical cues.

Here, two new macroscale descriptions of drug/nutrient-limited tissue growth are introduced, obtained by means of two-scale asymptotics. First, a multiphase viscous fluid model is employed to describe the dynamics of a growing tissue within a porous scaffold (of the kind employed in tissue engineering applications) at the microscale. Secondly, the coupling between growth and elastic deformation is considered, employing a morpho-elastic description of a growing poroelastic medium. Importantly, in this work, the restrictive assumptions typically made on the underlying model to permit a more straightforward multiscale analysis are relaxed, by considering finite growth and deformation at the pore scale.

In each case, a multiple scales analysis provides an effective macroscale description, which incorporates dependence on the microscale structure and dynamics provided by prototypical `unit cell-problems'. Importantly, due to the complexity that we accommodate, and in contrast to many other similar studies, these microscale unit cell problems are themselves parameterised by the macroscale dynamics.

In the first case, the resulting model comprises a Darcy flow, and differential equations for the volume fraction of cells within the scaffold and the concentration of nutrient, required for growth. Stokes-type cell problems retain multiscale dependence, incorporating active cell motion [1]. Example numerical simulations indicate the influence of microstructure and cell dynamics on predicted macroscale tissue evolution. In the morpho-elastic model, the effective macroscale dynamics are described by a Biot-type system, augmented with additional terms pertaining to growth, coupled to an advection--reaction--diffusion equation [2].

[1] HOLDEN, COLLIS, BROOK and O'DEA. (2018). A multiphase multiscale model for nutrient limited tissue growth, ANZIAM (In press)

[2] COLLIS, BROWN, HUBBARD and O'DEA. (2017). Effective Equations Governing an Active Poroelastic Medium, Proceedings of the Royal Society A. 473, 20160755

Dr Nicola Beer heads up the Department of Stem Cell Engineering at the new Novo Nordisk Research Centre Oxford. Her team will use human stem cells to derive metabolically-relevant cells and tissues such as islets, hepatocytes, and adipocytes todiscover novel secreted factors and corresponding signalling pathways which modify cell function, health, and viability. Bycombining in vitro-differentiated human stem cell-derived models with CRISPR and other genomic targeting techniques, the teamassay cell function from changes in a single gene up to a genome-wide scale. Understanding the genes and pathways underlying cell function (and dysfunction) highlights potential targets for new Type 2 Diabetes therapeutics. Dr Beer will talk about the work ongoing in her team, as well as more broadly about the role of human stem cells in drug discovery and patient treatment.

A wide range of chronic degenerative diseases of mankind result from the accumulation of altered forms of self proteins, resulting in cell toxicity, tissue destruction and chronic inflammatory processes in which the body’s immune system contributes to further cell death and loss of function. A hallmark of these conditions, which include major disease burdens such as Alzheimer’s Disease and type II diabetes, is the formation of long fibrillar polymers that are deposited in expanding tangled masses called plaques. Recently, similarities between these pathological accumulations and physiological mechanisms for organising intracellular space have been recognised, and formal demonstrations that amyloid accumulations form hydrogels have confirmed this link. We are interested in the pathological consequences of amyloid hydrogel formation and in order to study these processes we combine modelling of the assembly process with biophysical measurement of gelation and its cellular consequences.

Please see https://www.eventbrite.co.uk/e/qbiox-colloquium-dunn-school-seminar-hil…

for further details

T cells stimulation by antigen (peptide-MHC, pMHC) initiates adaptive immunity, a major factor contributing to vertebrate fitness. The T cell antigen receptor (TCR) present on the surface of T cells is the critical sensor for the recognition of and response to “foreign" entities, including microbial pathogens and transformed cells. Much is known about the complex molecular machine physically connected to the TCR to initiate, propagate and regulate signals required for cellular activation. However, we largely ignore the physical distribution, dynamics and reaction energetics of this machine before and after TCR binding to pMHC. I will illustrate a few basic notions of TCR signalling and potent quantitative in-cell approaches used to interpret TCR signalling behaviour. I will provide two examples where mathematical formalisation will be welcome to better understand the TCR signalling process.

Please see https://www.eventbrite.co.uk/e/qbiox-colloquium-dunn-school-seminar-hil… for further details.

Bacteria swim by rotating semi-rigid helical flagellar filaments, using an ion driven rotary motor embedded in the membrane. Bacteria are too small to sense a spatial gradient and therefore sense changes in time, and use the signals to bias their direction changing pattern to bias overall swimming towards a favourable environment. I will discuss how interdisciplinary research has helped us understand both the mechanism of motor function and its control by chemosensory signals.

Please see https://www.eventbrite.co.uk/e/qbiox-colloquium-dunn-school-seminar-hil…

for details.

Please note that this seminar will take place at the Physical and Theoretical Chemistry Laboratory within the
Department of Chemistry, room, PTCL lecture theatre.

The ability of cells to sense and respond to the mechanical properties of their environments is fundamental to cellular behaviour, with stiffness found to be a key control parameter. The physical mechanisms underpinning mechanosensing are, however, not well understood. I here consider the key physical cellular behaviours of active contractility of the internal cytoskeleton and cell growth, coupling these into mechanical models. These models suggest new distinct mechanisms of mechanotransduction in cells and tissues.

I will discuss a new theoretical approach to information and decisions in signalling systems and relate this to new experimental results about the NF-kappaB signalling system. NF-kappaB is an exemplar system that controls inflammation and in different contexts has varying effects on cell death and cell division. It is commonly claimed that it is information processing hub, taking in signals about the infection and stress status of the tissue environment and as a consequence of the oscillations, transmitting higher amounts of information to the hundreds of genes it controls. My aim is to develop a conceptual and mathematical framework to enable a rigorous quantifiable discussion of information in this context in order to follow Francis Crick's counsel that it is better in biology to follow the flow of information than those of matter or energy. In my approach the value of the information in the signalling system is defined by how well it can be used to make the "correct decisions" when those "decisions" are made by molecular networks. As part of this I will introduce a new mathematical method for the analysis and simulation of large stochastic non-linear oscillating systems. This allows an analytic analysis of the stochastic relationship between input and response and shows that for tightly-coupled systems like those based on current models for signalling systems, clocks, and the cell cycle this relationship is highly constrained and non-generic.

This will be a whistle-stop tour of a few topics on infectious disease modelling, mainly influenza. Topics to include:

• challenges in capturing dynamics of pathogens with multiple co-circulating strains
• untangling the 2009 influenza pandemic from medical insurance claims data from the US
• bioinformatic methods to detect viral packaging signals
• and a big science project (top secret until the talk!)

Julia will be visiting the Mathematical Institute on sabbatical this term, and hopes this talk will help us find areas of overlapping interests.

Image use continues to increase in both biomedical sciences and clinical practice. State of the art acquisition techniques allow characterisation from subcellular to whole organ scale, providing quantitative information of structure and function. In the heart, for example, images acquired from a single modality (cardiac MRI) can characterise micro- and macrostructure, describe mechanical function and measure blood flow. In the lungs, new contrast agents can be used to visualise the flow of gas in free breathing subjects. This provides rich new sources of information as well as new challenges to extract data in a way that is useful to clinicians as well as computer modellers.
I will describe efforts in my group to use the latest advances in machine learning to analyse images, and explain how we are applying these to the development of accurate computer models of the heart.
 

Hypoxia, i.e. a reduction in dissolved oxygen concentration below physiologically normal levels, has been identified as playing a critical role
in the progression of many types of disease and as a key determinant of the success of cancer treatment. It poses a particular challenge for treatments
such as radiotherapy, photodynamic and sonodynamic therapy which rely on the production of reactive oxygen species. Strategies for treating hypoxia have
included the development of hypoxia-selective drugs as well as methods for directly increasing blood oxygenation, e.g. hyperbaric oxygen therapy, pure
oxygen or carbogen breathing, ozone therapy, hydrogen peroxide injections and administration of suspensions of oxygen carrier liquids. To date, however,
these approaches have delivered limited success either due to lack of proven efficacy and/or unwanted side effects. Gas microbubbles, stabilised by a
biocompatible shell have been used as ultrasound contrast agents for several decades and have also been widely investigated as a means of promoting drug
delivery. This talk will present our recent research on the use of micro and nanobubbles to deliver both drug molecules and oxygen simultaneously to a
tumour to facilitate treatment.

We adopt the paradigm of understanding how the heart develops during pregnancy as a first principal to inform on adult heart repair and regeneration. Our target for cell-based repair is the epicardium and epicardium-derived cells (EPDCs) which line the outside of the forming heart and contribute vascular endothelial and smooth muscle cells to the coronary vasculature, interstitial fibroblasts and cardiomyocytes. The epicardium can also act as a source of signals to condition the growth of the underlying embryonic heart muscle. In the adult heart, whilst the epicardium is retained, it is effectively quiescent. We have sought to extrapolate the developmental potential of the epicardium to the adult heart following injury by stimulating dormant epicardial cells to give rise to new muscle and vasculature. In parallel, we seek to modulate the local environment into which the new cells emerge: a cytotoxic mixture of inflammation and fibrosis which prevents cell engraftment and integration with survived heart tissue. To this end we manipulate the lymphatic vessels in the heart given that, elsewhere in the body, the lymphatics survey the immune system and modulate inflammation at peripheral injury sites. We recently described the development of the cardiac lymphatic vasculature and revealed in the adult heart that they undergo increased vessel sprouting (lymphangiogenesis) in response to injury, to improve function, remodelling and fibrosis. We are currently investigating whether increased lymphangiogenesis functions to clear immune cells and constrain the reparative response for optimal healing.