## Rachel Howard : Monitoring the systemic immune response to cancer therapy

- Mathematical Biology ( 246 Views )Complex interactions occur between tumor and host immune system during cancer development and treatment, and a weak systemic immune response can be prognostic of poor patient outcomes. We strive to not only better understand the dynamic behavior of circulating immune cell populations before and during cancer therapy, but also to monitor these dynamic changes to facilitate real-time prediction of patient outcomes and potentially therapy adaptation. I will provide examples of both theoretical (mathematical) and data-driven (epidemiological) approaches to incorporating established systemic immune markers into clinical decision-making. First, coupling models of local tumor-immune dynamics and systemic T cell trafficking allows us to simulate the evolution of tumor and immune cell populations in anatomically distant sites following local therapy, in turn identifying the optimal treatment target for maximum reduction of global tumor burden. Second, improved understanding of how circulating immune markers vary both within and between individual patients can allow more accurate risk stratification at diagnosis, and personalized prediction of patient response to therapy. The importance of multi-disciplinary collaborations in making predictive and prognostic models clinically relevant will be discussed.

## Daniel Lew : Modeling the effect of vesicle traffic on polarity establishment in yeast

- Mathematical Biology ( 231 Views )There are two generally accepted models for the cell biological positive feedback loops that allow yeast cells to break symmetry and establish an axis of polarity. Both have been subjects of published mathematical analyses. Here I will argue that the models used to support a vesicle trafficking model incorporated a simplifying assumption that seemed innocuous but in fact was critical to their success. The assumption is not physically plausible, and its removal means that the model fails. I will show how changing other assumptions can make the model work, but there is no experimental support for those changes. And without them, the vesicle trafficking model perturbs polarity, rather than establishing polarity

## Johannes Reiter : Minimal intratumoral heterogeneity in untreated cancers

- Mathematical Biology ( 219 Views )Genetic intratumoral heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. I will discuss the extent of genetic heterogeneity within untreated cancers with particular regard to its clinical relevance. While genomic heterogeneity within primary tumors is associated with relapse, heterogeneity among treatmentâ??naÃ¯ve metastases has not been comprehensively assessed. We analyzed sequencing data for 76 untreated metastases from 20 patients and inferred cancer phylogenies for breast, colorectal, endometrial, gastric, lung, melanoma, pancreatic, and prostate cancers. We found that within individual patients a large majority of driver gene mutations are common to all metastases. Further analysis revealed that the driver gene mutations that were not shared by all metastases are unlikely to have functional consequences. A mathematical model of tumor evolution and metastasis formation provides an explanation for the observed driver gene homogeneity. Last, we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44 patients. These data indicate that the cells within the primary tumors that gave rise to metastases are genetically homogeneous with respect to functional driver gene mutations and suggest that future efforts to develop combination therapies have the capacity to be curative.

## John Dallon : Modeling Fibroblast Populated Collagen Lattices

- Mathematical Biology ( 215 Views )In order to better understand wound contraction fibroblast populated collagen lattices have been studied for many years. Â In this talk I will discuss mathematical models for lattice contraction. Â The models are formulated with components at the cellular and sub cellular level with the goal of understanding the macroscopic behavior of the lattice.

## Suncica Canic : Fluid-composite structure interaction and blood flow

- Mathematical Biology ( 210 Views )Fluid-structure interaction problems with composite structures arise in many applications. One example is the interaction between blood flow and arterial walls. Arterial walls are composed of several layers, each with different mechanical characteristics and thickness. No mathematical results exist so far that analyze existence of solutions to nonlinear, fluid-structure interaction problems in which the structure is composed of several layers. In this talk we will summarize the main difficulties in studying this class of problems, and present a computational scheme based on which a proof of the existence of a weak solution was obtained. Our results reveal a new physical regularizing mechanism in FSI problems: inertia of the thin fluid-structure interface with mass regularizes evolution of FSI solutions. Implications of our theoretical results on modeling the human cardiovascular system will be discussed. This is a joint work with Boris Muha (University of Zagreb, Croatia), Martina Bukac (U of Notre Dame, US) and Roland Glowinski (UH). Numerical results with vascular stents were obtained with S. Deparis and D. Forti (EPFL, Switzerland), and with A. Quaini (UH). Collaboration with medical doctors Dr. S. Little (Methodist Hospital Houston) and Dr. Z. Krajcer (Texas Heart Institute) is also acknowledged.

## Jeremy Gunawardena : The Hopfield Barrier in eukaryotic gene regulation

- Mathematical Biology ( 201 Views )John Hopfield pointed out, in his seminal paper on kinetic proofreading, that if a biochemical system operates at thermodynamic equilibrium there is a barrier to how well it can achieve high-fidelity in transcription and translation. Hopfield showed that the only way to bypass this barrier is to dissipate energy and maintain the system away from equilibrium. Eukaryotic gene regulation uses dissipative mechanisms, such as nucleosome remodelling, DNA methylation and post-translational modification of histones, which are known to play a critical regulatory role but have been largely ignored in quantitative treatments. I will describe joint work with my colleague Angela DePace in which we use the recently-developed, graph-theoretic Â?linear frameworkÂ? to show that the sharpness with which a gene is turned Â?onÂ? or Â?offÂ? in response to an upstream transcription factor is limited if the regulatory system operates at equilibrium, even with arbitrary degrees of higher-order cooperativity. In contrast, if the regulatory system is maintained away from equilibrium, substantially higher degrees of sharpness can be achieved. We suggest that achieving sharpness in gene regulation exhibits a Hopfield Barrier, and uncover, along the way, a new interpretation for the ubiquitously used, but poorly justified, Hill function.

## Cristan Tomasetti : Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention

- Mathematical Biology ( 193 Views )Cancers are caused by mutations that may be inherited, induced by environmental factors, or result from DNA replication errors (R). We studied the relationship between the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries throughout the world. The data revealed a strong correlation (median = 0.80) between cancer incidence and normal stem cell divisions in all countries, regardless of their environment. The major role of R mutations in cancer etiology was supported by an independent approach, based solely on cancer genome sequencing and epidemiological data, which suggested that R mutations are responsible for two-thirds of the mutations in human cancers. All of these results are consistent with epidemiological estimates of the fraction of cancers that can be prevented by changes in the environment. Moreover, they accentuate the importance of early detection and intervention to reduce deaths from the many cancers arising from unavoidable R mutations.

## Elliot Cartee : Control-Theoretic Models of Environmental Crime

- Mathematical Biology ( 188 Views )We present two models of perpetrators' decision-making in extracting resources from a protected area. It is assumed that the authorities conduct surveillance to counter the extraction activities, and that perpetrators choose their post-extraction paths to balance the time/hardship of travel against the expected losses from a possible detection. In our first model, the authorities are assumed to use ground patrols and the protected resources are confiscated as soon as the extractor is observed with them. The perpetrators' path-planning is modeled using the optimal control of randomly-terminated process. In our second model, the authorities use aerial patrols, with the apprehension of perpetrators and confiscation of resources delayed until their exit from the protected area. In this case the path-planning is based on multi-objective dynamic programming. Our efficient numerical methods are illustrated on several examples with complicated geometry and terrain of protected areas, non-uniform distribution of protected resources, and spatially non-uniform detection rates due to aerial or ground patrols.

## David Basanta : The ecology of cancer: mathematical modelling and clinical implications

- Mathematical Biology ( 179 Views )Decades of research in cancer have yielded scant results other than highlighting the need for new approaches that could go beyond the tried and tested molecular-based ones. Recent clinical studies show that tumour heterogeneity and selection, the ingredients of Darwinian evolution, can explain cancer progression towards malignancy as well as recurrence after treatment. In this talk I will describe mathematical and computational models that explore cancer evolutionary dynamics and that can explain how the interactions between the tumour with its environment (the tumour ecosystem) can yield a better understanding of cancer biology and lead to better and more efficacious treatments for cancer patients.

## Stanca Ciupe : Models of antibody responses in HIV

- Mathematical Biology ( 174 Views )One of the first immunologic responses against HIV infection is the presence of neutralizing antibodies that seem able to inactivate several HIV strains. Moreover, in vitro studies have shown the existence of monoclonal antibodies that exhibit broad crossclade neutralizing potential. Yet their number is low and slow to develop in vivo. In this paper, we investigate the potential benefits of inducing poly-specific neutralizing antibodies in vivo throughout immunization. We develop a mathematical model that considers the activation of families of B lymphocytes producing poly-specific and strain-specific antibodies and use it to demonstrate that, even if such families are successful in producing neutralizing antibodies, competition between them may limit the poly-specific response allowing the virus to escape. We modify this model to account for viral evolution under the pressure of antibody responses in natural HIV infection as well as the need to neutralize more than one viral spike. The model can reproduce viral escape under certain conditions of B lymphocyte competition. Using these models we provide explanations for the observed antibody failure in controlling natural infection and predict quantitative measures that need to be satisfied for long-term control of HIV infection.

## Rick Durrett : Spatial evolutionary games with weak selection

- Mathematical Biology ( 165 Views )Recently a mathematical theory has been developed for spatial games with weak selection, i.e., the payoff differences between strategies are small. The key to the analysis is that when space an time are suitably rescaled the limit is partial differential equation (PDE). This approach can be used to analyze all 2 x 2 games, but there are a number of 3 x 3 games for which the behavior of the limiting PDE is not known. In this talk we will describe simulation results for two cases that are not considered by rigorous results: rock-paper scissors and bistable games. We will begin by describing results for a two strategy game that arises from studying pancreatic cancer and shows that theoretical predictions work even when selection is not very weak. This is joint work with Mridu Nanda, a student at North Carolina School for Science and Math.

## Michael Mackey : Understanding, treating and avoiding hematological disease

- Mathematical Biology ( 158 Views )This talk will trace many years of work mathematical modeling hematological diseases. The Â?understandÂ? part talks about the use of mathematical to figure out what causes cyclical neutropenia, and the Â?treatÂ? part refers to work on treating cyclical neutropenia using recombinant cytokines. The Â?avoidÂ? part deals with current ongoing work trying to obviate the deleterious effects of chemotherapy on blood cell productionÂ?one of the major negative side effects of chemotherapy.

## John Bush : Biocapillarity

- Mathematical Biology ( 157 Views )We report the results of our integrated experimental and theoretical investigations of biological systems dominated by interfacial effects. Particular attention is given to elucidating natural strategies for water-repellency, walking on water, underwater breathing, and drinking.

## Nick Moore : How focused flexibility maximizes the thrust production of flapping wings

- Mathematical Biology ( 154 Views )Birds, insects, and fish all exploit the fact that flexible wings or fins generally perform better than their rigid counterparts. Given the task of designing an optimal wing, though, it is not clear how to best distribute the flexibility: Should the wing be uniformly flexible along its length, or could some advantage be gained by making certain sections more rigid than others? I will discuss this question by using a 2D small-amplitude model for the fluid-structure interaction combined with an efficient Chebyshev PDE solver. Numerical optimization shows that concentrating flexibility near the leading edge of the wing maximizes thrust production, an arrangement that resembles the torsional-joint flexibility mechanism found in insect wings. I will discuss the possibility of extending into three dimensions to address the question of optimal wing architecture more generally.

## Adriana Dawes : Protein localization at the single cell level: Interplay between biochemistry, mechanics and geometry

- Mathematical Biology ( 153 Views )Cells are highly organized and complex structures, with the capacity to segregate specific factors to spatially disjoint regions in a process called polarization. Polarization, which specifies a spatial axis in the cell, is a highly conserved biological process and is required for proper embryonic development, wound healing, and many other normal and pathological biological functions. Despite the importance of polarization, we do not fully understand how this protein segregation is initiated and maintained. In this talk, I will show how we can use numerical and analytical approaches to investigate how symmetry breaking begins the process of polarization, and how the geometry of the cell may play a role in the establishment and maintenance of spatial patterns associated with polarization.

## Jacob Scott : Understanding the evolution of resistance: a comprehensive and integrated mathematical and experimental research program.

- Mathematical Biology ( 150 Views )The evolution of resistance remains an elusive problem in the treatment of both cancer and infectious disease, and represents one of the most important medical problems of our time. While the illnesses are different on several non-trivial levels including timescale and complexity, the underlying biological phenomenon is the same: Darwinian evolution. To comprehensively approach these problems, I have focussed my attention on building a broad suite of investigations centered around the causes and consequences of the evolutionary process in these contexts. I will discuss my and my collaborator's efforts to; model the evolutionary process on the genomic scale in both an analytic (Markov process) and stochastic (individual based model and inference) format; to quantify in vitro competition and interaction between cancer cell lines through an evolutionary game theoretic lens using time-lapse microscopy and computer vision; and to understand the evolutionary contingencies inherent in collateral sensitivity in E. coli and ALK mutated non-small cell lung cancer.

## Tom Kepler : Microevolution in the Immune System: A Computational Systems Approach--second lecture

- Mathematical Biology ( 149 Views )Vaccines protect their recipients by inducing long-term structural changes in populations of immune cells. Part of that restructuring is exactly analogous to Darwinian Selection. New antibody molecules are created by somatic mutation of existing antibody genes. Subsequently, the immune cell populations that possess these mutated receptors overtake the "wild-type" immune cells due to the selective advantage they have acquired. Thus the immune system is vastly better prepared to recognize and eliminate the eliciting pathogen the next time around. New sequencing and biosynthesis technologies, together with mathematical and computational tools, now allow us to investigate this fascinating and important phenomenon more deeply than ever before. I will illustrate this development with examples from the immune response to HIV infection. Second lecture will focus on specifically mathematical questions.

## Jim Nolen : Sticky limit theorems for statistics in singular spaces.

- Mathematical Biology ( 147 Views )This talk is about extending classical limit theorems of probability (law of large numbers, central limit theorem) to a non-Euclidean setting. I'll talk about new and interesting phenomena observed when sampling independent points from certain singular geometric spaces. The main result is a limit theorem -- the "sticky central limit theorem" -- which applies to the mean or barycenter of a family of independent samples as the number of samples grows. The theorem shows that the geometry of the underlying space may have an interesting effect on the asymptotic fluctuations of the sample means, in a way that does not occur with independent samples in Euclidean space. One motivation for thinking about statistics in singular geometric spaces comes from evolutionary biology; one can consider phylogenetic trees as points in a metric space of the sort discussed in this talk. Apart from this basic motivation, however, the talk will have little biological content and will be mainly about probability.

## Rick Durrett : Branching Process Models of Cancer

- Mathematical Biology ( 145 Views )It is common to use a multitype branching process to model the accumulation of mutations that leads to cancer progression, metastasis, and resistance to treatment. In this talk I will describe results about the time until the first type k (cell with k mutations) and the growth of the type k population obtained in joint work with Stephen Moseley, and their use in evaluating possible screening strategies for ovarian cancer, work in progress with Duke undergraduate Kaveh Danesh. The point process representation of the limit, which is a one-sided stable law, together with results from 10-60 years ago leads to remarkable explicit formulas for Simpson's index and the size of the largest clone. These results are important in understanding tumor diversity which can present serious obstacles to treatment. The last topic is joint work with Jasmine Foo, Kevin Leder, John Mayberry, and Franziska Michor

## Steven Baer : Multiscale Modeling of Neural Subcircuits and Feedback Mechanisms in the Outer Plexiform Layer of the Retina

- Mathematical Biology ( 143 Views )Visual processing begins in the outer plexiform layer of the retina, where

bipolar, horizontal, and photoreceptor cells interact. In vertebrates, the

onset of dim backgrounds can enhance small spot flicker responses of

retinal horizontal cells. This flicker response is called background-

induced flicker enhancement. The underlying mechanism for the feedback

is unclear but competing hypotheses have been proposed. One is the GABA

hypothesis, which states that the inhibitory neurotransmitter GABA,

released from horizontal cells, mediates the feedback by blocking calcium

channels. Another is the ephaptic hypothesis, which contends that calcium

entry is regulated by changes in the electrical potential within the

intersynaptic space between cones and horizontal cells. In this study, a

continuum spine model of cone-horizontal cell synaptic circuitry is

formulated. The model captures two spatial scales - the scale of an

individual synapse and the scale of the receptive field involving hundreds

to thousands of synapses. We show that the ephaptic mechanism produces

reasonable qualitative agreement with the temporal dynamics exhibited by

flicker enhancement experiments. We find that although GABA produces

enhancement, this mechanism alone is insufficient to reproduce the

experimental results. We view this multiscale continuum approach as a

first step in formulating a multi-layer mathematical model of retinal

circuitry, which would include the other Â?brain nucleiÂ? within the retina:

the inner plexiform layer where bipolar, amacrine, interplexiform, and

ganglion cells interact.

## Mainak Patel : Temporal Binding Emerges as a Rapid and Accurate Encoding Tool Within a Network Model of the Locust Antennal Lobe

- Mathematical Biology ( 143 Views )The locust olfactory system interfaces with the external world through antennal receptor neurons (ORNs), which represent odors in a distributed, combinatorial manner. ORN axons bundle together to form the antennal nerve, which relays sensory information centrally to the antennal lobe (AL). Within the AL, an odor produces a stimulus-specific temporal progression of neuronal spiking, inspiring the hypothesis that the AL encodes odors through dynamically evolving ensembles of active cells. Such a coding strategy, however, requires higher olfactory centers to integrate a prolonged dynamic profile of AL signals prior to stimulus assessment, a process that is likely to be slow and inconsistent with the generation of quick behavioral responses. Our modeling work has led us to propose an alternate hypothesis: the dynamical interplay of fast and slow inhibition within the locust AL induces transient correlations in the spiking activity of an odor-dependent neural subset, giving rise to a temporal binding code and allowing rapid stimulus detection by downstream elements.

## Rodica Curtu : Mixed-Mode Activity Patterns in Neuronal Networks with Lateral Inhibition

- Mathematical Biology ( 141 Views )Stimulus tuning in a reduced model for neural competition leads to

## Phil Holmes : The neural dynamics of decision making: multiple scales in a single brain

- Mathematical Biology ( 141 Views )I will describe a range of models, from the cellular to cortical scales, that illuminate how we perceive stimuli and make decisions. Large networks composed of individual spiking neurons can capture biophysical details of neuromodulation and synaptic transmission, but their complexity renders them opaque to analysis. Employing methods of mean field and dynamical systems theory, I will argue that these high-dimensional stochastic differential equations can be reduced to simple drift-diffusion processes used by cognitive psychologists to fit behavioral data. This allows us to relate them to optimal methods from statistical decision theory, and prompts new questions on why we fail to make good choices.

## Jake Taylor-King : Generalized Jump Processes and Osteocyte Network Formation

- Mathematical Biology ( 141 Views )My talk will have two parts. PART I, From Birds to Bacteria: Generalised Velocity Jump Processes. There are various cases of animal movement where behaviour broadly switches between two modes of operation, corresponding to a long distance movement state and a resting or local movement state. In this talk, I will give a mathematical description of this process, adapted from Friedrich et. al. (2006). The approach allows the specification any running or waiting time distribution along with any angular and speed distributions. The resulting system of partial integro-differential equations are tumultuous and therefore it is necessary to both simplify and derive summary statistics. We derive an expression for the mean squared displacement, which shows good agreement with experimental data from the bacterium Escherichia coli and the gull Larus fuscus. Finally a large time diffusive approximation is considered via a Cattaneo approximation (Hillen, 2004). This leads to the novel result that the effective diffusion constant is dependent on the mean and variance of the running time distribution but only on the mean of the waiting time distribution. We also consider the Levy regime where the variance of the running distribution tends to infinity. This leads to a fractional diffusion equation for superdiffusive Levy walks and can be solved analytically. Our theory opens up new perspectives both for the systematic derivation of such equations, and for experimental data analysis of intermittent motion. I will also briefly discuss recent developments (by other researchers) within the field of velocity jump processes. PART II: Modelling Osteocyte Network Formation: Healthy and Cancerous Environments. Advanced prostate, breast, and lung cancer can metastasize to bone. In pathological bone, the highly regulated bone remodeling signaling pathway is disrupted. Within bone dendritic osteocytes form a spatial network allowing communication between osteocytes and the osteoblasts located on the bone surface. This communication network facilitates coordinated bone formation. In the presence of a cancerous microenvironment, the morphology of this network changes. Commonly osteocytes appear to be either overdifferentiated (i.e., there are more dendrites) or underdeveloped (i.e., dendrites do not fully form). In addition to structural changes, preliminary studies measuring the number of osteocytes per unit area using pathology slides show that the number density of osteocytes change from healthy to metastatic prostate and breast cancer xenografted mice. We present a stochastic agent-based model for bone formation incorporating osteoblasts and osteocytes that allows us to probe both network structure and number density of osteocytes in bone. Our model both allows for the simulation of our spatial network model and analysis of mean-field equations in the form of integro-partial differential equations. We consider variations of our model to test specific physiological hypotheses related to osteoblast differentiation; for example we can predict how changing measurable biological parameters, such as rates of bone secretion, rates of dendrite growth and rates of osteoblast differentiation can allow for qualitatively different network morphologies, and vice versa. We thenuse our model to hypothesize reasons for the limited efficacy of zoledronate therapy on metastatic breast cancer.

## Cecilia Clementi : A multiscale approach to characterize macromolecular dynamics and functions

- Mathematical Biology ( 140 Views )A multiscale approach to characterize macromolecular dynamics and functions The understanding of emerging collective behaviors in biomolecular complexes represents a major challenge in modern biophysics. As a first step toward the study of such processes we have applied multi-resolution nonlinear dimensionality reduction and diffusion analysis to obtain reliable low-dimensional representations and models for the dynamics of apparently high-dimensional complex systems such as proteins in a biological environment. The results clearly show that the proposed methods can efficiently find low dimensional representations of a complex process such as protein folding.

## L. Ridgway Scott : Digital biology: protein-ligand interactions

- Mathematical Biology ( 137 Views )The digital nature of biology is crucial to its functioning as an information system, as well in building hierarchical components in a repeatable way. We explain how protein systems can function as discrete components, despite the importance of non-specific forces due to the hydrophobic effect. That is, we address the question of why proteins bind to ligands predictably and not in a continuous distribution of places, the way grease forms into blobs. We will give a detailed description of how data mining in the PDB can reveal how proteins interact. We highlight the role of the hydrophobic effect, but we see that it works inversely to the usual concept of hydrophobic interaction. Our work suggests the need for a more accurate model of the dielectric effect in the vicinity of a protein surface, and we discuss some advances in this direction. Our research also provides an understanding of how molecular recognition and signaling can evolve. We give an example of the use of our ideas in drug design.