Doron Levy : Modeling the role of the immune response in chronic myelogenous leukemia
- Mathematical Biology ( 124 Views )Tyrosine kinase inhibitors (TKIs), such as imatinib (IM), have significantly improved treatment of chronic myelogenous leukemia (CML). However, the majority of patients are not cured for undetermined reasons. It turns out that many patients who otherwise responded well to IM therapy still show variations in their BCR-ABL transcripts. In this talk we will overview mathematical models for leukemia, drug resistance, and stem cells. Our main focus will be on our recent results concerning mathematical models that integrate CML and an autologous immune response. This is a joint work with G. Clapp, T. Lepoutre, and F. Nicolini.
Robert Guy : Models of Cytoplasmic Streaming in Motile Amoeboid Cells
- Mathematical Biology ( 97 Views )Inside every eukaryotic cell is the nucleus, organelles, and the surrounding cytoplasm, which typically accounts for 50% of the cell volume. The cytoplasm is a complex mixture of water, protein, and a dynamic polymer network. Cells use cytoplasmic streaming to transmit chemical signals, to distribute nutrients, and to generate forces involved in locomotion. In this talk we present two different models related to cytoplasmic streaming in amoeboid cells. In the first part of the talk, we present a computational model to describe the dynamics of blebbing, which occurs when the cytoskeleton detaches from the cell membrane, resulting in the pressure-driven flow of cytosol towards the area of detachment and the local expansion of the cell membrane. The model is used to explore the relative roles in bleb dynamics of cytoplasmic viscosity, permeability of the cytoskeleton, and elasticity of the membrane and cytoskeleton. In the second part of the talk we examine how flow-induced instabilities of cytoplasm are related to the structural organization of the giant amoeboid cell Physarum polycephalum. We use a multiphase flow model that treats both the cytosol and cytoskeleton as fluids each with its own material properties and internal forces, and we discuss instabilities of the sol/gel mixture that produce flow channels within the gel. We analyze a reduced model and offer a new and general explanation for how fluid flow is involved in cytoskeletal reorganization.
Eric Lauga : Optimality in cellular hydrodynamics
- Mathematical Biology ( 95 Views )Fluid mechanics plays a crucial role in many cellular processes. One example is the external fluid mechanics of motile cells such as bacteria, spermatozoa, algae, and essentially half of the microorganisms on earth. The most commonly-studied organisms exploit the bending or rotation of a small number of flagella (short whip-like organelles, length scale from a few to tens of microns) to create fluid-based propulsion. Ciliated microorganisms swim by exploiting the coordinated surface beating of many cilia (which are short flagella) distributed along their surface. After a short introduction to the fundamentals of fluid-based locomotion on small scales, we pose separate optimization problems addressing the optimal geometries and locomotion gaits of low-Reynolds-number swimmers. First, we characterize the optimal dynamics of simple flapping swimmers with two degrees of freedom. Second, we derive analytically and computationally the optimal waveform of an elastic flagellum, such as the one employed by eukaryotic cells for propulsion. Third, we investigate the optimal shapes of helical propellers, and use our results to help rationalize the shape selection mechanism in bacterial flagella. Finally, we characterize the optimal locomotion by surface distortions of blunt swimmers, and demonstrate the appearance of waves, reminiscent of the metachronal waves displayed by ciliated organisms.
Jacob Scott : Understanding the evolution of resistance: a comprehensive and integrated mathematical and experimental research program.
- Mathematical Biology ( 142 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.
Lisa Fauci : Waving rings and swimming in circles: some lessons learned through biofluiddynamics
- Mathematical Biology ( 88 Views )Dinoflagellates swim due to the action of two eucaryotic flagella - a trailing, longitundinal flagellum that propagates planar waves, and a transverse flagellum that propagates helical waves. The transverse flagellum wraps around the cell in a plane perpendicular to the trailing flagellum, and is thought to provide both forward thrust along with rotational torque. Motivated by the intriguing function of this transverse flagellum, we study the fundamental fluid dynamics of a helically-undulating ring in a viscous fluid. We contrast this biofluiddynamic study, where the kinematics of the waveform are taken as given, with a model of mammalian sperm hyperactivated motility. Here, our goal is to examine how the complex interplay of fluid dynamics, biochemistry, and elastic properties of the flagellum give rise to the swimming patterns observed.
Grzegorz A. Rempala, PhD DSc : Contact Processes and Stochastic Models of Epidemics
- Mathematical Biology ( 192 Views )I will discuss some old and new results related to the analysis of stochastic SIR-type epidemics on a configuration model (CM) random graph having a fixed degree distribution p_k. In particular, I will describe the relevant large graph limit result which yields the law of large numbers (LLN) for the edge-based process. I will also discuss the applications of the LLN approximation in building a "network-free" SIR Markov hybrid model which can be used for epidemic parameters inference. The hybrid model idea appears particularly relevant in the context of the recent Ebola and the Zika epidemics.
Daniel Linder : Parameter Inference in Biochemical Reaction Networks
- Mathematical Biology ( 84 Views )Systems biologists seek to understand the higher-level organizational properties that a proposed system exhibits from the interactions of its many lower level components. It is then typically beneficial to learn, in a statistical sense, the nature of these interactions from experimental data; this is sometimes called reverse engineering. In this talk I will discuss some methods found in the literature for learning the kinetic parameters from stochastic system trajectories measured at discrete time points. I will also discuss estimating the system topology, or network structure, with the stoichiometric algebraic statistical model and detail its relationship with kinetic parameter estimation. Finally, I will discuss some ongoing work aimed at improving both parameter estimation and system topology estimation.
Adriana Dawes : Protein localization at the single cell level: Interplay between biochemistry, mechanics and geometry
- Mathematical Biology ( 144 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.
Marty Golubitsky : Homeostasis and Network Invariants
- Mathematical Biology ( 104 Views )We discuss the question: What properties of solutions to coupled cell network systems are invariant under changes of coordinates that preserve network structure? This question was motivated by trying to understand the biological phenomenon of homeostasis in a mathematically satisfactory way. In its simplest mathematical form homeostasis can be described as follows. Given a stable equilibrium $x(lambda)$ of a system that depends on an input parameter $lambda$: When is some coordinate (say $x_j(lambda)$) approximately constant? First, we translate approximately constant to derivative approximately 0. This allows us to search for regions of homeostasis in a model using bifurcation theory like formulas. Second, we claim that there is a sense in which homeostasis can be thought of as a network invariant. This is joint work with Ian Stewart.
Suzanne Lenhart : Optimal Harvesting in Fishery Models
- Mathematical Biology ( 99 Views )We discuss two types of partial differential equation models of fishery harvesting problems. We consider steady state spatial models and diffusive spatial-temporal models. We characterize the distribution of harvest effort which maximizes the harvest yield, and in the steady state case, also minimizes the cost of the effort. We show numerical results to illustrate various cases. The results inform ongoing debate about the use of reserves (regions where fishing is not allowed), and are increasingly relevant as technology enables enforcement of spatially structured harvest constraints.
Jill Galagher : Targeting the phenotype: Treatment strategies for heterogeneous cancer
- Mathematical Biology ( 124 Views )Targeted cancer drugs attack pathway specific phenotypes and can lead to very positive outcomes when a particular phenotype dominates the population of a specific tumor. However, these drugs often fail because not all cells express the targeted phenotype to the same degree. This leads to a heterogeneous response to treatment, and ultimate recurrence of the cancer as sensitive cells die off and resistant cells take over. We explore how treatment strategies informed by a tumors phenotypic mix, can help slow the emergence of resistance and stave off tumor recurrence. We use an off-lattice agent-based model that incorporates inheritance of two phenotypes proliferation rate and migration speed and is modulated by a space limiting selection force. We find how and when distinct distributions of phenotypes require different treatment strategies.
Rick Durrett : Branching Process Models of Cancer
- Mathematical Biology ( 127 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
Cecilia Clementi : A multiscale approach to characterize macromolecular dynamics and functions
- Mathematical Biology ( 118 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.
Joshua Vogelstein : Consistent Graph Classification applied to Human Brain Connectome Data
- Mathematical Biology ( 170 Views )Graphs are becoming a favorite mathematical object for representation of data. Yet, statistical pattern recognition has focused almost entirely on vector valued data in Euclidean space. Graphs, however, live in graph space, which is non-Euclidean. Thus, most inference techniques are not even defined for graph valued data. Previous work in the classification of graph-valued data typically follows one of two recipes. (1) Vectorize the adjacency matrices of the graphs, and apply standard machine learning techniques. (2) Compute some number of graph invariants (e.g., clustering coefficient, or degree distribution) for each graph, and then apply standard machine learning techniques. We follow a different recipe based in the probabilistic theory of pattern recognition. First, we define a joint graph-class model. Given this model, we derive classifiers which we prove are consistent; that is, they converge to the Bayes optimal classifier. Specifically, we build two consistent classifiers for graph valued data, a parametric and a non-parametric version. In a sense, these classifiers span the spectrum of complexity, the former is consistent for graphs sampled from relatively simple random graph distributions, the latter is consistent for graphs sampled from (nearly) any random graph distribution. Although both classifiers assume that all our graphs have labeled vertices, we generalize these results to also incorporate unlabeled graphs, as well as weighted and multigraphs. We apply these graph classifiers to human brain data. Specifically, using diffusion MRI, we can obtain large brain-graphs (10,000 vertices) for each subject, where vertices correspond to voxels. We then coarsen the graphs spatially to obtain smaller (70 vertex) graphs per subject. Using <50 subjects, we are able to achieve nearly 85% classification accuracy, with results interpretable to neurobiologists with regard to the brain regions of interest.
Mike Reed : Consequences of Levodopa Therapy for Parkinsons Disease
- Mathematical Biology ( 107 Views )Parkinsons disease has been traditionally thought of as a dopaminergic (DA) disease in which cells of the substantia nigra pars compacta (SNc) die. However, accumulating evidence implies an important role for the serotonergic (5HT) system in Parkinsons disease. We use a mathematical model to investigate the consequences of levodopa therapy on the serotonergic system and on the pulsatile release of DA from dopaminergic and serotonergic terminals in the striatum. We compute the time course of DA release in the striatum from both 5HT and DA neurons and show how the time course changes as more and more SNc cells die. This enables us to explain the shortening of the therapeutic time window for the efficacy of levodopa as Parkinsons disease progresses. Finally, we study the effects 5HT1a and 5HT1b autoreceptor agonists and explain why they have a synergistic effect and why they lengthen the therapeutic time window for LD therapy. Our results are consistent with and help explain results in the experimental literature and provide new predictions that can be tested experimentally.
Jean Clairambault : Drug resistance in cancer: biological and medical issues, and continuous models of structured population dynamics
- Mathematical Biology ( 119 Views )Considering cancer as an evolutionary disease, we aim at understanding the means by which cancer cell populations develop resistance mechanisms to drug therapies, in order to circumvent them by using optimised therapeutic combinations. Rather than focusing on molecular mechanisms such as overexpression of intracellular drug processing enzymes or ABC transporters that are responsible for resistance at the individual cell level, we propose to introduce abstract phenotypes of resistance structuring cancer cell populations. The models we propose rely on continuous adaptive dynamics of cell populations, and are amenable to predict asymptotic evolution of these populations with respect to the phenotypic traits of interest. Drug-induced drug resistance, the question we are tackling from a theoretical and experimental point of view, may be due to biological mechanisms of different natures, mere local regulation, epigenetic modifications (reversible, nevertheless inheritable) or genetic mutations (irreversible), according to the extent to which the genome of the cells in the population is affected. In this respect, the models we develop are more likely to be biologically corresponding to epigenetic modifications, although eventual induction of emergent resistant cell clones due to mutations under drug pressure is not to be completely excluded. From the biologist's point of view, we study phenotypically heterogeneous, but genetically homogeneous, cancer cell populations under stress by drugs. According to the cell populations at stake and to the exerted drug pressure, is drug resistance in cancer a permanently acquired phenotypic trait or is it reversible? Can it be avoided or overcome by rationally (model-guided) designed combinations of drugs? These are some of the questions we will try to answer in a collaboration between a team of mathematicians and another one of biologists, both dealing with cancer and Darwinian - possibly also Lamarckian - evolution of cell populations.
Joshua Plotkin : Generalized Markov models in population genetics
- Mathematical Biology ( 107 Views )Population geneticists study the dynamics of alternative genetic types in a replicating population. Most theoretical work rests on a simple Markov chain, called the Wright-Fisher model, to describe how an allele's frequency changes from one generation to the next. We have introduced a broad class of Markov models that share the same mean and variance as the Wright-Fisher model, but may otherwise differ. Even though these models all have the same variance effective population size, they encode a rich diversity of alternative forms of genetic drift, with significant consequences for allele dynamics. We have characterized the behavior of standard population-genetic quantities across this family of generalized models. The generalized population models can produce startling phenomena that differ qualitatively from classical behavior -- such as assured fixation of a new mutant despite the presence of genetic drift. We have derived the forward-time continuum limits of the generalized processes, analogous to Kimura's diffusion limit of the Wright-Fisher process. Finally, we have shown that some of these exotic models are more likely than the Wright-Fisher model itself, given empirical data on genetic variation in Drosophila populations. Joint work with Ricky Der and Charlie Epstein.
John Bush : Biocapillarity
- Mathematical Biology ( 142 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.
Mainak Patel : Temporal Binding Emerges as a Rapid and Accurate Encoding Tool Within a Network Model of the Locust Antennal Lobe
- Mathematical Biology ( 125 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.
Sandy Anderson : Hijacking Homeostatsis: How Heterogeneity Drives Tumor Progression and Treatment Failure
- Mathematical Biology ( 95 Views )Heterogeneity in cancer is an observed fact, both genotypically and phenotypically. Cell-cell variation is seen in almost all aspects of cancer from early development all the way through to invasion and subsequent metastasis. Our current understanding of this heterogeneity has mainly focused at the genetic scale with little information on how this variation translates to actual changes in cell phenotypic behavior. Given that many genotypes can lead to the same cellular phenotype, it is important that we quantify the range and scope of this heterogeneity at the phenotypic scale as ultimately this variability will dictate the aggressiveness of the tumor and its treatability. Central to our understanding of this heterogeneity is how the tumor cells interact with each other and with their microenvironment. Since it is these very interactions that drive selection and that ultimately define the ecology of the tissue in which the tumor is developing. Considering an organ as an ecological system, means that we should view normal tissue homeostasis as an equilibrium that cancer cells must disrupt if they are to be successful. Disruption of this equilibrium is often one of the first events in cancer development, as the normal control mechanisms of the tissue are damaged or ignored. We will discuss the interplay between homeostasis, heterogeneity, evolution and ecology in cancer progression and treatment failure with an emphasis on the metabolism of breast cancer.
Suncica Canic : Fluid-composite structure interaction and blood flow
- Mathematical Biology ( 192 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.
Leonid Berlyand : PDE/ODE models of motility in active biosystems
- Mathematical Biology ( 106 Views )In the first part of the talk we present a review of our work on PDE models of swimming bacteria. First we introduce a stochastic PDE model for a dilute suspension of self-propelled bacteria and obtain an explicit asymptotic formula for the effective viscosity (E.V.) that explains the mechanisms of the drastic reduction of E.V.. Next, we introduce a model for semi-dilute suspensions with pairwise interactions and excluded volume constraints. We compute E.V. analytically (based on a kinetic theory approach) and numerically. Comparison with the dilute case leads to a phenomenon of stochasticity arising from a deterministic system. We develop a ODE/PDE model that captures the phase transition, an appearance of correlations and large scale structures due to interbacterial interactions. Collaborators: S. Ryan, B. Haines, (PSU students); I. Aronson, A. Sokolov, D. Karpeev (Argonne); In the second part of the talk we discuss a system of two parabolic PDEs arising in modeling of motility of eukaryotic cells on substrates. The two key properties of this system are (i) presence of gradients in the coupling terms (gradient coupling) and (ii) mass (volume) preservation constraints. We derive the equation of the motion of the cell boundary, which is the mean curvature motion perturbed by a novel nonlinear term and prove that the sharp interface property of initial conditions is preserved in time. This novel term leads to surprising features of the motion of the interface such as discontinuities of the interface velocity and hysteresis. This is joint work with V. Rybalko and M. Potomkin.
Gregory Herschlag : A mechanochemical model for auto-regulation of lung airway surface liquid volume
- Mathematical Biology ( 107 Views )I will present a proof-of-principle model for auto-regulation of liquid volume in the lung airway surface layer (ASL). The model couples biochemical kinetics, transient ASL volume, and homeostatic mechanical stresses. The work is based on the hypothesis that ASL volume is sensed through soluble mediators and phasic stresses generated by beating cilia and global percussive and air drag forces. Simulations demonstrate that homeostatic volume regulation is a natural consequence of the model and the underlying hypotheses. The model successfully reproduces many experimental results and passes qualitative sensitivity tests. These results compel an advanced airway hydration model in which detailed kinetics of multiple molecular pathways, feedback to ASL viscoelasticity properties, and stress signaling from the ASL to the cilia and epithelial cells are taken into account.
Ezra Miller : Applying persistent homology to brain artery and vein imaging
- Mathematical Biology ( 112 Views )Persistent homology measures geometric structures using topological invariants. When the structures are magnetic resonance images of branching arteries, for example, persistent homology records the connectedness of an increasing subset of the vessels. Although the theory of persistent homology is relatively well developed, and many aspects of its behavior are understood in synthetic examples, only recently have applications to genuine experimental data begun. This talk explains what we have learned about the geometry of blood vessels in aging human brains, as well as lessons this exploration has taught us about applications of persistent homology in general. These lessons inform further potential applications of persistent homology in statistical problems from biological and medical imaging. The main results are joint with Paul Bendich, Steve Marron, Aaron Pieloch, and Sean Skwerer (Math junior faculty, Stat faculty, Math undergrad, and Operations Research grad student). The talk will be accessible to advanced mathematics and statistics undergraduates, medical and biological researchers, statistics and mathematics faculty, and everybody in between.
David Anderson : Stochastic models of biochemical reaction systems: network structure and qualitative dynamics
- Mathematical Biology ( 103 Views )Biochemical reaction networks can be represented as graphs, with chemical complexes serving as vertices and reaction channels serving as directed edges. To each such network there is an associated stochastic process that models the behavior of the underlying system of interest. In this talk I will present results that relate the structure of the reaction network to the possible dynamics of the model. I will pay particular attention to how the results pertaining to the stochastic models compare and contrast with similar results pertaining to deterministic models.
Tom Kepler : Microevolution in the Immune System: A Computational Systems Approach--second lecture
- Mathematical Biology ( 137 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.
Tom Kepler : Microevolution in the Immune System: A Computational Systems Approach
- Mathematical Biology ( 107 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.