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.

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

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.

The behavior of inextensible fibers immersed in a fluid is of interest in a variety of applications ranging from polymer suspensions to actin filament transport. In these cases, the dynamics of an immersed fiber can play a large role in the observed macroscale fluid dynamics. The method of regularized Stokeslets provides a way to calculate fluid velocities in the Stokes fluid flow regime due to a collection of regularized point-forces without computing fluid velocities on an underlying grid. In this discussion, the method of Regularized Stokeslets will be used to model the dynamics of an inextensible flexible fiber immersed in a two-dimensional cellular background flow in comparison with results found in the experimental and mathematical literature. Studying this scenario with regularized Stokeslets provides insight into the documented stretch-coil transition and macroscale random walk behavior supported by mathematical models and experimental results.

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.  

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.

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.

Cancer emerges due to an evolutionary process in somatic tissue. The fundamental laws of evolution can best be formulated as exact mathematical equations. Therefore, the process of cancer initiation and progression is amenable to mathematical investigation. Of special importance are changes that occur early during malignant transformation because they may result in oncogene addiction and represent promising targets for therapeutic intervention. Here we describe a mathematical approach, called Retracing the Evolutionary Steps in Cancer (RESIC), to deduce the temporal sequence of genetic events during tumorigenesis from crosssectional genomic data of tumors at their fully transformed stage. When applied to a dataset of 70 advanced colorectal cancers, our algorithm accurately predicts the sequence of APC, KRAS, and TP53 mutations previously defined by analyzing tumors at different stages of colon cancer formation. We further validate the method with glioblastoma and leukemia sample data and then apply it to complex integrated genomics databases, finding that high-level EGFR amplification appears to be a late event in primary glioblastomas. RESIC represents the first evolutionary mathematical approach to identify the temporal sequence of mutations driving tumorigenesis and may be useful to guide the validation of candidate genes emerging from cancer genome surveys.

Cochlear implants are neural prostheses that restore a sense of hearing to individuals with severe to profound deafness. Two fundamental theoretical questions that we face are: How does the auditory nerve respond to electrical stimulation? And how is sound information represented in the spike trains of auditory nerve fibers? We will discuss model-based efforts to investigate these questions. I will focus on the development of reduced models that incorporate essential biological features of this complicated system, and remain useful tools for analyzing neural coding.

Using a point process model of the auditory nerve, I simulate amplitude modulation detection, a common test of temporal resolution. I find that the temporal information in the simulated spike trains does not limit modulation sensitivity in cochlear implant users, and discuss how the point process framework can be extended to include additional biophysical mechanisms. Next, I illustrate how spatial spread of excitation and neural degeneration can lead to of within- and across-patient variability in listening outcomes. This points toward an important goal of computational modeling: to develop patient-specific models that can be used to optimize stimulation strategies for individual cochlear implant users.

Gels formed from mixtures of polymers and solvent are ubiquitous in physiological systems. The structure and properties of a gel can change dramatically in response to chemical modulation. Two examples of the influence of chemistry on gel properties will be discussed. The structure of fibrin gels that form during blood clotting is strongly influenced by the concentration of the enzyme thrombin that produces the fibrin monomers from which the gel is built. Presumably at higher thrombin concentrations, fibrin monomers are produced more rapidly from the precursor fibrinogen molecules. I will present an analysis of a possible mechanism of fibrin branching that can explain the sensitivity of fibrin structure to the rate of supply of monomers. Mucin gel is released from vesicles in goblet cells. During this exocytotic process, the polyelectrolyte mucin gel swells to many times its original volume at a very rapid rate. I will present a model in which this swelling is triggered by an exchange of divalent calcium ions in the vesicle and monovalent sodium ions in the extracellular space, and in which the ion concentrations and the rheological properties of the mucin gel determine its equilibrium size and the dynamics of its swelling.

Many pulse-coupled dynamical systems possess synchronous attracting states. Even stochastically driven model networks of Integrate and Fire neurons demonstrate synchrony over a large range of parameters. We study the interplay between fluctuations which de-synchronize and synaptic coupling along the network connections that synchronize the network by calculating the probability to see repeated cascading total firing events, during which all the neurons in the network fire at once. Using this characterization of synchrony we investigate the significance of the local network topology and of more physiological additions to the model on the model neuronal networks ability to synchronize. The mean time between total firing events characterizes the perfectly synchronous state, and we compute this from a first-passage time problem in terms of a Fokker-Planck equation for a single neuron.

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.

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.

Abstract: The construction of flagellar motors in motile bacteria such as Salmonella is a carefully regulated genetic process. Among the structures that are built are the hook and the filament. The length of the hook is tightly controlled while the length of filaments is less so. However, if a filament is broken off it will regrow, while a broken hook will not regrow. The question that will be addressed in this talk is how Salmonella detects and regulates the length of these structures. This is related to the more general question of how physical properties (such as size or length) can be detected by chemical signals and what those mechanisms are. In this talk, I will present mathematical models for the regulation of hook and filament length. The model for hook length regulation is based on the hypothesis that the hook length is determined by the rate of secretion of the length regulatory molecule FliK and a cleavage reaction with the gatekeeper molecule FlhB. A stochastic model for this interaction is built and analyzed, showing excellent agreement with hook length data. The model for filament length regulation is based on the hypothesis that the growth of filaments is diffusion limited and is measured by negative feedback involving the regulatory protein FlgM. Thus, the model includes diffusion on a one-dimensional domain with a moving boundary, coupled with a negative feedback chemical network. The model shows excellent qualitative agreement with data, although there are some interesting unresolved issues related to the quantitative results.

Elevations in systolic blood pressure are believed to be closely linked to the pathogenesis and progression of renal diseases. It has been hypothesized that the afferent arteriole (AA) protects the glomerulus from the damaging effects of hypertension by sensing increases in systolic blood pressure and responding with a compensatory vasoconstriction. To investigate this hypothesis, we developed a mathematical model of the myogenic response of an AA smooth muscle cell, based on an arteriole model by Gonzalez-Fernandez and Ermentrout (Math Biosci 1994). renal hemodynamic regulation. The model incorporates ionic transport, cell membrane potential, contraction of the AA smooth muscle cell, and the mechanics of a thick-walled cylinder. The model represents a myogenic response based on a pressure-induced shift in the voltage dependence of calcium channel openings: with increasing transmural pressure, model vessel diameter decreases; and with decreasing pressure, vessel diameter increases. Further, the model myogenic mechanism includes a rate-sensitive component that yields constriction and dilation kinetics similar to behaviors observed in vitro. A parameter set is identified based on physical dimensions of an AA in a rat kidney. Model results suggest that the interaction of Ca2+ and K+ fluxes mediated by voltage-gated and voltage-calcium-gated channels, respectively, gives rise to periodicity in the transport of the two ions. This results in a time-periodic cytoplasmic calcium concentration, myosin light chains phosphorylation, and crossbridges formation with the attending muscle stress. Further, the model predicts myogenic responses that agree with experimental observations, most notably those which demonstrate that the renal AA constricts in response to increases in both steady and systolic blood pressures. The myogenic model captures these essential functions of the renal AA, and it may prove useful as a fundamental component in a multi-scale model of the renal microvasculature suitable for investigations of the pathogenesis of hypertensive renal diseases.

Inferential summaries of tree estimates are useful in the setting of evolutionary biology, where phylogenetic trees have been built from DNA data since the 1960's. In bioinformatics, psychometrics and data mining, hierarchical clustering techniques output the same mathematical objects, and practitioners have similar questions about the stability and `generalizability' of these summaries. I will present applications of the Billera, Holmes, Vogtman (2001) distance to inferential problems both in the frequentist (bootstrap) and Bayesian contexts. I will compare the tree of trees representation to the Euclidean approximations of treespace made available through Multidimensional Scaling of the matrix of distances between trees. We also provide applications of the distances between trees to hierarchical clustering trees constructed from microarrays and phylogenetic trees of metagenomic data of bacteria in the gut. This talk contains joint work with John Chakerian and Alfred Spormann.