The segregation of chromosomes during cell division is accomplished by kinetochore machinery that uses depolymerizing microtubules to pull the chromosomes to opposite poles of the dividing cell. While much is known about molecular motors that pull by walking or push by polymerizing, the mechanism of how a pulling force can be achieved by depolymerization is still unresolved. In this talk, I will describe a new model for the depolymerization motor that is used by eukaryotic cells to segregate chromosomes during mitosis. In the process we will explore the use of Huxley-type models (population models) of protein binding and unbinding to study load-velocity curves of several different motor-like proteins.

Many patterns in Nature and industry arise from the system minimizing an appropriate energy. Torn plastic sheets and growing leaves provide striking examples of pattern forming systems which can transition from single wavelength geometries (leaves) to complex fractal-like shapes (lettuce). These fractal-like patterns seem to have many length scales, i.e. the same amount of extra detail can be seen when looking closer (“statistical self-similarity”). It is a mystery how such complex patterns could arise from energy minimization alone. In this talk I will address this puzzle by showing that such patterns naturally arise from the sheet adopting a hyperbolic non-Euclidean geometry. However, there are many different hyperbolic geometries that the growing leaf could select. I will show using techniques from analysis, differential geometry and numerical optimization that the fractal like patterns are indeed the natural minimizers for the system. I will also discuss the implications of our work to developing shape changing soft matter which can be implemented in soft machines.

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.

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 treatment‑naïve 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.

Israel experienced an outbreak of wild poliovirus type 1 (WPV1) in 2013-14, detected through environmental surveillance of the sewage system. No cases of acute flaccid paralysis were reported, and the epidemic subsided after a bivalent oral polio vaccination (bOPV) campaign. As we approach global eradication, polio will increasingly be detected only through environmental surveillance. However, we have lacked the theory to translate environmental surveillance into public health metrics; it is a priori unclear how much environmental surveillance can even say about population-level disease dynamics. We developed a framework to convert quantitative polymerase chain reaction (qPCR) cycle threshold data into scaled WPV1 and OPV1 concentrations for inference within a deterministic, compartmental infectious disease transmission model. We used differential algebra and profile likelihood techniques to perform identifiability analysis, that is, to assess how much information exists in the data for the model, and to quantify inference uncertainty. From the environmental surveillance data, we estimated the epidemic curve and transmission dynamics, determining that the outbreak likely happened much faster than previously thought. Our mathematical modeling approach brings public health relevance to environmental data that, if systematically collected, can guide eradication efforts.

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.

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.

This talk will trace many years of work mathematical modeling hematological diseases. The ‘understand’ part talks about the use of mathematical to figure out what causes cyclical neutropenia, and the ‘treat’ part refers to work on treating cyclical neutropenia using recombinant cytokines. The ‘avoid’ part deals with current ongoing work trying to obviate the deleterious effects of chemotherapy on blood cell production—one of the major negative side effects of chemotherapy.

In this talk, we will introduce a deterministic malaria model for determining the drug administration protocol that leads to the smallest first malaria episodes during the wet season. To explore the effects of administering the malaria drug on different days during wet season while minimizing the potential harmful effects of drug overdose, we will define 40 drug administration protocols. Our results fit well with the clinical studies of Coulibaly et al. at a site in Mali. In addition, we will provide protocols that lead to small number of first malaria episodes during the wet season than the protocol of Coulibaly et al. In the second part of the talk, we will use our malaria model to "capture" the 2013 Centers of Disease Control and Prevention (CDC) reported data on the 2011 number of imported malaria cases in the US. Furthermore; we will use our "fitted" malaria models for the top 20 countries of malaria acquisition by US residents to study the impact of protecting US residents from malaria infection when they travel to malaria endemic areas, the impact of protecting residents of malaria endemic regions from mosquito bites and the impact of killing mosquitoes in those endemic areas on the 2013 CDC malaria surveillance data.

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.

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.

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.

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.

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.

Circadian rhythms are biological oscillations that align our physiology and behavior with the 24-hour environmental cycles conferred by the Earth’s rotation. In this talk, I will discuss two projects that focus on circadian clock cells in the brain and the entrainment of circadian rhythms to the light-dark cycle. Most of what we know about the electrical activity of circadian clock neurons comes from studies of nocturnal (night-active) rodents, hindering the translation of this knowledge to diurnal (day-active) humans. In the first part of the talk, we use data assimilation and patch-clamp recordings from the diurnal rodent Rhabdomys pumilio to build the first mathematical models of the electrophysiology of circadian neurons in a day-active species. We find that the electrical activity of circadian neurons is similar overall between nocturnal and diurnal rodents but that there are some interesting differences in their responses to inhibition. In the second part of the talk, we use tools from dynamical systems theory to study the reentrainment of a model of the human circadian pacemaker following perturbations that simulate jet lag. We show that the reentrainment dynamics are organized by invariant manifolds of fixed points of a 24-hour stroboscopic map and use these manifolds to explain a rapid reentrainment phenomenon that occurs under certain jet lag scenarios.

Biological oscillators such as the cell cycle, circadian clocks, and metabolic rhythms are ubiquitous across the domains of life. These biochemical oscillators co-exist in the same cells, often sharing and competing for resources. Are there mechanisms and regulatory principles that ensure harmony between these oscillators? Recent studies have shown that in addition to the transcriptional circadian clock, many organisms (including Arabidopsis) have a circadian redox rhythm driven by the organism's metabolic activities. It has been hypothesized that the redox rhythm is linked to the circadian clock, but the mechanism and the biological significance of this link have only begun to be investigated. In the first half of my talk, I will describe our work (in collaboration with the Dong lab at Duke) on the coupling of redox rhythms and the plant circadian clock. In the second half of my talk, I will discuss our work on the coupling of yeast metabolic cycle and the cell division cycle.

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.

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.

The use of delay differential equations (DDEs) to study biological phenomena has a long history, when the rate of change of model variables depends their previous history. Today, DDEs occupy a central place in models of infectious disease dynamics, epidemiology, ecology and tumor growth. In this talk, I will present a delayed partial differential equation (PDE) model of tumor growth and treatment. The model accounts for cell cycle arrest and cell death induced by chemotherapy, and explicitly includes intracellular signaling pathways relevant to drug action. The model is simplified to give a 1D hyperbolic PDE, which is further reduced to a nonlinear, non-autonomous DDE by projecting along characteristics. Necessary and sufficient conditions for the global stability of the cancer-free equilibrium are derived and conditions under which the system evolves to periodic solutions are determined. This has clinical implications since it leads to a lower bound for the amount of therapy required to affect a cure. Finally, I will present a clinical application of the model, by applying it to the treatment of ovarian cancers. Two types of drugs are considered – platinum-based chemotherapeutic agents that are the current standard of care for most solid tumors, and small molecule cell death inducers that are currently under development. The model is calibrated versus in vitro experimental results, and is then used to predict optimal doses and administration time scheduling for the treatment of a tumor growing in vivo.

Certain strains of the influenza virus form coherent single, globally circulating viral populations. Multiple models of viral evolution have considered the virus on this level, identifying immune and structural factors underlying the observed changes in viral genotype. In this talk, I outline an alternative approach for studying viral evolution, considering events at the level of within-host viral growth and transmission. In particular, I describe statistical approaches to infer the extent to which natural selection acts upon the viral population within the course of a single infection, on the basis of genome sequencing data from Sanger sequencing, and next-generation technologies. Examining data from evolutionary experiments conducted with a reassortant H5N1 influenza virus, I discuss the potential for using data from evolutionary experiments to predict the potential evolution of this virus in a human population.

Stochastic evolutionary models of biological sequences are widely used for phylogenetic inference and ancestral reconstruction. However, at long divergence times sequences enter the "twilight zone" of homology detection and reconstruction becomes very difficult. We describe a stochastic evolutionary model for protein 3D structure using elements of shape theory. This model significantly resolves this uncertainty and stabilizes evolutionary inferences. We also provide theoretical bounds on inferring evolutionary divergence times via connections to the probabilistic "cutoff phenomenon", in which a Markov chain remains far equilibrium for an extended period followed by a rapid transition into equilibrium. We show that this cutoff explains several previously reported problems with common default priors for Bayesian phylogenetic analysis, and suggest a new class of priors to address these problems.

Advances in high-throughput genomics have facilitated the development of pooled population sequencing techniques which involve the en masse sequencing of tens to hundreds of individual genomes in a single sequencing reaction. Pooled population sequencing methods have numerous applications in quantitative, population and evolutionary genetics. I will discuss some of the statistical and computational challenges associated with the analysis of pooled sequence data in the context of quantitative trait locus (QTL) mapping and detecting selection during experimental evolution.

Mathematical modeling has become a widely-used tool for integrating
biological data, designing experiments, and ultimately understanding
biological systems. In recent years two important challenges for the
successful use of mathematical models have become apparent. One is that
models contain parameters that determine the behavior of the model, and
the values of these parameters are often hard to determine from the
available biological data. The other challenge is that many biological
systems exhibit a great deal of heterogeneity in behavior, so even if the
model parameters could be perfectly calibrated by pooling cell behaviors
to produce an “average cell model”, this model may not provide a good
description of any single cell in the population. In this seminar I will
describe a technique that we are using to integrate mathematical modeling
into experimental studies in a way that addresses both of these challenges.
We study endocrine pituitary cells that release a variety of hormones into
the blood, and our aim is to develop an approach for modeling the
behaviors of these cells with enough accuracy so that we can use the
models to make and test predictions in real time.

RNA-Seq is a new technology for measuring the content of a transcriptome using high-throughput sequencing technology. I will provide a self-contained introduction to the technology, and proceed to discuss some interesting mathematical questions we have had to address in order to realize the potential of "comparative transcriptomics" for comparing and contrasting transcriptomes. We will start with the "freshman's dream", and proceed to examine issues related to maximum matching, the (phylogenetic) space of trees and Simpson's paradox. This is joint work with my current and former students Natth Bejraburnin, Nicolas Bray, Adam Roberts, Cole Trapnell and Meromit Singer.

Glutathione (GSH), a tripeptide formed from glutamate, cysteine, and
glycine, is arguably the most important antioxidant in the body. NAPQI, a
byproduct of acetaminophen (APAP) metabolism which is toxic to liver
cells, is neutralized by GSH. Although produced in great quantity by the
liver, in cases of APAP overdose demand for GSH can outstrip supply,
causing liver failure. Currently, patients presenting to the ER with APAP
overdose are given an infusion of cysteine since it is believed to be the
rate-limiting amino acid in GSH synthesis, however, there is evidence that
under some circumstances glutamate can become rate-limiting. Complicating
the issue is that in most hepatocytes, glutamate is not absorbable from
blood plasma but is formed from glutamine, which is produced in large
amounts by the skeletal muscle. In order to develop better rescue
protocols for APAP overdose, we have developed a mathematical model of
glutamate and glutamine metabolism in the rat. We have also investigated
how model parameters should change in the case of increased cortisol
production, such as occurs during sepsis, trauma, burns, and other
pathological states; the cortisol-stressed state has been studied in rats
by giving them dexamethasone. We compare model predictions with
experimental data for the normal, healthy rat and dexamethasone-stressed
rat. Biological parameters are taken from the literature wherever possible.

A major focus of synthetic biology is to engineer gene circuits to perform user-defined functions. These gene circuits can serve as well-defined models to probe basic biological questions of broad significance. In this talk, I will discuss our efforts along this line of research, whereby we have engineered gene circuits to program bacterial dynamics in time and space, guided by quantitative modeling and experiments. Insights learnt from these circuits have implications for developing new strategies to combat bacterial pathogens or to fabricate new materials.

Stochastic modeling and analysis can help answer pressing medical questions. In this talk, I will attempt to justify this claim by describing recent work on two problems in medicine. The first problem concerns ovarian tissue cryopreservation, which is a proven tool to preserve ovarian follicles prior to gonadotoxic treatments. Can this procedure be applied to healthy women to delay or eliminate menopause? How can it be optimized? The second problem concerns medication nonadherence. What should you do if you miss a dose of medication? How can physicians design dosing regimens that are robust to missed/late doses? I will describe (a) how stochastics theory offers insights into these questions and (b) the mathematical questions that emerge from this investigation. The first problem is based on joint work with Joshua Johnson (University of Colorado School of Medicine), John Emerson (Yale University), and Kutluk Oktay (Yale School of Medicine).