Applications of Mathematics in Biology,

Physiology, and Medicine

A Conference in honor of
Charles S. Peskin´s and David M. McQueen's
60th Birthdays

October 20th – 21st, 2006

Courant Institute of Mathematical Sciences

New York University

ORGANIZING COMMITTEE:

Paul J. Atzberger, UCSB

Lisa Fauci, Tulane
John Rinzel, NYU
Daniel Tranchina, NYU

SUPPORT: Courant Institute of Mathematical Sciences

CONFIRMED SPEAKERS:

Paul J. Atzberger, UCSB

Christoph Börgers, Tufts
Lisa Fauci, Tulane
Aaron Fogelson, Utah
Dan Forger, U. Mich.
Boyce Griffith, NYU
Sam Isaacson, Utah
Laura Miller, UNC
Yoichiro Mori, NYU
Mette Olufsen, NCSU
Arjun Raj, MIT
John Rinzel, NYU
Tamar Schlick, NYU
Arthur Sherman, NIH
 Final Program

Friday: (all talks and coffee breaks are located at CIMS Room 109)

CIMS RM. 109

8:30AM - 9:30AM Breakfast and Coffee
(all talks & breaks)
9:30AM – 10:00AM Opening Remarks
Arjun Raj,
10:00AM - 10:30AM Stochastic Processes in Cell Biology.
MIT.
Paul J. Atzberger,
A Stochastic Immersed Boundary Method for
University of
10:30AM - 11:00AM Microscopic Fluid Dynamics : Toward
California-Santa
Modeling Cellular Mechanics.
Barbara.
11:00AM - 11:30AM Coffee Break
The reaction-diffusion master equation and
Samuel Isaacson,
11:30AM - 12:00PM spatially continuous stochastic reaction-
University of Utah.
diffusion models.
12:00PM – 2:00PM Lunch on your own
Tamar Schlick,
2:00PM - 2:30PM A Tale of Histone Tails.
New York University.
Using Simple Stochastic Differential Equations Michael Mascagni,
2:30PM - 3:00PM to Solve Complicated Partial Differential Florida State
Equations. University.
3:00PM - 3:30PM Coffee Break
Daniel Forger,
Towards a Detailed Understanding of the
3:30PM - 4:00PM University of
Mammalian Timekeeping.
Michigan.
Mette Olufsen,
Short term regulation during postural change
4:00PM - 4:30PM North Carolina State
from sitting to standing.
University.
CIMS 13th Floor
5:00PM Wine and Cheese Reception
Lounge
Saturday: (all talks and coffee breaks are located at CIMS Room 109)

CIMS RM. 109

9:00AM - 10:00AM Breakfast and Coffee
(all talks & breaks)
Arthur Sherman,
Ionic and Metabolic Oscillations in Pancreatic
10:00AM - 10:30AM National Institutes of
Beta-Cells.
Health, NIDDK.
Timing computations in the auditory brain John Rinzel,
10:30AM - 11:00AM
stem. New York University.
11:00AM - 11:30AM Coffee Break
Christoph Börgers,
11:30AM - 12:00PM Gamma oscillations and attention.
Tufts University.
12:00PM - 2:00PM Lunch on your own
Yoichiro Mori,
Three-Dimensional Model of Cellular Electrical
2:00PM - 2:30PM University of British
Activity.
Columbia.
Boyce Griffith,
Towards an Electro-Mechano-Fluidic Model of
2:30PM - 3:00PM Courant Institute, New
the Heart.
York University.
3:00PM - 3:30PM Coffee Break
Computational Modeling of Arterial Platelet Aaron Fogelson,
3:30PM - 4:00PM
Thrombosis. Univerisity of Utah.
Laura Miller,
Fluid dynamics and mechanosensing in the
4:00PM - 4:30PM University of North
developing embryonic heart.
Carlolina.
Lisa Fauci,
4:30PM - 5:00PM Biofluidmechanics of reproduction.
Tulane University.
Outside Courant
5:00PM - 5:30PM Group Photograph
(weather permitting)
6:00PM – 8:30PM Banquet Dinner NYU Kimmel Hall
 Abstracts
A Stochastic Immersed Boundary Method for Microscopic Fluid Dynamics : Toward
Modeling Cellular Mechanics, Paul J. Atzberger, University of California-Santa
Barbara.

Abstract: The immersed boundary method is one modeling approach which has been
widely applied to macroscopic systems involving flexible elastic structures which interact
with a fluid. At sufficiently small length scales thermal fluctuations become significant
and must be taken into account. In this talk, we shall discuss an extension of the
immersed boundary method framework which incorporates thermal fluctuations through
appropriate stochastic forcing terms in the fluid equations. This gives a system of stiff
SPDE's for which standard numerical approaches perform poorly. We discuss a
numerical method which exploits stochastic calculus to handle stiff features of the
equations. We further show how this numerical method can be applied in practice to
model the basic microscopic dynamics of polymers, polymer knots, membrane sheets,
and vesicles. We also discuss preliminary work on modeling the mechanics of cellular
structures.

Gamma oscillations and attention, Christoph Börgers, Tufts University.

Abstract: Gamma frequency (approximately 40 Hz) oscillations in electrical fields in the

brain are known to be correlated with various forms of attention. I will talk about
mechanisms underlying gamma oscillations, and about ways in which these oscillations
may be useful in vigilance and stimulus selection. This is work done in collaboration with
Nancy Kopell and Steven Epstein.

Biofluidmechanics of reproduction, Lisa Fauci, Tulane University.

Abstract: Complex fluid-structure interactions are central to mammalian fertilization.

Motile spermatozoa, muscular contractions of the uterus and oviduct, as well as ciliary
beating generate forces that drive fluid motion. At the same time, the dynamic shapes of
these biostructures are determined by the fluid mechanics. In this talk we will give an
overview of the classical work in fluid dynamics that has been applied to reproduction.
We will also present recent computational models, based upon an immersed boundary
framework, that promise to provide insight into these complex, coupled dynamical
systems.

Computational Modeling of Arterial Platelet Thrombosis, Aaron Fogelson, Univerisity

of Utah.
Abstract: Arterial blood clots (thrombi) that form as a consequence of artherosclerotic
plaque rupture are comprised largely of aggregates of platelets. These thrombi form
under conditions in which the flow changes substantially both in space (initially because
of the plaque, later also because of the clots) and in time (as the thrombi develop). We
present a continuum model that describes platelet thrombosis initiated by a ruptured
atherosclerotic plaque in a coronary-artery-sized vessel. It includes full treatment of the
fluid dynamics, and the aggregation of platelets in response to the plaque rupture and
further chemical signals. In the model, the growing clots influence the fluid motion by a
distribution of forces that act on the fluid rather than by an explicit change in fluid
domain geometry. Among the behaviors seen with this model are the growth of wall-
adherent platelet thrombi to occlude the vessel and stop the flow, and the transient growth
and subsequent embolization of thrombi leaving behind a passivated injured surface. The
model will be the basis for an exploration of the interactions among flow, biology, and
vessel geometry during arterial thrombosis.

Towards a Detailed Understanding of the Mammalian Timekeeping, Daniel Forger,

University of Michigan.

Abstract: Charles Peskin and I developed a detailed mathematical model of the circadian
(~24-hour) clock within most mammalian cells. In line with much of Peskin's work, this
model coupled a careful description of biological data (without unjustified mathematical
simplifications) with extensive in silico experiments. This model has general large
interest from the biological community, and I will describe experiments carried out in
several labs which test predictions from this model. In particular, this model has been
used to show that the most well studied (and first identified) mammalian clock mutation
behaves in an opposite manner to what had been previously thought, and that genetic
mutations in certain clock genes may actually lead to more accurate timekeeping.
Inspired by the work of McQueen and Peskin, I will also describe ongoing efforts to
develop a multi-scale model of the human circadian system which bridges the molecular
biology within a single cell with predictive models of human alertness and performance.

Towards an Electro-Mechano-Fluidic Model of the Heart, Boyce Griffith, Courant

Institute, New York University.

Abstract:Although the equations that describe cardiac mechanics (including blood,

muscle, and valve mechanics) and electrophysiology are different, in both cases a
realistic treatment demands the use of methods that account for anisotropy,
inhomogeneity, and complex geometries. We employ a unified theoretical framework,
the immersed boundary (IB) method, for both aspects of cardiac physiology. This unified
approach not only yields methodological overlap but also allows for substantial software
reuse. We also anticipate that this approach will greatly simplify the task of coupling our
models of cardiac mechanics and electrophysiology.

This talk will include an overview of recent work on the application of an adaptive
version of the IB method to the three-dimensional simulation of blood flow in the heart. I
shall also discuss the application of the IB framework to the bidomain equations of
cardiac electrophysiology. Computer animations of both fluid mechanical and
electrophysiological simulation results will be shown.

This is joint work with Charlie Peskin (CIMS), Dave McQueen (CIMS), and Rich
Hornung (LLNL).

The reaction-diffusion master equation and spatially continuous stochastic reaction-

diffusion models, Samuel Isaacson, University of Utah.

Abstract: We will present several mathematical models for studying reaction-diffusion

processes wherein both noise in the chemical reaction process and diffusion of individual
molecules may be important. In particular, we will examine the relation between the
reaction-diffusion master equation model of spatially distributed stochastic chemical
kinetics and models that track individual particles. Our analysis will demonstrate the
importance of modeling point binding, equivalently binding to a small target, in
understanding the reaction-diffusion master equation.

Using Simple Stochastic Differential Equations to Solve Complicated Partial

Differential Equations, Michael Mascagni, Florida State University.

Abstract: This talk begins with an overview of methods to solve PDEs based on the
representation of point solutions of the PDEs as expected values of functionals of
stochastic processes defined by the Feynman-Kac formula. The particular stochastic
processes that arise in the Feynman-Kac formula are solutions to specific SDEs defined
by the characteristics of the differential operator in the PDE. The Feynman-Kac formula
is applicable to wide class of linear initial and initial-boundary value problems for elliptic
and parabolic PDEs. We then concentrate our attention on elliptic boundary value
problems that arise in applications in materials science and biochemistry. These problems
are similar in that the PDEs to be solved are rather simple, and hence the associated SDEs
that arise in the Feynman-Kac formula are likewise simple. However, the geometry of the
problem is often complicated and amenable to several acceleration approaches particular
to these simple SDEs. We will specifically describe the walk on spheres, Greens function
first passage, last passage, walk on the boundary, and walk on subdomains methods in
this context. These methods will be presented in the setting of several applications
studied by the author and his research collaborators.

Fluid dynamics and mechanosensing in the developing embryonic heart, Laura Miller,
University of North Carolina.

Abstract: The embryonic vertebrate hearts develops from a simple heart tube into a valve
and chambered pump through a series of complicated morphological changes. During this
transformation, the flow patterns within the heart are constantly changing due to changes
in the viscosity of the fetal blood, chamber and valve morphology, and the kinematics of
contraction. Cardiac endothelial cells can sense and respond to local variations in shear
stress caused by such changes in the larger scale fluid dynamics. A number of recent
studies suggest that these fluid dynamic signals are responsible for triggering biochemical
cascades within the cell, leading to the transcription of genes necessary for cardiac
morphogenesis.

One aspect of heart development that is particularly sensitive to alterations in cardiac

flow patterns is the development of the heart valves. The focus of this study is to
understand how the cardiac cushions, which later become the valves, are formed through
a complex interaction of flow, mechanosensing, biochemical cascades within the cell, and
changes in morphology. On the macroscale, flow patterns change as the cardiac cushions
begin to bulge out from the endocardial wall. Such changes in cardiac flow patterns cause
temporal and spatial variations in shear stress along the endothelial lining of the heart
tube. This aspect of the problem was studied using the immersed boundary method to
describe how shear depends upon Reynolds number and morphology. The next level of
the study is to determine how a range of shear and pressure changes might be detected by
cardiac endothelial cells through the extracellular glycocalyx. This component of the
problem has been studied using a dynamically scaled flow tank and physical models of
the glycocalyx. Flow velocities through the model glycocalyx were measured directly
over a range of free stream velocities and possible configurations of the glycocalyx. On
both levels, several fluid dynamic transitions occur which may be important for the
signaling of the development of the valves.

Three-Dimensional Model of Cellular Electrical Activity, Yoichiro Mori, University of

British Columbia.

Abstract: We present a three-dimensional model of cellular electrical activity. This model

takes into account the three-dimensional geometry of biological tissue as well as ionic
concentration dynamics, both of which are neglected in conventional models of
electrophysiology.

We use both asymptotic and analytic methods to study the system of equations. We find
in particular that the model possesses multiple spatiotemporal scales.

This modelling methodology is applied to cardiac physiology. Numerical simulations

with this model is used to explore an anomalous mode of action potential propagation:
cardiac action potential propagation without gap junctions.

Short term regulation during postural change from sitting to standing, Mette Olufsen,
North Carolina State University.

Abstract:When standing up, blood is pooled in the legs due to the effect of gravity
resulting in a drop in systemic arterial pressure and widening of the blood flow velocity.
This can be modeled by increasing the blood pressure in the compartments representing
the lower body. To restore blood pressure and blood flow velocity a number of regulatory
mechanisms are activated. The most important mechanisms are autonomic reflexes
mediated by the sympathetic nervous system and cerebral autoregulation mediated by
changes in concentrations of oxygen and carbon dioxide. The response to standing is an
increase in nervous activity, which results in increased heart rate and cardiac contractility,
vasoconstriction of the systemic arterioles, and changes in unstressed volume and venous
compliance. The response by the cerebral autoregulation is to dilate arterioles in the
cerebral vascular bed. It is not clear how the autonomic and autoregulation interacts; one
theory suggests that vasoconstriction, resulting from increased sympathetic activity, has
an effect throughout the body, but that cerebral vasoconstriction gets overridden (possibly
with a significant delay) by autoregulation resulting in a net vasodilatation of the cerebral
vascular bed. In this work we demonstrate how mathematical modeling can be used to
predict the interaction between autonomic and autoregulation, and to identify sensitive
model parameters.

Stochastic Processes in Cell Biology, Arjun Raj, MIT.

Abstract:Until rather recently, biologists have thought of the molecular biology of cells
as consisting of largely deterministic processes. With the advent of new experimental
techniques, however, scientists have discovered that not only are many of these processes
stochastic, but that the stochastic behavior can have real consequences for cellular
function. In this talk, we describe two different examples of stochastic models of
processes in cellular biology.

In the first, we model the separation of sister chromosomes to daughter cells during the
anaphase A phase of mitosis. We model the driving force as arising from a Brownian
ratchet and investigate the role chromosome flexibility plays in the dynamics of such a
molecular motor. In particular, we are able to reproduce the classical experimental results
of Nicklas by showing that chromosomes of very different sizes all move at the same
speed when chromosomes are very flexible.

In the second, we examine the basic process of gene expression in mammalian cells. We
developed an experimental system through which we were able to detect and count
individual molecules of a specific mRNA in single cells. Surprisingly, we found that the
numbers of mRNA fluctuated widely from cell to cell. These observations are consistent
with a model of gene expression in which genes themselves randomly transition between
active and inactive states. This large amount of randomness raises interesting questions
about how cells are able to function reliably in the presence of such large random
fluctuations.

Timing computations in the auditory brain stem, John Rinzel, New York University.

Abstract:Sound localization involves precise temporal processing by neurons in the

auditory brain stem. The first neurons in the auditory pathway to receive input from both
ears can distinguish interaural time differences (ITDs) in the sub-millisecond range.
These cells in the mammalian medial superior olive (MSO) have specialized biophysical
features: two dendrites, each receiving input from only one side; very short membrane
time constant (as little as 0.5 ms); specialized ionic channel properties, including a low-
voltage activated K+ current, I-KLT. This I-KLT contributes to phasic firing (just one
spike in response to a step of current, at onset), precise phase-locking, and extremely
timing-sensitive coincidence detection. We will describe the temporal feature-selecting
properties of MSO cells based on biophysical (HH-like) modeling, in vitro (gerbil)
electrophysiology and application of concepts from dynamical systems theory and coding
theory.

A Tale of Histone Tails, Tamar Schlick, New York University.

Abstract: Eukaryotic chromatin is the fundamental protein/nucleic acid unit that stores
the genetic material. Understanding how chromatin fibers fold and unfold as well as
details of their structure and dynamics on a range of spatial and dynamical scales is
important for interpreting fundamental biological processes like DNA replication and
transcription regulation.

Using a new mesoscopic model of oligonucleosome chains and a tailored

configurational-bias Monte Carlo method that efficiently samples the possible
conformational states of oligonucleosomes, we elucidate the role of each histone tail in
regulating chromatin structure and detail the global folding pattern. Analyses indicate that
the H4 histone tails are most important in terms of mediating internucleosomal
interactions, especially in highly compact chromatin with linker histones, followed by
H3, H2A, and H2B tails in decreasing order of importance. In addition to mediating
internucleosomal interactions, the H3 histone tails crucially screen the electrostatic
repulsion between the entering/exiting DNA linkers. The H2A and H2B tails distribute
themselves along the periphery of chromatin fibers and thus are important for mediating
fiber/fiber interactions. A delicate balance between tail-mediated internucleosomal
attraction and electrostatic repulsion among DNA linkers allows adjacent DNA linkers to
align perpendicular to each other in linker histone-deficient chromatin, leading to the
formation of an irregular zigzag-folded fiber with dominant pairwise interactions between
nucleosomes i and i+/-4. With linker histone proteins included, the global folding pattern
changes markedly, so that the dominant pairwise interactions occur between nucleosomes
i and i+/-3.

Ionic and Metabolic Oscillations in Pancreatic Beta-Cells, Arthur Sherman, National

Institutes of Health, NIDDK.

Abstract:Insulin is secreted in pulses with a period of about five minutes from the beta-
cells of the pancreas. These pulses are in turn driven by oscillations of cytosolic calcium.
Two parallel streams of investigation over more than two decades have studied metabolic
oscillations and ionic mechanisms as possible sources of the calcium oscillations. We
propose that the two are linked by a potassium channel, K(ATP), that senses the ATP and
ADP levels in the cell. This directly transduces metabolic oscillations into oscillations of
membrane potential and calcium. However, calcium can also affect metabolism both by
stimulating ATP-consuming pumps and by depolarizing the mitochondria. A unified
model that combines the above elements and can thereby explain a diverse set of
experimental observations using only a few simple assumptions will be presented.