Spatially distributed stochastic dynamical systems in biology
Monday 20th June 2016 to Friday 24th June 2016
09:00 to 09:20  Registration  
09:20 to 09:30  Welcome from Christie Marr (INI Deputy Director)  
09:30 to 09:45  Programme Summary by Radek Erban  INI 1  
09:45 to 10:30 
Daniel Coombs (University of British Columbia) Interpretation and modelling with superresolution microscopy
Coauthors: Libin Abraham (University of British
Columbia), Alejandra Herrera (University of British Columbia),
Michael R Gold (University of British Columbia), Keng Chou
(University of British Columbia), Reza Tafteh (University of
British Columbia), Joshua Scurll (University of British Columbia),
Henry Lu (University of British Columbia), Ki Woong Sung
(University of British Columbia) I will describe recent progress in interpretation and modelling of B cell signalling based on superresolution light microscopy (primarily, STORM imaging and single particle tracking). 
INI 1  
10:30 to 11:00  Morning Coffee  
11:00 to 11:45 
Nathanael Hoze (ETH Zürich) Recovering a stochastic process from superresolution noisy ensembles of single particle trajectories
Coauthor: David Holcman (ENS Paris)
Recovering a stochastic process from noisy ensembles of single particle trajectories is resolved here using the Langevin equation as a model. The massive redundancy contained in single particle trajectories allows recovering local parameters of the underlying physical model. However, point localization is perturbed by instrumental noise, which, although of the order of ~10 nanometers, affects the estimation of biophysical parameters such as the drift and diffusion of the motion. Moreover, even if the acquisition frequency of modern tracking algorithm is very high, it is not instantaneous, and this biases parameter estimation. Here, we use several parametric and nonparametric estimators to compute the first and second moment of the process and to recover the local drift, its derivative and the diffusion tensor, in diffusion processes whose observation is perturbed by instrumental noise and noninstantaneous sampling rate. Using a local asymptotic expansion of the estimators and computing the empirical transition probability function, we develop here a method to deconvolve the instrumental from the physical noise. We use numerical simulations to explore the range of validity for the estimators. The present analysis allows characterizing what can exactly be recovered from the statistics of superresolution microscopy trajectories used in molecular tracking and underlying cellular function. 
INI 1  
11:45 to 12:30 
Maria Bruna Diffusion of finitesize particles and application to heterogeneous domains
Coauthor: Jonathan Chapman (University of Oxford)
We discuss nonlinear FokkerPlanck models describing diffusion processes with particle interactions. These models are motivated by the study of many particle systems in biology, and arise as the populationlevel description of a stochastic particlebased model. In particular, we consider a system of impenetrable diffusing spheres and use the method of matched asymptotic expansions to obtain a systematic model reduction. In the second part of the talk, we discuss how this method can be used to derive an effective transport equation in heterogeneous domains, such as porous media or crowded environments. A nice feature of this approach is that it can easily account for macroscopic gradients in porosity or crowding. 
INI 1  
12:30 to 13:30  Lunch @ Wolfson Court  
14:00 to 14:45 
Stefan Engblom (Uppsala Universitet) Stability and strong convergence in multiscale methods for spatial stochastic kinetics
Coauthors: Pavol Bauer (Uppsala university),
Augustin Chevallier (ENS Cachan), Stefan Widgren (National
Veterinary Institute) Recent progress in spatial stochastic modeling within the reactiontransport framework will be reviewed. I will first look at the issues with guaranteeing wellposedness of the involved mathematical and numerical models. Armed with this and the Laxprinciple, I will then present an analysis of splitstep methods and multiscale approximations, all performed in a pathwise, or "strong" sense. These analytical techniques hint at how effective (i.e. parallel) numerical implementations can be designed. Some fairly largescale simulations will serve as illustrations of the inherent flexibility of the modeling framework. While much of the initial motivation for this work came from problems in cell biology, I will also highlight examples from epidemics and neuroscience. Related Links

INI 1  
14:45 to 15:30 
Radek Erban (University of Oxford) From molecular dynamics to Brownian dynamics
I will discuss methods for spatiotemporal modelling in molecular and cell
biology, including allatom and coarsegrained molecular dynamics (MD) and
stochastic reactiondiffusion models, with the aim of developing and analysing
multiscale methods which use MD simulations in parts of the computational domain
and (lessdetailed) stochastic reactiondiffusion approaches in the remainder of
the domain. The main goal of this multiscale methodology is to use a detailed
modelling approach in localized regions of particular interest (in which
accuracy and microscopic details are important) and a less detailed model in
other regions in which accuracy may be traded for simulation efficiency.
Applications using allatom MD include intracellular dynamics of ions and ion
channels. Applications using coarsegrained MD include protein binding to
receptors on the cellular membrane, where modern stochastic reactiondiffusion
simulators of intracellular processes can be used in the bulk and a ccurately
coupled with a (more detailed) MD model of protein binding which is used close
to the membrane. References: [1] Radek Erban, "Coupling allatom molecular dynamics simulations of ions in water with Brownian dynamics", Proceedings of the Royal Society A, Volume 472, Number 2186, 20150556 (2016) [2] Radek Erban, "From molecular dynamics to Brownian dynamics", Proceedings of the Royal Society A, Volume 470, Number 2167, 20140036 (2014) Related Links

INI 1  
15:30 to 16:00  Afternoon Tea  
16:00 to 16:45 
Ramon Grima (University of Edinburgh) Exact and approximate solutions for spatial stochastic models of biochemical systems
Coauthors: Claudia Cianci (University of
Edinburgh), Stephen Smith (University of Edinburgh) Stochastic effects in chemical reaction systems have been mostly studied via the chemical master equation, a nonspatial discrete stochastic formulation of chemical kinetics which assumes wellmixing and pointlike interactions between molecules. These assumptions are in direct contrast with what experiments tells us about the nature of the intracellular environment, namely that diffusion plays a fundamental role in intracellular dynamics and that the environment itself is highly nondilute (or crowded). I will here describe our recent work on obtaining (i) exact expressions for the solution of the reactiondiffusion master equation (RDME) and its crowded counterpart (cRDME) in equilibrium conditions and (ii) approximate expressions for the moments in nonequilibrium conditions. The solutions portray an emerging picture of the combined influence of diffusion and crowding on the stochastic properties of chemical reaction networks. Related Links 
INI 1  
16:45 to 18:00  Welcome Wine Reception and Poster Session 
09:00 to 09:45 
Aleksandar Donev (New York University) Fast Reactive Brownian Dynamics
I will describe a particlebased algorithm for reactiondiffusion problems
that combines Brownian dynamics with a Markov reaction process. The microscopic
model simulated by our Split Reactive Brownian Dynamics (SRBD) algorithm is
based on the Doi or volumereactivity model. This model applies only to
reactions with at most two reactants, which is physically realistic. Let us
consider the simple reaction A+B>product. In the Doi model, particles are
independent spherical Brownian walkers (this can be relaxed to account for
hydrodynamic interactions), and while an A and a B particle overlap, there is a
Poisson process with a given microscopic reaction rate for the two particles to
react and give a product. Our goal is to simulate this complex Markov process in
dense systems of many particles, in the presence of multiple reaction channels.
Our algorithm is inspired by the Isotropic Direct Simulation Monte Carlo (IDSMC) method and the next subvolume method. Strang splitting is used to separate diffusion and reaction; this is the only approximation made in our method. In order to process reactions without approximations, with the particles frozen in place, we use an eventdriven algorithm. We divide the system into a grid of cells such that only particles in neighboring cells can react. Each cell schedules the next potential reaction to happen involving a particle in that cell and a particle in one of the neighboring cells, and an event queue is used to select the next cell in which a reaction may happen. Note that, while a grid of cells is used to make the algorithm efficient, the results obtained by the SRBD method are gridindependent and thus free of grid artifacts, such as loss of Galilean invariance and sensitivity of the results to the grid spacing. I will compare our SRBD method with gridbased methods, such as (C)RDME and a variant of RDME that we call Split Brownian Dynamics with Reaction Master Equation (SBDRME), on a problem involving the spontaneous f 
INI 1  
09:45 to 10:30 
Konstantinos Spiliopoulos Metastability and Monte Carlo Methods for Multiscale Problems
Rare events, metastability and Monte Carlo methods for stochastic dynamical
systems have been of central scientific interest for many years now. In this
article we focus on rough energy landscapes, that are modeled as multiscale
stochastic dynamical systems perturbed by small noise. Large deviations deals
with the estimation of rare events. Depending on the type of interaction of the
fast scales with the strength of the noise we get different behavior, both for
the large deviations and for the corresponding Monte Carlo methods. We describe
how to design asymptotically provably efficient importance sampling schemes for
the estimation of associated rare event probabilities, such as exit
probabilities,hitting probabilities, hitting times, and expectations of
functionals of interest. Standard Monte Carlo methods perform poorly in these
kind of problems in the small noise limit. In the presence of multiple scales
one faces additional difficulties and straightforward adaptation of importance
sampling schemes for standard small noise diffusions will not produce efficient
schemes. Theoretical results are supplemented by numerical simulation
studies.

INI 1  
10:30 to 11:00  Morning Coffee  
11:00 to 11:45 
Frank Noe (Freie Universität Berlin) InteractingParticle ReactionDiffusion Simulations: Endocytosis
We have introduced interactingparticle reactiondiffusion (iPRD) simulations
as a hybrid between molecular dynamics simulations and particlebased
reactiondiffusion simulations. iPRD is a suitable modeling framework for many
cellular signaling processes, especially such processes involving dense protein
mixtures, supramolecular architectures or protein scaffolds at membranes. I will
introduce to the theory behind iPRD and present computational algorithms. One of our key application areas is clathrinmediated endocytosis in neurons, and I will briefly elude to simulations of protein recruitment to clathrincoated pits and the interplay between membraneassociated proteins and membrane deformation in endocytosis. Related Links 
INI 1  
11:45 to 12:30 
Avrama Blackwell (George Mason University) Computationally efficient simulation of signaling pathways underlying synaptic plasticity
Coauthors: JedrzejewskiSzmek, Zbigniew (George Mason
University), JedrzejewskaSzmek, Joanna (George Mason University) Longlasting forms of long term potentiation (LTP) represent one of the major cellular mechanisms underlying learning and memory. The degree to which neuromodulatory systems, e.g. betaadrenergic receptors or dopamine receptors, modify LTP and memory is still unclear. Computational modeling of the signaling pathways activated by neuromodulatory and cortical inputs is one approach for investigating these issues. Cortical inputs are spatially specific, often synapse onto spines and produce changes in small numbers of molecules. In contrast, neuromodulatory inputs tend to to be spatially dispersed. The interaction between these two inputs can lead to changes lasting minutes to hours. Because of the heavy computational cost of performing simulations at these diverse spatial and temporal scales, we have developed an asynchronous, adaptive tauleaping algorithm for reactiondiffusion systems. For every reaction and diffusion channel at each step of the simulation the more efficien t of an exact stochastic event or a tauleap is implemented from the priority queue. This new approach removes the inherent tradeoff between speed and accuracy in stiff systems which was present in all tauleaping methods by allowing each reaction channel to proceed at its own pace. We use our computational efficient tau leaping algorithm to investigate how activation of neuromodulatory systems interacts with cortical inputs to modify the development of synaptic plasticity. Related Links

INI 1  
12:30 to 13:30  Lunch @ Wolfson Court  
14:00 to 14:45 
Andrew Rutenberg (Dalhousie University) Models of Microtubule Acetylation
Microtubule (MT) acetylation is done posttranslationally in the MT lumen by
the acetyltransferase alphaTAT1. A simple picture is that alphaTAT1 enters the
lumen at the open ends of MT, and diffuses inside while acetylating.
Complicating this picture, alphaTAT1 is approximately half the luminal diameter
 indicating that it may undergo singlefile diffusion (SFD). Computationally,
we explore the consequences of SFD in this system. Experimentally, in
collaboration with the group of Guillaume Montagnac (Institut Gustave Roussy),
immunofluorescence techniques allows us to measure the acetylation pattern of
individual MT. We try to reconcile the computational and experimental
approaches, and highlight open questions.

INI 1  
14:45 to 15:30 
Kevin Sanft (University of North Carolina) Spatial simulation and analysis of actin filament dynamics and wave propagation
Coauthors: Hans Othmer (University of Minnesota),
Yougan Cheng (University of Minnesota) Actin filaments play an important role in many cellular processes, including cell motility. We present a stochastic model of actin filament dynamics in a threedimensional Cartesian domain. Actin monomers bind to nucleation sites on the membrane and polymerize to form filaments (Factin). Factin polymers interact with membranebound nucleation promoting factors via a positive feedback loop. The resulting model produces waves of actin filaments that propagate along the membrane. Simulating polymer growth presents challenges to traditional Gillespietype simulations. We describe a rulebased simulation approach to handle the many states of actin filament growth. Finally, we discuss techniques for managing the simulation output data. 
INI 1  
15:30 to 16:00  Afternoon Tea  
16:00 to 17:00 
Yannis Kevrekidis (Princeton University) Rothschild Lecture: Mathematics for datadriven modeling  The science of crystal balls
In mathematical modeling one typically progresses
from observations of the world (and some serious thinking!) to equations
for a model, and then to the analysis of the model to make predictions.
Good mathematical models give good predictions (and
inaccurate ones do not)
>  but the computational tools for analyzing them are
the same: algorithms that are typically based on closed form
equations. While the skeleton of the process remains the same, today
we witness the development of mathematical techniques that operate
directly on observations data, and "circumvent" the
serious thinking that goes into selecting variables and parameters and writing
equations. The process then may appear to the user a little like
making predictions by
"looking into a crystal ball". Yet the "serious
thinking" is still there and uses the same and some new mathematics:
it goes into building algorithms that "jump directly"
from data to the analysis of the model (which is never available in closed form)
so as to make predictions.
I will present a couple of efforts that illustrate
this new path from data to predictions. It really is the same old path,
but it is travelled by new means.

INI 1  
17:00 to 18:00  Reception 
09:00 to 09:45 
Tom Chou (University of California, Los Angeles) Path integralbased Bayesian inference of bond energy and mobility Coauthors: Josh Chang (NIH), PakWing Fok (Univ. of Delaware) A Bayesian interpretation is given for regularization terms for parameter functions in inverse problems. Fluctuations about the extremal solution depend on the regularization terms  which encode prior knowledge  provide quantification of uncertainty. After reviewing a general pathintegral framework, we set up a number of applications that arise in biophysics. The inference of bond energies and bond coordinate mobilities from dynamic force spectroscopy experiments are worked out in detail. Related Links http://faculty.biomath.ucla.edu/tchou/ 
INI 1  
09:45 to 10:30 
Zaida LutheySchulten (University of Illinois at UrbanaChampaign) Simulations of Cellular Processes: From Single Cells to Colonies
Coauthors: Michael J. Hallock (University of Illinois
at UrbanaChampaign), Joseph R. Peterson (University of Illinois at
UrbanaChampaign), John A. Cole (University of Illinois at
UrbanaChampaign), Tyler M. Earnest (University of Illinois at
UrbanaChampaign), John E. Stone (University of Illinois at
UrbanaChampaign) Highperformance computing now allows integration of data from cryoelectron tomography, super resolution imaging, various –omics, and systems biology reaction studies into coherent computational models of cells and cellular processes functioning under in vivo conditions. Here we analyze the stochastic reactiondiffusion dynamics of ribosome biogenesis in slow growing bacterial cells undergoing DNA replication and probe the metabolic reprogramming that occurs within dense colonies of Escherichia coli cells over periods of hours. Using our GPUbased Lattice Microbe software, the some 1300 reactions and 250 species involved in transcription, translation and ribosome assembly are described in terms of reactiondiffusion master equations and simulated over a cell cycle of two hours. The ribosome biogenesis simulations account for DNA replication that takes place within the cell cycle, and the results are compared to super resolution imaging results. In the case of the c ell colony simulations, reactiondiffusion kinetics of the surrounding medium are coupled with the cellular metabolic networks to demonstrate how small colonies of interacting bacterial cells differentially respond to the competition for resources according to their position in the colony. The predicted metabolic reprogramming has been observed experimentally. Finally we will report on the progress we have achieved to date and how supercomputers will provide us a window into cellular dynamics within bacterial and eukaryotic cells. 
INI 1  
10:30 to 11:00  Morning Coffee  
11:00 to 11:45 
Kit Yates (University of Bath) Developing PDEcompartment hybrid frameworks for modeling stochastic reactiondiffusion processes
Coauthor: Mark Flegg (University of Monash) Spatial reactiondiffusion models have been employed to describe many emergent phenomena in biology. The modelling technique most commonly adopted is systems of partial differential equations (PDEs), which assumes there are sufficient densities of particles that a continuum approximation is valid. However, the simulation of computationally intensive individualbased models has become a popular way to investigate the effects of noise in reactiondiffusion systems. The specific stochastic models with which we shall be concerned in this talk are referred to as `compartmentbased' or `onlattice'. These models are characterised by a discretisation of the computational domain into a grid/lattice of `compartments'. Within each compartment particles are assumed to be wellmixed and are permitted to react with other particles within their compartment or to transfer between neighbouring compartments. In this work we develop two hybrid algorithms in which a PDE in one region of the domain is coupled to a compartmentbased model in the other. Rather than attempting to balance average fluxes, our algorithms answer a more fundamental question: `how are individual particles transported between the vastly different model descriptions?' First, we present an algorithm derived by carefully redefining the continuous PDE concentration as a probability distribution. Whilst this first algorithm shows very strong convergence to analytic solutions of test problems, it can be cumbersome to simulate. Our second algorithm is a simplified and more efficient implementation of the first, it is derived in the continuum limit over the PDE region alone. We test our hybrid methods for functionality and accuracy in a variety of different scenarios by comparing the averaged simulations to analytic solutions of PDEs for mean concentrations. Related Links

INI 1  
11:45 to 12:30 
Erik De Schutter (Okinawa Institute of Science and Technology) Accurate ReactionDiffusion Operator Splitting on Tetrahedral Meshes for Parallel Stochastic Molecular Simulations
Coauthors: Hepburn, Iain (OIST), Chen, Weiliang
(OIST) Spatial stochastic molecular simulations in biology are limited by the intense computation required to track molecules in space either by particle tracking or voxelbased methods, meaning that the serial limit has already been reached in subcellular models. This calls for parallel simulations that can take advantage of the power of modern supercomputers. GPU parallel implementations have been described for particle tracking methods [1,2] and for voxelbased methods [3], where good parallel performance gain up to 2 order of magnitude have been demonstrated but this depends strongly on model specificity. MPI parallel implementations have gained less attention than GPU implementations to date but offer several advantages including a greater range of platform support from personal computers to advanced supercomputer clusters. An initial MPI implementation for irregular grids has been described and almost ideal speedup demonstrated but only up to 4 cores [4], which indicates the potential for good scalability of such implementations. We describe an operator splitting implementation for irregular grids with a novel method to improve accuracy over LieTrotter splitting that is somewhat comparable to taureduction but without the performance cost. We systematically investigate parallel performance for a range of models and mesh partitionings using the STEPS simulation platform [5]. Finally we introduce a whole cell parallel simulation of a published reactiondiffusion model [6] within a detailed, complete neuron morphology and demonstrate a speedup of 3 orders of magnitude over serial computations. [1] L Dematte 2012. IEEE/ACM Trans. Comput. Biol. Bioinf. 9: 655667 [2] DV Gladkov et al. 2011. Proc. 19th High Perf. Comp. Symp. 151158 [3] E Roberts, JE Stone, Z LutheySchulten 2013. J. Comp. Chem. 34: 245–255 [4] A Hellander et al. 2014. J. Comput. Phys. 266: 89100 [5] I Hepburn et al. 2012. BMC Syst. Biol. 6:36 [6] H Anwar et al. 2013. J. Neurosci. 33: 1584815867 Related Links

INI 1  
12:30 to 13:30  Lunch @ Wolfson Court  
13:30 to 17:00  Free Afternoon  
19:30 to 22:00  Formal Dinner at Emmanuel College 
09:00 to 09:45 
Jun Allard (University of California, Irvine) Clustering of cell surface receptors: Simulating the mesoscale between reactiondiffusion and atomistic scales
Coauthor: Omer Dushek (Oxford) Many biological molecules, including cell surface receptors, form denselypacked clusters that are weakly bound, mechanically soft, and have volumes on the same order as the volumes of the proteins they interact with. Preventing the formation of clusters dramatically attenuates proper cell function in many examples (including T cell activation and allergen activation in Mast cells), but for unknown reason. Therefore, receptor clusters involve biology hidden at the mesoscale between individual protein structure (~0.1nm) and the cellscale signaling pathways of populations of diffusing protein (~1000nm). In some parameter regimes, clusters comprise 10100 molecules tied to fixed locations on the cell surface by molecular tethers. The Dushek Lab is developing an in vitro setup that mimics this regime, and find that the time courses of binding and enzymatic reactions are nontrivial and cannot be fit to simple ODE models. On the other hand, fitting to explicitly spatial simulatio ns with volume exclusion is prohibitively slow. Here we present a fast algorithm for tethered reactions with volume exclusion. The algorithm exploits, first, the spatiallyfixed tethers, allowing us to construct a single nearestneighbor tree, and, second, a separation of timescales between the fast diffusion of molecular domains and slow binding and catalytic reactions. This allows use of a hybrid MetropolisGillespie algorithm: on the fast timescale of domain motion, efficient equilibrium algorithms that include volume exclusion provide the effective concentrations for the slow timescale of binding and catalysis, which are simulated using a maximallyfast nextevent algorithm. Crucially, we employ dynamic connectedsetdiscovery subroutines to simulate the minimal subset of molecules each time step. The algorithm has computational time scaling approximately with the number of molecules and can reproduce the nontrivial time courses observed experimentally. Related Links

INI 1  
09:45 to 10:30 
Denis Grebenkov (École Polytechnique) Rigorous results on firstpassage times for surfacemediated diffusion
Coauthors: JeanFrancois Rupprecht (National University
of Singapore, Singapore), Olivier Bénichou (CNRS  UPMC, France),
Raphael Voituriez (CNRS  UPMC, France) We present an exact calculation of the mean firstpassage time to a target on the surface of a 2D or 3D spherical domain, for a molecule alternating phases of surface diffusion on the domain boundary and phases of bulk diffusion. The presented approach is based on an integral equation which can be solved analytically. Explicit solutions are provided for normal and biased diffusion in a general annulus with an arbitrary number of regularly spaced targets on a partially reflecting surface. In the framework of this minimal model of surfacemediated reactions, we show analytically that the mean reaction time can be minimized as a function of the desorption rate from the surface. As a consequence, an intermittent exploration process may enhance search and reaction, as compared to pure surface diffusion or pure bulk diffusion. Our method is applicable to extended targets of arbitrary size (i.e., beyond the narrow escape limit). Higherorder moments and the probability distribution of the firstpassage time can also be derived. Related Links

INI 1  
10:30 to 11:00  Morning Coffee  
11:00 to 11:45 
Scott McKinley (Tulane University) Anomalous Diffusion and Random Encounters in Living Systems
Due to the rapid growth of animal movement data obtained by GPS, radio
tracking collars and other means, there is a growing recognition that classical
models of encounter rates among animal populations should be revisited. Recent
theoretical investigations have demonstrated that biologically relevant
modifications to classical assumptions about individual behavior can bring about
nontrivial changes in the formulation of populationscale dynamical systems. In
particular, the combination of tracking data with habitat information has
revealed the substantial impact that environmental factors have on animal
movement and sociality. In this talk, I will review some of the existing
conventional wisdom that supports the use of socalled “Levy flight” models that
seek to describe animal movement in the absence of environmental cues. However,
through a few examples, I will make the case that animal movement patterns
should not be separated from the spatial environmental features that shape them.
In fact, animal sensing and decisionmaking are “leadingorder” effects, and
their study gives rise to new ecological observations and novel mathematical
challenges.

INI 1  
11:45 to 12:30 
Ruth Baker (University of Oxford) tbaCell biology processes: model building and validation using quantitative data
Cell biology processes such as motility, proliferation and death are
essential to a host of phenomena such as development, wound healing and tumour
invasion, and a huge number of different modelling approaches have been applied
to study them. In this talk I will explore a suite of related models for the
growth and invasion of cell populations. These models take into account
different levels of detail on the spatial locations of cells and, as a result,
their predictions can differ depending on the relative magnitudes of the various
model parameters. To this end, I will discuss how one might determine the
applicability of each of these models, and the extent to which inference
techniques can be used to estimate their parameters, using both cell and
populationlevel quantitative data.

INI 1  
12:30 to 13:30  Lunch @ Wolfson Court  
14:00 to 14:45 
Julien Berro (Yale University) Quantitative approaches to unravel the molecular mechanisms of clathrinmediated endocytosis
Eukaryotic cells ubiquitously use clathrinmediated endocytosis to
internalize nutrients, receptors and recycle plasma membrane. Defects in
endocytosis are implicated in multiple diseases such as cancer, neuropathies,
metabolic syndromes, and the endocytic machinery can be hijacked by some
pathogens to infect cells. During clathrinmediated endocytosis, the endocytic
machinery shapes a ~50nm diameter vesicle from the flat plasma membrane in less
than 20 seconds. When membrane tension is high, a dynamic actin cytoskeleton is
necessary for endocytosis to proceed. Despite intensive studies on most of the
endocytic proteins, it remains unknown how the actin network produces the forces
necessary to deform the plasma membrane during endocytosis. In this talk, we will show how the development of new quantitative methods can be key to unravel the molecular mechanisms of complex biological processes such as endocytosis. We will focus on new methods to measure the temporal evolution of a) the number of molecules of endocytic proteins, b) their residence times in the endocytic structure, c) the nanometerscale deformations of the endocytic structure, and d) methods to increase the quality and the temporal resolution of noisy datasets. We will also show how these data are invaluable to constrain mathematical models that we have developed to test hypotheses and make experimentally testable predictions. 
INI 1  
14:45 to 15:30 
Lei Zhang (Peking University) Noise Attenuation during the Development of Spatial Pattern
Coauthor: Qing Nie (UC Irvine) Morphogens provide positional information for spatial patterns of gene expression during development. However, stochastic effects such as local fluctuations in morphogen concentration and noise in signal transduction make it difficult for cells to respond to their positions accurately enough to generate sharp boundaries between gene expression domains. In this talk, I will present a novel noise attenuation mechanism during the development of spatial pattern. First, we investigate the boundary sharpening in the zebrafish hindbrain. Computational analyses of spatial stochastic models show, surprisingly, that a combination of noise in RA concentration and noise in hoxb1a/krox20 expression promotes sharpening of boundaries between adjacent segments. Second, we integrate spatial and temporal noise attenuation in the BMPFGF signaling network in the dorsal telencephalon. We demonstrate that perturbing FGF signaling transiently will lead to a noisier boundary with loss of boundary s harpness and a global delay in development. 
INI 1  
15:30 to 16:00  Afternoon Tea  
16:00 to 16:45 
Jonathan Wattis (University of Nottingham) Dynamics of DNA basepair breathing, telomere loss and telomere clustering
We start by analysing a model of basepair breathing in DNA using a system of stochastic ordinary differential equations to describe the distances between bases in a sequence of bases that contains a defect. We describe how the parameters in the SODE model are obtained from allatom MD simulations (AMBER) using a maximum likelihood algorithm. The result is a model which explains how basepair breathing depends on the twist of the double helix. This work is in collaboration with Cipri Duduiala, Ian Dryden and Charlie Laughton (Phys Rev E, 80, 061906, 2009 and Physica D 240, 12541261, 2011). Telomeres are sequences of bases at the ends of chromosomes. During replication, they are shortened due to imperfect replication of the DNA. We present a variety of models of telomere loss, using an evolving distribution of telomere lengths, and analyse this mechanism of aging in cell populations using a combination of theoretical and analytical techniques. This work formed part of the PhD thesis of Qi Qi, cosupervised by Helen Byrne (http://eprints.nottingham.ac.uk/12258 and Bull Math Biol 76, 1241, 2014). Finally, we outline ongoing work modelling (in collaboration with David Holcman) on the formation of proteintelomere clusters in yeast cells, using coagulationfragmentation equations to describe the cluster size and composition. 
INI 1 
09:00 to 09:45 
Paul Bressloff (University of Utah) Diffusion in randomly switching environments
In this talk we review recent work with Sean Lawley on diffusion in randomly
switching environments. One of the fundamental transport processes in biological
cells is the exchange of ions, proteins and other macromolecules between
subcellular domains, or between the interior and exterior of the cell, via
stochastically gated membrane pores and channels. For example, the nucleus of
eukaryotes is surrounded by a protective nuclear envelope within which are
embedded nuclear pore complexes (NPCs). The NPCs are the sole mediators of
exchange between the nucleus and cytoplasm, which requires the formation of
complexes with chaperone molecules known as karyopherins. Other examples include
the membrane transport of particles via voltagegated and ligandgated ion
channels, and intercellular gapjunction coupling. One example at the more
macroscopic level is the passive diffusion of oxygen during insect respiration.
We show how each of these systems can be modeled in terms of diffusio n in a
bounded domain with (partially) switching boundaries, and use a combination of
PDE theory and probabilistic methods to determine statistical properties of the
system. We highlight important differences between cases where the diffusing
particles switch conformational state and cases where the boundary physically
switches.

INI 1  
09:45 to 10:30 
Heinz Koeppl (Technische Universität Darmstadt) Statistical inference of singlecell and singlemolecule dynamics
Singlecell and singlemolecule experimental techniques expose the randomness of cellular processes and invite a stochastic description. In this talk I will present our efforts to solve inverse problems related to stochastic cellular dynamics. First, we provide a inference framework that accounts for extrinsic and intrinsic noise contributions present in singlecell measurements. For that, we show that stochastic components of a cellular process can be marginalised exactly such that the inference remains tractable. Second, we present singlemolecule experimental data to study transcriptional kinetics in live yeast cells. A stochastic models for the system is presented and biophysical parameters such elongation speed, termination rate etc are inferred from single transcriptionsite intensities. Moreover, optimal filtering or state estimation is performed to reconstruct the most likely position of single RNAP molecules on the gene.

INI 1  
10:30 to 11:00  Morning Coffee  
11:00 to 11:45 
Assaf Amitai (Massachusetts Institute of Technology) Changes in local chromatin structure during homology search: effects of local contacts on search time
Coauthors: Andrew Seeber (Friedrich Miescher Institute
for Biomedical Research), Susan M. Gasser (Friedrich Miescher Institute
for Biomedical Research), David Holcman (Ecole Normale Supérieure)
Doublestrand break (DSB) repair by homologous recombination (HR) requires an efficient and timely search for a homologous template. Here we developed a statistical method of analysis based on singleparticle trajectory data which allows us to extract forces acting on chromatin at DSBs. We can differentiate between extrinsic forces from the actin cytoskeleton and intrinsic alterations on the nucleosomal level at the cleaved MAT locus in budding yeast. Using polymer models we show that reduced tethering forces lead to local decondensation near DSBs, which reduces the mean first encounter time by two orders of magnitude. Local decondensation, likely stems from loss of internal mechanical constraints and a local redistribution of nucleosomes that depends on chromatin remodelers. Simulations verify that local changes in internucleosomal contacts near DSBs would shorten drastically the time required for a longrange homology search. 
INI 1  
11:45 to 12:30 
David Holcman (CNRS  Ecole Normale Superieure Paris) Advanced Lecture (U. of Cambridge): Analysis of electrodiffusion in dendritic spines for synaptic transmission
This lecture presents recent methods to study electrodiffusion and the PoissonNernstPlanck
equation (PNP) in bounded domains. The methods are used to interpret and deconvolve
voltage dye (Arclight) signal from
dendritic spine and to extract the IV relation. The geometry of the spine plays
a crucial roles in defining this relation.

INI 1  
12:30 to 13:30  Lunch @ Wolfson Court 