Fisher, Jasmin

Hajnal, Alex

Hall, Benjamin A.

Jackson, Ethan

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376a Monday, February 17, 2014monoribosomes. These ribosome-protected mRNA fragments are purified and
prepared for high throughput sequencing to map the position of cellular ribo-
somes and quantify levels of translation. By comparing ribosome profiling
levels with RNA-seq measurements of mRNA levels we find many new cases
of genes whose translation only occurs during the proper phase of the cell cycle.
We find that a majority of ORFs have a >2-fold change in translation efficiency
during the cell cycle. This suggests that Caulobacter uses cell cycle-specific
regulation of translation to ensure proper timing of gene expression.Computational Systems Biology
1895-Pos Board B625
Modelling the Mechanics of the Circulation: Blood Rheology and
Atherosclerosis
Glaucia Pereira, Rob Krams, Berend van Wachem.
Imperial College London, London, United Kingdom.
In this work, we test the hypothesis that a redistribution of blood particles is
related to predilection sites of atherosclerosis,which is characterised by the
deposition of lipid material and inflammatory cells. The focal distribution
of lesions, shear stress,and mass transport play an important role[1] because
shear stress scales inversely with enhanced transport of species in the vessel
wall. Also, because 46% of blood volume is made up of particles, blood
compounds have wide-reaching effects on the coupling of blood flow to
the vessel walls. Indeed, some works have shown changes in flow rate,
apparent viscosity and flow patterns due to particle’s shape and/or concentra-
tion[2,3,4,5,6] besides literature usually focus on microcirculation that is
driven by diffusive transport and differs in many other ways to the me-
chanics of circulation in large vessels. Here, we present some results(Fig.1)
to support the hypothesis that flow trends related to atheroma development
might be more accurately described by multiphase flow models[7], which
is the subject of ongoing
research.
[1] C.G.Caro, Arterioscler.
Thromb. Vasc. Biol. (2009).
[2] M.Zastawny et.al., J.
Multiph. Flow (2012).
[3] G.Pereira, Biophysical
Journal (2013).
[4] K.Sugiyama et.al., J.
Comput. Mech. (2010).
[5] G.Pereira. Multiscale
Modelling in Medicine and
Biology Conference (2012).
[6] F.Thomas, M.Sc. Thesis,
Imperial College London
(2012).
[7] B.Wachem’s Group,
Multiflow: http://www.multi
flow.org/1896-Pos Board B626
Stochastic Discrete Effects in a Simple Gene Circuit with Delayed Negative
Feedback
Eder Zavala, Tatiana T. Marquez-Lago.
Okinawa Institute of Science and Technology, Onna, Japan.
Negative feedback loops are ubiquitous motifs in gene regulation processes,
providing cells with control mechanisms to perform key decisions. Conse-
quently, they have received a lot of recent attention in the efficient design of
synthetic gene circuits. The interconnected biochemical reactions composing
negative feedback loops are discrete and random by nature, and are more accu-
rately described by stochastic models. These models, however, often make as-
sumptions yielding erroneous predictions, or simply miss out on important
discrete stochastic effects. One such common omission is the explicit delays
that separate the initiation of transcription and translation from the appearance
of their corresponding functional products. Thus, delay-induced stochastic os-
cillations and other delay-induced stochastic discrete effects have remained
relatively unexplored at the single-cell level. In our work (Zavala and
Marquez-Lago, submitted), we study oscillatory and multimodal behavior in
a simple gene circuit with delayed negative feedback by systematically
analyzing the influence of negative feedback strength and transcriptional/trans-
lational delays on expression dynamics. We carry out single-cell simulations
producing exact trajectories of the Delay Chemical Master Equation, thus
avoiding any approximation errors, and demonstrate an oscillatory regime
emerges through a stochastic Hopf bifurcation. Furthermore, we characterizeconditions under which stochastic oscillations produce bursts, and vice versa.
In conformity with previous results (Marquez-Lago et al., BiophysJ 2010)
we show that the same gene circuit architecture is capable of multimodal
behavior and burst-like expression. Most importantly, we describe how explicit
delays produce novel non-classic effects, not yet reported in the literature.
1897-Pos Board B627
Predicting and Retrodicting Fate Patterns in C. elegans Vulval Develop-
ment using Logic Programming
Benjamin A. Hall1, Ethan Jackson2, Alex Hajnal3, Jasmin Fisher1.
1Microsoft Research Cambridge, Cambridge, United Kingdom, 2Microsoft
Research, Redmond, WA, USA, 3Institute of Molecular Life Sciences,
University of Zurich, Zurich, Switzerland.
Vulval development in C. elegans is a paradigm for understanding how cell fate
determination leads to organogenesis. The fate pattern of a row of six cells is
specified by spatial and temporal controls, and the competition of the LET-
23/SEM-5/LET-60/MAPK and Delta/Notch signalling pathways. Formal veri-
fication techniques applied to state models of vulval development have been
shown as a powerful approach for demonstrating how the signalling systems
interact and determine cell fate. However, the computational requirements of
verification approaches become prohibitive as model complexity increases.
Here we apply a logic programming based approached to derive minimal
models of vulval development, increasing the speed of prediction of fate pattern
from genotype by up to four orders of magnitude. This increase in speed further
allows us to infer or ‘retrodict’ genotypes from the final fate pattern. We apply
this new technique to understand how highly variable cell fates arises when the
precise morphogen gradient of LIN-3 is effectively randomised by diffusion in
dig-1 mutations. We further apply this to the study of let-23 mosaic mutations,
and find that the resulting model refinements reconcile our approach with
historical experimental data. Based our new findings we propose that logic pro-
gramming provides an efficient approach for design and analysis of experi-
mental data.
1898-Pos Board B628
Modeling Electrical Activity in Intestinal L-Cells
Michela Riz, Morten Gram Pedersen.
University of Padova, Padova, Italy.
Glucagon-like peptide 1 (GLP1) is an insulinotropic hormone released from in-
testinal L-cells in response to food ingestion. It is responsible for the so-called
incretin effect, i.e. the fact that glucose ingested orally elicits a greater insulin
response than glucose administered intravenously, even when glucose concen-
trations in plasma are matched.
In addition, GLP1 inhibits glucagon secretion, slows gastric emptying, regu-
lates appetite and food intake. All these actions have made GLP1 an appealing
target for the development of new treatments of type 2 diabetes. In this context,
the comprehension of the sensory and secretory pathways, which is still poorly
understood, becomes essential. The stimulus-secretion pathway in L-cells in-
cludes electrical activity to transduce glucose sensing to calcium-stimulated
exocytosis.
We build a mathematical Hodgkin-Huxley-like model of electrical activity of
L-cells based on recent data on primary colonic L-cells. The model includes
ATP-sensitive Kþ-channels (K(ATP)-channels), voltage gated Naþ- and
Kþ-channels and low- and high-voltage activated Ca2þ-channels. The model
incorporates also the sodium glucose cotransporter SGLT1, which has been
reported to be the primary glucose sensing machinery in L-cells.
The model reproduces satisfactorily electrical activity consisting of action po-
tentials in response to glucose. A role for sodium and calcium channels for the
upstroke, and activation of potassium channels for the downstroke, is demon-
strated by simulating ion channel blockage. Electrical activity is a result of
the inward current due to sodium-glucose cotransport, proving the central
role of SGLT1. K(ATP)-channel closure is shown to contribute to electrical ac-
tivity, since lower K(ATP)-conductance reduces the threshold for SGLT1
conductance where electrical activity is initiated.
The model is shown to be useful for hypothesis testing and as a starting-point
for future investigations of the signals underlying GLP-1 secretion, which
might eventually lead to new antidiabetic drugs aiming at increasing endoge-
nous GLP-1 release.
1899-Pos Board B629
Investigation of Novel Zap-70 Functionality in T Cell Signaling Pathways
using Computational Modeling
Maria P. Frushicheva1, Arthur Weiss2, Arup K. Chakraborty1.
1Massachusetts Institute of Technology, Cambdridge, MA, USA, 2University
of California San Francisco, San Francisco, CA, USA.
Aberrant regulation of cellular processes in immune systems can result in hu-
man disease. Therefore, we need a better understanding of the mechanistic


Predicting and Retrodicting Fate Patterns in C. elegans Vulval Development using Logic Programming 

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Predicting and Retrodicting Fate Patterns in C. elegans Vulval Development using Logic Programming

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