66 research outputs found
Emergence of switch-like behavior in a large family of simple biochemical networks
Bistability plays a central role in the gene regulatory networks (GRNs)
controlling many essential biological functions, including cellular
differentiation and cell cycle control. However, establishing the network
topologies that can exhibit bistability remains a challenge, in part due to the
exceedingly large variety of GRNs that exist for even a small number of
components. We begin to address this problem by employing chemical reaction
network theory in a comprehensive in silico survey to determine the capacity
for bistability of more than 40,000 simple networks that can be formed by two
transcription factor-coding genes and their associated proteins (assuming only
the most elementary biochemical processes). We find that there exist reaction
rate constants leading to bistability in ~90% of these GRN models, including
several circuits that do not contain any of the TF cooperativity commonly
associated with bistable systems, and the majority of which could only be
identified as bistable through an original subnetwork-based analysis. A
topological sorting of the two-gene family of networks based on the presence or
absence of biochemical reactions reveals eleven minimal bistable networks
(i.e., bistable networks that do not contain within them a smaller bistable
subnetwork). The large number of previously unknown bistable network topologies
suggests that the capacity for switch-like behavior in GRNs arises with
relative ease and is not easily lost through network evolution. To highlight
the relevance of the systematic application of CRNT to bistable network
identification in real biological systems, we integrated publicly available
protein-protein interaction, protein-DNA interaction, and gene expression data
from Saccharomyces cerevisiae, and identified several GRNs predicted to behave
in a bistable fashion.Comment: accepted to PLoS Computational Biolog
The capacity for multistability in small gene regulatory networks
<p>Abstract</p> <p>Background</p> <p>Recent years have seen a dramatic increase in the use of mathematical modeling to gain insight into gene regulatory network behavior across many different organisms. In particular, there has been considerable interest in using mathematical tools to understand how multistable regulatory networks may contribute to developmental processes such as cell fate determination. Indeed, such a network may subserve the formation of unicellular leaf hairs (trichomes) in the model plant <it>Arabidopsis thaliana</it>.</p> <p>Results</p> <p>In order to investigate the capacity of small gene regulatory networks to generate multiple equilibria, we present a chemical reaction network (CRN)-based modeling formalism and describe a number of methods for CRN analysis in a parameter-free context. These methods are compared and applied to a full set of one-component subnetworks, as well as a large random sample from 40,680 similarly constructed two-component subnetworks. We find that positive feedback and cooperativity mediated by transcription factor (TF) dimerization is a requirement for one-component subnetwork bistability. For subnetworks with two components, the presence of these processes increases the probability that a randomly sampled subnetwork will exhibit multiple equilibria, although we find several examples of bistable two-component subnetworks that do not involve cooperative TF-promoter binding. In the specific case of epidermal differentiation in <it>Arabidopsis</it>, dimerization of the GL3-GL1 complex and cooperative sequential binding of GL3-GL1 to the CPC promoter are each independently sufficient for bistability.</p> <p>Conclusion</p> <p>Computational methods utilizing CRN-specific theorems to rule out bistability in small gene regulatory networks are far superior to techniques generally applicable to deterministic ODE systems. Using these methods to conduct an unbiased survey of parameter-free deterministic models of small networks, and the <it>Arabidopsis </it>epidermal cell differentiation subnetwork in particular, we illustrate how future experimental research may be guided by network structure analysis.</p
Unresolved Unidentified Source Contribution to the Gamma-ray Background
The large majority of EGRET point sources remain without an identified
low-energy counterpart, and a large fraction of these sources are most likely
extragalactic. Whatever the nature of the extragalactic EGRET unidentified
sources, faint unresolved objects of the same class must have a contribution to
the diffuse extragalactic gamma-ray background (EGRB). Understanding this
component of the EGRB, along with other guaranteed contributions from known
sources, is essential if we are to use this emission to constrain exotic
high-energy physics. Here, we follow an empirical approach to estimate whether
a potential contribution of unidentified sources to the EGRB is likely to be
important, and we find that it is. Additionally, we show how upcoming GLAST
observations of EGRET unidentified sources, as well as of their fainter
counterparts, can be combined with GLAST observations of the Galactic and
extragalactic diffuse backgrounds to shed light on the nature of the EGRET
unidentified sources even without any positional association of such sources
with low-energy counterparts.Comment: 11 pages, 5 figures, submitted to Ap
New Sensitivity to Solar WIMP Annihilation using Low-Energy Neutrinos
Dark matter particles captured by the Sun through scattering may annihilate
and produce neutrinos, which escape. Current searches are for the few
high-energy neutrinos produced in the prompt decays of some final states. We
show that interactions in the solar medium lead to a large number of pions for
nearly all final states. Positive pions and muons decay at rest, producing
low-energy neutrinos with known spectra, including nuebar through neutrino
mixing. We demonstrate that Super-Kamiokande can thereby provide a new probe of
the spin-dependent WIMP-proton cross section. Compared to other methods, the
sensitivity is competitive and the uncertainties are complementary.Comment: 5 pages, 4 figure
Gamma-ray signatures of annihilation to charged leptons in dark matter substructure
Due to their higher concentrations and small internal velocities, Milky Way
subhalos can be at least as important as the smooth halo in accounting for the
GeV positron excess via dark matter annihilation. After showing how this can be
achieved in various scenarios, including in Sommerfeld models, we demonstrate
that, in this case, the diffuse inverse-Compton emission resulting from
electrons and positrons produced in substructure leads to a nearly-isotropic
signal close to the level of the isotropic GeV gamma-ray background seen by
Fermi. Moreover, we show that HESS cosmic-ray electron measurements can be used
to constrain multi-TeV internal bremsstrahlung gamma rays arising from
annihilation to charged leptons.Comment: 8 pages, 4 figures; minor updates to match published versio
Unidentified EGRET Sources and the Extragalactic Gamma-Ray Background
The large majority of EGRET point sources remain to this day without an
identified low-energy counterpart. Whatever the nature of the EGRET
unidentified sources, faint unresolved objects of the same class must have a
contribution to the diffuse gamma-ray background: if most unidentified objects
are extragalactic, faint unresolved sources of the same class contribute to the
background, as a distinct extragalactic population; on the other hand, if most
unidentified sources are Galactic, their counterparts in external galaxies will
contribute to the unresolved emission from these systems. Understanding this
component of the gamma-ray background, along with other guaranteed
contributions from known sources, is essential in any attempt to use gamma-ray
observations to constrain exotic high-energy physics. Here, we follow an
empirical approach to estimate whether a potential contribution of unidentified
sources to the extragalactic gamma-ray background is likely to be important,
and we find that it is. Additionally, we comment on how the anticipated GLAST
measurement of the diffuse gamma-ray background will change, depending on the
nature of the majority of these sources.Comment: 6 pages, 3 figures, to appear in proceedings of "The Multi-Messenger
Approach to High Energy Gamma-Ray Sources", Barcelona, 4-7 July 2006;
comments welcom
A luminosity constraint on the origin of unidentified high energy sources
The identification of point sources poses a great challenge for the high
energy community. We present a new approach to evaluate the likelihood of a set
of sources being a Galactic population based on the simple assumption that
galaxies similar to the Milky Way host comparable populations of gamma-ray
emitters. We propose a luminosity constraint on Galactic source populations
which complements existing approaches by constraining the abundance and spatial
distribution of any objects of Galactic origin, rather than focusing on the
properties of a specific candidate emitter. We use M31 as a proxy for the Milky
Way, and demonstrate this technique by applying it to the unidentified EGRET
sources. We find that it is highly improbable that the majority of the
unidentified EGRET sources are members of a Galactic halo population (e.g.,
dark matter subhalos), but that current observations do not provide any
constraints on all of these sources being Galactic objects if they reside
entirely in the disk and bulge. Applying this method to upcoming observations
by the Fermi Gamma-ray Space Telescope has the potential to exclude association
of an even larger number of unidentified sources with any Galactic source
class.Comment: 18 pages, 4 figures, to appear in JPhys
A New Approach to Searching for Dark Matter Signals in Fermi-LAT Gamma Rays
Several cosmic ray experiments have measured excesses in electrons and
positrons, relative to standard backgrounds, for energies from ~ 10 GeV - 1
TeV. These excesses could be due to new astrophysical sources, but an
explanation in which the electrons and positrons are dark matter annihilation
or decay products is also consistent. Fortunately, the Fermi-LAT diffuse gamma
ray measurements can further test these models, since the electrons and
positrons produce gamma rays in their interactions in the interstellar medium.
Although the dark matter gamma ray signal consistent with the local electron
and positron measurements should be quite large, as we review, there are
substantial uncertainties in the modeling of diffuse backgrounds and,
additionally, experimental uncertainties that make it difficult to claim a dark
matter discovery. In this paper, we introduce an alternative method for
understanding the diffuse gamma ray spectrum in which we take the intensity
ratio in each energy bin of two different regions of the sky, thereby canceling
common systematic uncertainties. For many spectra, this ratio fits well to a
power law with a single break in energy. The two measured exponent indices are
a robust discriminant between candidate models, and we demonstrate that dark
matter annihilation scenarios can predict index values that require "extreme"
parameters for background-only explanations.Comment: v1: 11 pages, 7 figures, 1 table, revtex4; v2: 13 pages, 8 figures, 1
table, revtex4, Figure 4 added, minor additions made to text, references
added, conclusions unchanged, published versio
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