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