Information transfer in signaling pathways : a study using coupled simulated and experimental data

Background: The topology of signaling cascades has been studied in quite some detail. However, how information is processed exactly is still relatively unknown. Since quite diverse information has to be transported by one and the same signaling cascade (e.g. in case of different agonists), it is clear that the underlying mechanism is more complex than a simple binary switch which relies on the mere presence or absence of a particular species. Therefore, finding means to analyze the information transferred will help in deciphering how information is processed exactly in the cell. Using the information-theoretic measure transfer entropy, we studied the properties of information transfer in an example case, namely calcium signaling under different cellular conditions. Transfer entropy is an asymmetric and dynamic measure of the dependence of two (nonlinear) stochastic processes. We used calcium signaling since it is a well-studied example of complex cellular signaling. It has been suggested that specific information is encoded in the amplitude, frequency and waveform of the oscillatory Ca2+-signal. Results: We set up a computational framework to study information transfer, e.g. for calcium signaling at different levels of activation and different particle numbers in the system. We stochastically coupled simulated and experimentally measured calcium signals to simulated target proteins and used kernel density methods to estimate the transfer entropy from these bivariate time series. We found that, most of the time, the transfer entropy increases with increasing particle numbers. In systems with only few particles, faithful information transfer is hampered by random fluctuations. The transfer entropy also seems to be slightly correlated to the complexity (spiking, bursting or irregular oscillations) of the signal. Finally, we discuss a number of peculiarities of our approach in detail. Conclusion: This study presents the first application of transfer entropy to biochemical signaling pathways. We could quantify the information transferred from simulated/experimentally measured calcium signals to a target enzyme under different cellular conditions. Our approach, comprising stochastic coupling and using the information-theoretic measure transfer entropy, could also be a valuable tool for the analysis of other signaling pathways

Information transfer in signaling pathways : a study using coupled simulated and experimental data

Background: The topology of signaling cascades has been studied in quite some detail. However, how information is processed exactly is still relatively unknown. Since quite diverse information has to be transported by one and the same signaling cascade (e.g. in case of different agonists), it is clear that the underlying mechanism is more complex than a simple binary switch which relies on the mere presence or absence of a particular species. Therefore, finding means to analyze the information transferred will help in deciphering how information is processed exactly in the cell. Using the information-theoretic measure transfer entropy, we studied the properties of information transfer in an example case, namely calcium signaling under different cellular conditions. Transfer entropy is an asymmetric and dynamic measure of the dependence of two (nonlinear) stochastic processes. We used calcium signaling since it is a well-studied example of complex cellular signaling. It has been suggested that specific information is encoded in the amplitude, frequency and waveform of the oscillatory Ca2+-signal. Results: We set up a computational framework to study information transfer, e.g. for calcium signaling at different levels of activation and different particle numbers in the system. We stochastically coupled simulated and experimentally measured calcium signals to simulated target proteins and used kernel density methods to estimate the transfer entropy from these bivariate time series. We found that, most of the time, the transfer entropy increases with increasing particle numbers. In systems with only few particles, faithful information transfer is hampered by random fluctuations. The transfer entropy also seems to be slightly correlated to the complexity (spiking, bursting or irregular oscillations) of the signal. Finally, we discuss a number of peculiarities of our approach in detail. Conclusion: This study presents the first application of transfer entropy to biochemical signaling pathways. We could quantify the information transferred from simulated/experimentally measured calcium signals to a target enzyme under different cellular conditions. Our approach, comprising stochastic coupling and using the information-theoretic measure transfer entropy, could also be a valuable tool for the analysis of other signaling pathways

Transition from stochastic to deterministic behavior in calcium oscillations

Simulation and modeling is becoming more and more important when studying complex biochemical systems. Most often, ordinary differential equations are employed for this purpose. However, these are only applicable when the numbers of participating molecules in the biochemical systems are large enough to be treated as concentrations. For smaller systems, stochastic simulations on discrete particle basis are more accurate. Unfortunately, there are no general rules for determining which method should be employed for exactly which problem to get the most realistic result. Therefore, we study the transition from stochastic to deterministic behavior in a widely studied system, namely the signal transduction via calcium, especially calcium oscillations. We observe that the transition occurs within a range of particle numbers, which roughly corresponds to the number of receptors and channels in the cell, and depends heavily on the attractive properties of the phase space of the respective systems dynamics. We conclude that the attractive properties of a system, expressed, e.g., by the divergence of the system, are a good measure for determining which simulation algorithm is appropriate in terms of speed and realism

Intermediate filament–membrane attachments function synergistically with actin-dependent contacts to regulate intercellular adhesive strength

By tethering intermediate filaments (IFs) to sites of intercellular adhesion, desmosomes facilitate formation of a supercellular scaffold that imparts mechanical strength to a tissue. However, the role IF–membrane attachments play in strengthening adhesion has not been directly examined. To address this question, we generated Tet-On A431 cells inducibly expressing a desmoplakin (DP) mutant lacking the rod and IF-binding domains (DPNTP). DPNTP localized to the plasma membrane and led to dissociation of IFs from the junctional plaque, without altering total or cell surface distribution of adherens junction or desmosomal proteins. However, a specific decrease in the detergent-insoluble pool of desmoglein suggested a reduced association with the IF cytoskeleton. DPNTP-expressing cell aggregates in suspension or substrate-released cell sheets readily dissociated when subjected to mechanical stress whereas controls remained largely intact. Dissociation occurred without lactate dehydrogenase release, suggesting that loss of tissue integrity was due to reduced adhesion rather than increased cytolysis. JD-1 cells from a patient with a DP COOH-terminal truncation were also more weakly adherent compared with normal keratinocytes. When used in combination with DPNTP, latrunculin A, which disassembles actin filaments and disrupts adherens junctions, led to dissociation up to an order of magnitude greater than either treatment alone. These data provide direct in vitro evidence that IF–membrane attachments regulate adhesive strength and suggest furthermore that actin- and IF-based junctions act synergistically to strengthen adhesion

Probing the mass function of halo dark matter via microlensing

The simplest interpretation of the microlensing events observed towards the Large Magellanic Clouds is that approximately half of the mass of the Milky Way halo is in the form of MAssive Compact Halo Objects with $M \sim 0.5 M_{\odot}$. It is not possible, due to limits from star counts and chemical abundance arguments, for faint stars or white dwarves to comprise such a large fraction of the halo mass. This leads to the consideration of more exotic lens candidates, such as primordial black holes, or alternative lens locations. If the lenses are located in the halo of the Milky Way, then constraining their mass function will shed light on their nature. Using the current microlensing data we find, for four halo models, the best fit parameters for delta-function, primordial black hole and various power law mass functions. The best fit primordial black hole mass functions, despite having significant finite width, have likelihoods which are similar to, and for one particular halo model greater than, those of the best fit delta functions . We then use Monte Carlo simulations to investigate the number of microlensing events necessary to determine whether the MACHO mass function has significant finite width. If the correct halo model is known, then $\sim$ 500 microlensing events will be sufficient, and will also allow determination of the mass function parameters to $\sim 5$.Comment: 28 pages including 14 figures, version to appear in ApJ, minor changes to discussio

Primordial black hole production due to preheating

During the preheating process at the end of inflation the amplification of field fluctuations can lead to the amplification of curvature perturbations. If the curvature perturbations on small scales are sufficiently large, primordial black holes (PBHs) will be overproduced. In this paper we study PBH production in the two-field preheating model with quadratic inflaton potential. We show that for many values of the inflaton mass m, and coupling g, small scale perturbations will be amplified sufficiently, before backreaction can shut off preheating, so that PBHs will be overproduced during the subsequent radiation dominated era.Comment: 5 pages, 3 eps figures. Minor changes to match version to appear in PRD as a rapid communicatio

Inclusive growth in English cities: mainstreamed or sidelined?

<p>The concept of inclusive growth is increasingly presented as offering prospects for more equitable social outcomes. However, inclusive growth is subject to a variety of interpretations and lacks definitional clarity. In England, via devolution, cities are taking on new powers for policy domains that can influence inclusive growth outcomes. This opens up opportunities for innovation to address central issues of low pay and poverty. This paper examines the extent to which inclusive growth concerns form a central or peripheral aspect in this new devolution through the content analysis of devolution agreements. It concludes that inclusive growth concerns appear to be largely sidelined.</p

Critical collapse and the primordial black hole initial mass function

It has normally been assumed that primordial black holes (PBHs) always form with mass approximately equal to the mass contained within the horizon at that time. Recent work studying the application of critical phenomena in gravitational collapse to PBH formation has shown that in fact, at a fixed time, PBHs with a range of masses are formed. When calculating the PBH initial mass function it is usually assumed that all PBHs form at the same horizon mass. It is not clear, however, that it is consistent to consider the spread in the mass of PBHs formed at a single horizon mass, whilst neglecting the range of horizon masses at which PBHs can form. We use the excursion set formalism to compute the PBH initial mass function, allowing for PBH formation at a range of horizon masses, for two forms of the density perturbation spectrum. First we examine power-law spectra with $n>1$, where PBHs form on small scales. We find that, in the limit where the number of PBHs formed is small enough to satisfy the observational constraints on their initial abundance, the mass function approaches that found by Niemeyer and Jedamzik under the assumption that all PBHs form at a single horizon mass. Second, we consider a flat perturbation spectrum with a spike at a scale corresponding to horizon mass $\sim 0.5 M_{\odot}$, and compare the resulting PBH mass function with that of the MACHOs (MAssive Compact Halo Objects) detected by microlensing observations. The predicted mass spectrum appears significantly wider than the steeply-falling spectrum found observationally.Comment: 8 pages RevTeX file with ten figures incorporated (uses RevTeX and epsf). Minor changes to dicussion onl