The fidelity of dynamic signaling by noisy biomolecular networks

This is the final version of the article. Available from Public Library of Science via the DOI in this record.Cells live in changing, dynamic environments. To understand cellular decision-making, we must therefore understand how fluctuating inputs are processed by noisy biomolecular networks. Here we present a general methodology for analyzing the fidelity with which different statistics of a fluctuating input are represented, or encoded, in the output of a signaling system over time. We identify two orthogonal sources of error that corrupt perfect representation of the signal: dynamical error, which occurs when the network responds on average to other features of the input trajectory as well as to the signal of interest, and mechanistic error, which occurs because biochemical reactions comprising the signaling mechanism are stochastic. Trade-offs between these two errors can determine the system's fidelity. By developing mathematical approaches to derive dynamics conditional on input trajectories we can show, for example, that increased biochemical noise (mechanistic error) can improve fidelity and that both negative and positive feedback degrade fidelity, for standard models of genetic autoregulation. For a group of cells, the fidelity of the collective output exceeds that of an individual cell and negative feedback then typically becomes beneficial. We can also predict the dynamic signal for which a given system has highest fidelity and, conversely, how to modify the network design to maximize fidelity for a given dynamic signal. Our approach is general, has applications to both systems and synthetic biology, and will help underpin studies of cellular behavior in natural, dynamic environments.We acknowledge support from a Medical Research Council and Engineering and Physical Sciences Council funded Fellowship in Biomedical Informatics (CGB) and a Scottish Universities Life Sciences Alliance chair in Systems Biology (PSS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Accounting Hall of Fame induction: Charles Arthur Bowsher; Accounting Hall of Fame induction: Donald James Kirk; Accounting Hall of Fame induction: William Henry Beaver

For Charles Arthur Bowsher\u27s induction, the Citation was written by Daniel L. Jensen, Professor , The Ohio State University and read by Arhtur R. Wyatt, professor, University of Illinois and a Rseponse was made by Charles A. Bowsher. For Donald James Kirk\u27s induction, Remarks were made by Paul Kolton, the Citation written by Daniel L. Jensen, Professor, Fisher College of Business, The Ohio State University and read by Paul Kolton, Stamford, Connecticut and a Response made by Donald James Kirk. For the induction of William Henry Beaver, the Remarks were made by Charles T. Horngren, Professor, Stanford University, Hall of Fame Member and the Citation was written by Daniel L. Jensen, Professor, The Ohio State University and read by Charles T. Horngren, Professor, Stanford University, Hall of Fame member and a Response was made by William H. Beaver

On the criticality of inferred models

Advanced inference techniques allow one to reconstruct the pattern of interaction from high dimensional data sets. We focus here on the statistical properties of inferred models and argue that inference procedures are likely to yield models which are close to a phase transition. On one side, we show that the reparameterization invariant metrics in the space of probability distributions of these models (the Fisher Information) is directly related to the model's susceptibility. As a result, distinguishable models tend to accumulate close to critical points, where the susceptibility diverges in infinite systems. On the other, this region is the one where the estimate of inferred parameters is most stable. In order to illustrate these points, we discuss inference of interacting point processes with application to financial data and show that sensible choices of observation time-scales naturally yield models which are close to criticality.Comment: 6 pages, 2 figures, version to appear in JSTA

Information Transfer in Gonadotropin-Releasing Hormone (GnRH) Signaling:Extracellular Signal-Regulated Kinase (ERK)-Mediated Feedback Loops Control Hormone Sensing

Cell signaling pathways are noisy communication channels, and statistical measures derived from information theory can be used to quantify the information they transfer. Here we use single cell signaling measures to calculate mutual information as a measure of information transfer via gonadotropin-releasing hormone (GnRH) receptors (GnRHR) to extracellular signal-regulated kinase (ERK) or nuclear factor of activated T-cells (NFAT). This revealed mutual information values <1 bit, implying that individual GnRH-responsive cells cannot unambiguously differentiate even two equally probable input concentrations. Addressing possible mechanisms for mitigation of information loss, we focused on the ERK pathway and developed a stochastic activation model incorporating negative feedback and constitutive activity. Model simulations revealed interplay between fast (min) and slow (min-h) negative feedback loops with maximal information transfer at intermediate feedback levels. Consistent with this, experiments revealed that reducing negative feedback (by expressing catalytically inactive ERK2) and increasing negative feedback (by Egr1-driven expression of dual-specificity phosphatase 5 (DUSP5)) both reduced information transfer from GnRHR to ERK. It was also reduced by blocking protein synthesis (to prevent GnRH from increasing DUSP expression) but did not differ for different GnRHRs that do or do not undergo rapid homologous desensitization. Thus, the first statistical measures of information transfer via these receptors reveals that individual cells are unreliable sensors of GnRH concentration and that this reliability is maximal at intermediate levels of ERK-mediated negative feedback but is not influenced by receptor desensitization

PRIVATE SAVINGS IN TRANSITION ECONOMIES: ARE THERE TERMS OF TRADE SHOCKS?

The paper examines the impact of terms of trade shocks on private savings in the transition economies after accounting for the effect of other determinants. Economic agents in the transition economies are subject to tight credit constraints which are more pronounced during bad state of nature. Thus, adverse shocks to commodity prices in the world market can force them to reduce savings by a larger amount than they would otherwise have. Empirical analysis using a dynamic panel model and data from twenty one transition economies confirm that most of the determinants of savings identified in the literature also apply to the transition economies. Favorable movements in both the permanent and transitory components of the terms of trade have a significant positive impact on private savings with transitory movements having a larger impact than the permanent component. This reflects the lack of access to foreign borrowing that many of the transition economies have faced during the last decade. Although the impact of terms of trade shocks are found to be asymmetric, the magnitude of the impact appears to be small. The results are robust for alternative estimators, determinants, and country groupings.http://deepblue.lib.umich.edu/bitstream/2027.42/39958/3/wp572.pd

Non-parametric kernel estimation for symmetric Hawkes processes. Application to high frequency financial data

We define a numerical method that provides a non-parametric estimation of the kernel shape in symmetric multivariate Hawkes processes. This method relies on second order statistical properties of Hawkes processes that relate the covariance matrix of the process to the kernel matrix. The square root of the correlation function is computed using a minimal phase recovering method. We illustrate our method on some examples and provide an empirical study of the estimation errors. Within this framework, we analyze high frequency financial price data modeled as 1D or 2D Hawkes processes. We find slowly decaying (power-law) kernel shapes suggesting a long memory nature of self-excitation phenomena at the microstructure level of price dynamics.Comment: 6 figure

Evolution of Sex-Specific Traits through Changes in HOX-Dependent doublesex Expression

Analysis in Drosophila suggests that evolutionary changes in the spatial regulation of the transcription factor doublesex play a key role in the origin, diversification, and loss of sex-specific structures

Multiplexing information flow through dynamic signalling systems

We consider how a signalling system can act as an information hub by multiplexing information arising from multiple signals. We formally define multiplexing, mathematically characterise which systems can multiplex and how well they can do it. While the results of this paper are theoretical, to motivate the idea of multiplexing, we provide experimental evidence that tentatively suggests that the NF-κB transcription factor can multiplex information about changes in multiple signals. We believe that our theoretical results may resolve the apparent paradox of how a system like NF-κB that regulates cell fate and inflammatory signalling in response to diverse stimuli can appear to have the low information carrying capacity suggested by recent studies on scalar signals. In carrying out our study, we introduce new methods for the analysis of large, nonlinear stochastic dynamic models, and develop computational algorithms that facilitate the calculation of fundamental constructs of information theory such as Kullback–Leibler divergences and sensitivity matrices, and link these methods to a new theory about multiplexing information. We show that many current models such as those of the NF-κB system cannot multiplex effectively and provide models that overcome this limitation using post-transcriptional modifications

Host-specific pit-forming epizoans on Silurian crinoids

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75404/1/j.1502-3931.1978.tb01229.x.pd

A framework for parameter estimation and model selection from experimental data in systems biology using approximate Bayesian computation.

As modeling becomes a more widespread practice in the life sciences and biomedical sciences, researchers need reliable tools to calibrate models against ever more complex and detailed data. Here we present an approximate Bayesian computation (ABC) framework and software environment, ABC-SysBio, which is a Python package that runs on Linux and Mac OS X systems and that enables parameter estimation and model selection in the Bayesian formalism by using sequential Monte Carlo (SMC) approaches. We outline the underlying rationale, discuss the computational and practical issues and provide detailed guidance as to how the important tasks of parameter inference and model selection can be performed in practice. Unlike other available packages, ABC-SysBio is highly suited for investigating, in particular, the challenging problem of fitting stochastic models to data. In order to demonstrate the use of ABC-SysBio, in this protocol we postulate the existence of an imaginary reaction network composed of seven interrelated biological reactions (involving a specific mRNA, the protein it encodes and a post-translationally modified version of the protein), a network that is defined by two files containing 'observed' data that we provide as supplementary information. In the first part of the PROCEDURE, ABC-SysBio is used to infer the parameters of this system, whereas in the second part we use ABC-SysBio's relevant functionality to discriminate between two different reaction network models, one of them being the 'true' one. Although computationally expensive, the additional insights gained in the Bayesian formalism more than make up for this cost, especially in complex problems