Sensitivity Amplification in the Phosphorylation-Dephosphorylation Cycle: Nonequilibrium steady states, chemical master equation and temporal cooperativity

A new type of cooperativity termed temporal cooperativity [Biophys. Chem. 105 585-593 (2003), Annu. Rev. Phys. Chem. 58 113-142 (2007)], emerges in the signal transduction module of phosphorylation-dephosphorylation cycle (PdPC). It utilizes multiple kinetic cycles in time, in contrast to allosteric cooperativity that utilizes multiple subunits in a protein. In the present paper, we thoroughly investigate both the deterministic (microscopic) and stochastic (mesoscopic) models, and focus on the identification of the source of temporal cooperativity via comparing with allosteric cooperativity. A thermodynamic analysis confirms again the claim that the chemical equilibrium state exists if and only if the phosphorylation potential $\triangle G=0$, in which case the amplification of sensitivity is completely abolished. Then we provide comprehensive theoretical and numerical analysis with the first-order and zero-order assumptions in phosphorylation-dephosphorylation cycle respectively. Furthermore, it is interestingly found that the underlying mathematics of temporal cooperativity and allosteric cooperativity are equivalent, and both of them can be expressed by "dissociation constants", which also characterizes the essential differences between the simple and ultrasensitive PdPC switches. Nevertheless, the degree of allosteric cooperativity is restricted by the total number of sites in a single enzyme molecule which can not be freely regulated, while temporal cooperativity is only restricted by the total number of molecules of the target protein which can be regulated in a wide range and gives rise to the ultrasensitivity phenomenon.Comment: 42 pages, 13 figure

Comparison of data-driven uncertainty quantification methods for a carbon dioxide storage benchmark scenario

A variety of methods is available to quantify uncertainties arising with\-in the modeling of flow and transport in carbon dioxide storage, but there is a lack of thorough comparisons. Usually, raw data from such storage sites can hardly be described by theoretical statistical distributions since only very limited data is available. Hence, exact information on distribution shapes for all uncertain parameters is very rare in realistic applications. We discuss and compare four different methods tested for data-driven uncertainty quantification based on a benchmark scenario of carbon dioxide storage. In the benchmark, for which we provide data and code, carbon dioxide is injected into a saline aquifer modeled by the nonlinear capillarity-free fractional flow formulation for two incompressible fluid phases, namely carbon dioxide and brine. To cover different aspects of uncertainty quantification, we incorporate various sources of uncertainty such as uncertainty of boundary conditions, of conceptual model definitions and of material properties. We consider recent versions of the following non-intrusive and intrusive uncertainty quantification methods: arbitary polynomial chaos, spatially adaptive sparse grids, kernel-based greedy interpolation and hybrid stochastic Galerkin. The performance of each approach is demonstrated assessing expectation value and standard deviation of the carbon dioxide saturation against a reference statistic based on Monte Carlo sampling. We compare the convergence of all methods reporting on accuracy with respect to the number of model runs and resolution. Finally we offer suggestions about the methods' advantages and disadvantages that can guide the modeler for uncertainty quantification in carbon dioxide storage and beyond

Multiscale Granger causality

In the study of complex physical and biological systems represented by multivariate stochastic processes, an issue of great relevance is the description of the system dynamics spanning multiple temporal scales. While methods to assess the dynamic complexity of individual processes at different time scales are well-established, multiscale analysis of directed interactions has never been formalized theoretically, and empirical evaluations are complicated by practical issues such as filtering and downsampling. Here we extend the very popular measure of Granger causality (GC), a prominent tool for assessing directed lagged interactions between joint processes, to quantify information transfer across multiple time scales. We show that the multiscale processing of a vector autoregressive (AR) process introduces a moving average (MA) component, and describe how to represent the resulting ARMA process using state space (SS) models and to combine the SS model parameters for computing exact GC values at arbitrarily large time scales. We exploit the theoretical formulation to identify peculiar features of multiscale GC in basic AR processes, and demonstrate with numerical simulations the much larger estimation accuracy of the SS approach compared with pure AR modeling of filtered and downsampled data. The improved computational reliability is exploited to disclose meaningful multiscale patterns of information transfer between global temperature and carbon dioxide concentration time series, both in paleoclimate and in recent years

The Relative Humidity in an Isentropic Advection–Condensation Model: Limited Poleward Influence and Properties of Subtropical Minima

An idealized model of advection and condensation of water vapor is considered as a representation of processes influencing the humidity distribution along isentropic surfaces in the free troposphere. Results are presented for how the mean relative humidity distribution varies in response to changes in the distribution of saturation specific humidity and in the amplitude of a tropical moisture source. Changes in the tropical moisture source are found to have little effect on the relative humidity poleward of the subtropical minima, suggesting a lack of poleward influence despite much greater water vapor concentrations at lower latitudes. The subtropical minima in relative humidity are found to be located just equatorward of the inflection points of the saturation specific humidity profile along the isentropic surface. The degree of mean subsaturation is found to vary with the magnitude of the meridional gradient of saturation specific humidity when other parameters are held fixed. The atmospheric relevance of these results is investigated by comparison with the positions of the relative humidity minima in reanalysis data and by examining poleward influence of relative humidity in simulations with an idealized general circulation model. It is suggested that the limited poleward influence of relative humidity may constrain the propagation of errors in simulated humidity fields

Multifractional spacetimes, asymptotic safety and Ho\v{r}ava-Lifshitz gravity

We compare the recently formulated multifractional spacetimes with field theories of quantum gravity based on the renormalization group (RG), such as asymptotic safety and Ho\v{r}ava--Lifshitz gravity. The change of spacetime dimensionality with the probed scale is realized in both cases by an adaptation of the measurement tools ("rods") to the scale, but in different ways. In the multifractional case, by an adaptation of the position-space measure, which can be encoded into an explicit scale dependence of effective coordinates. In the case of RG-based theories, by an adaptation of the momenta. The two pictures are mapped into each other, thus presenting the fractal structure of spacetime in RG-based theories under an alternative perspective.Comment: 21 pages, 1 table. v2: discussion improved, references adde

Almost sure optimal hedging strategy

In this work, we study the optimal discretization error of stochastic integrals, in the context of the hedging error in a multidimensional It\^{o} model when the discrete rebalancing dates are stopping times. We investigate the convergence, in an almost sure sense, of the renormalized quadratic variation of the hedging error, for which we exhibit an asymptotic lower bound for a large class of stopping time strategies. Moreover, we make explicit a strategy which asymptotically attains this lower bound a.s. Remarkably, the results hold under great generality on the payoff and the model. Our analysis relies on new results enabling us to control a.s. processes, stochastic integrals and related increments.Comment: Published in at http://dx.doi.org/10.1214/13-AAP959 the Annals of Applied Probability (http://www.imstat.org/aap/) by the Institute of Mathematical Statistics (http://www.imstat.org

Probing the limits to microRNA-mediated control of gene expression

According to the `ceRNA hypothesis', microRNAs (miRNAs) may act as mediators of an effective positive interaction between long coding or non-coding RNA molecules, carrying significant potential implications for a variety of biological processes. Here, inspired by recent work providing a quantitative description of small regulatory elements as information-conveying channels, we characterize the effectiveness of miRNA-mediated regulation in terms of the optimal information flow achievable between modulator (transcription factors) and target nodes (long RNAs). Our findings show that, while a sufficiently large degree of target derepression is needed to activate miRNA-mediated transmission, (a) in case of differential mechanisms of complex processing and/or transcriptional capabilities, regulation by a post-transcriptional miRNA-channel can outperform that achieved through direct transcriptional control; moreover, (b) in the presence of large populations of weakly interacting miRNA molecules the extra noise coming from titration disappears, allowing the miRNA-channel to process information as effectively as the direct channel. These observations establish the limits of miRNA-mediated post-transcriptional cross-talk and suggest that, besides providing a degree of noise buffering, this type of control may be effectively employed in cells both as a failsafe mechanism and as a preferential fine tuner of gene expression, pointing to the specific situations in which each of these functionalities is maximized.Comment: 16 page