Toward realistic modeling of dynamic processes in cell signaling: quantification of macromolecular crowding effects

One of the major factors distinguishing molecular processes in vivo from biochemical experiments in vitro is the effect of the environment produced by macromolecular crowding in the cell. To achieve a realistic modeling of processes in the living cell based on biochemical data, it becomes necessary, therefore, to consider such effects. We describe a protocol based on Brownian dynamics simulation to characterize and quantify the effect of various forms of crowding on diffusion and bimolecular association in a simple model of interacting hard spheres. We show that by combining the elastic collision method for hard spheres and the mean field approach for hydrodynamic interaction (HI), our simulations capture the correct dynamics of a monodisperse system. The contributions from excluded volume effect and HI to the crowding effect are thus quantified. The dependence of the results on size distribution of each component in the system is illustrated, and the approach is applied as well to the crowding effect on electrostatic-driven association in both neutral and charged environments; values for effective diffusion constants and association rates are obtained for the specific conditions. The results from our simulation approach can be used to improve the modeling of cell signaling processes without additional computational burdens.     

On the precision of quasi steady state assumptions in stochastic dynamics

Many biochemical networks have complex multidimensional dynamics and there is a long history of methods that have been used for dimensionality reduction for such reaction networks. Usually a deterministic mass action approach is used; however, in small volumes, there are significant fluctuations from the mean which the mass action approach cannot capture. In such cases stochastic simulation methods should be used. In this paper, we evaluate the applicability of one such dimensionality reduction method, the quasi-steady state approximation (QSSA) [L. Menten and M. Michaelis, "Die kinetik der invertinwirkung," Biochem. Z 49, 333369 (1913)] for dimensionality reduction in case of stochastic dynamics. First, the applicability of QSSA approach is evaluated for a canonical system of enzyme reactions. Application of QSSA to such a reaction system in a deterministic setting leads to Michaelis-Menten reduced kinetics which can be used to derive the equilibrium concentrations of the reaction species. In the case of stochastic simulations, however, the steady state is characterized by fluctuations around the mean equilibrium concentration. Our analysis shows that a QSSA based approach for dimensionality reduction captures well the mean of the distribution as obtained from a full dimensional simulation but fails to accurately capture the distribution around that mean. Moreover, the QSSA approximation is not unique. We have then extended the analysis to a simple bistable biochemical network model proposed to account for the stability of synaptic efficacies; the substrate of learning and memory [J. E. Lisman, "A mechanism of memory storage insensitive to molecular turnover: A bistable autophosphorylating kinase," Proc. Natl. Acad. Sci. U.S.A. 82, 3055-3057 (1985)]. Our analysis shows that a QSSA based dimensionality reduction method results in errors as big as two orders of magnitude in predicting the residence times in the two stable states.     

Mathematics education research, its nature, and its purpose: A discussion of Lester's paper

This commentary discusses the framework for mathematics education researchers outlined in Lester's (2005) paper. The author reacts to (a) Lester's concern about the current political forces in the U.S. to define scientific research in education rigidly, and offers a possible reason—apart from political ideology—for the emergence of hese forces; (b) recapitulates lester's outline and model for theory-based research in mathematics education, and intereprets Lester's paper as a call to the MER community to respond to the current political forces that (inappropriately) shape our field and (c) addresses the role of mathematical context in MER, a topic absent from the paper's narrative.     

The effect of order and co‐ordination of the problem quantities on the difficulty of missing value proportion problems

One variable of the solution process of missing value proportion problems is the order co‐ordination of the missing value and the units of measure. A scheme is devised to analyse the syntactical structure of such problems in a standard self‐paced college arithmetic text. Student performance is assessed to determine the impact of this co‐ordination on problem difficulty.     

Weak Convergence of Weighted Empirical U-Statistics Processes for Dependent Random Variables

A weak convergence of the weighted empirical U-statistic with respect to the Skorohod topology is obtained for absolutely regular random variables. It is a generalization of the results of F. H, Ruymgaart and M. C. A. van Zuijlen (1991, J. Statist. Plann. Inference) for i.i.d. random variables.     

A Cramér-von Mises test for symmetry of the error distribution in asymptotically stationary stochastic models

This paper has to do with a Cramér-von Mises test for symmetry of the error distribution in a class of absolutely regular and non-necessarily stationary heteroscedastic models. The test statistic is based on the empirical characteristic function. Its convergence, as well as that of the residual-based empirical distribution function are established. From these results, the null cumulative distribution function of the test statistic is approximated. A simulation experiment shows that the test performs well on the examples tested.     

Parametric excitation of traveling waves in a circular non-dispersive medium

This paper discusses a special type of propagating waves created by parametric excitation in a circular taught string. The string, being a non-dispersive medium propagates deformations in a similar manner to electromagnetic waves in vacuum, both have simple wavelength–frequency relationship that play an important role here. Nonlinear equations are derived under the assumption of finite deformations, whose solution produces a square-wave like, limited-amplitude, traveling wave. Closed-form expressions are obtained for the parametric excitation characteristics of the nonlinear system and the steady-state traveling waves are described by a generalized eigenvalue problem. The latter relates the nonlinear elongation of the neutral axis to the participating wavelengths forming the propagating wave. Detailed numerical simulations are provided to validate the solution and to illustrate graphically the waveforms. It is shown that propagating sinusoidal parametric excitation gives rise to various square-wave like deformation shapes which a unique phenomenon is arising in non-dispersive media.     

Double negative: The necessity principle,commognitive conflict,and negative number operations

We use the DNR framework to analyze a classroom episode introducing negative integer exponents, comparing and contrasting our analysis with Sfard's recent commognitive analysis of a similar episode concerning multiplication of signed numbers. Students in both episodes objected to the standard rules for integer products or exponents, and they persisted in preferring their own rules even after the teacher justified the standard ones. We examine how pattern-based justifications may not address students’ intellectual needs, and we suggest other pedagogical strategies that promote student reasoning.