Using a continuum model to predict closure time of gaps in intestinal epithelial cell layers

A two-dimensional continuum model of collective cell migration is used to predict the closure of gaps in intestinal epithelial cell layers. The model assumes that cell migration is governed by lamellipodia formation, cell-cell adhesion, and cell-substrate adhesion. Model predictions of the gap edge position and complete gap closure time are compared with experimental measures from cell layer scratch assays (also called scratch wound assays). The goal of the study is to combine experimental observations with mathematical descriptions of cell motion to identify effects of gap shape and area on closure time and to propose a method that uses a simple measure (e.g., area) to predict overall gap closure time early in the closure process. Gap closure time is shown to increase linearly with increasing gap area; however, gaps of equal areas but different aspect ratios differ greatly in healing time. Previous methods that calculate overall healing time according to the absolute or percent change in gap area assume that the gap area changes at a constant rate and typically underestimate gap closure time. In this study, data from scratch assays suggest that the rate of change of area is proportional to the first power or square root power of area

DNA cyclization and looping in the wormlike limit: normal modes and the validity of the harmonic approximation

For much of the last three decades Monte Carlo-simulation methods have been the standard approach for accurately calculating the cyclization probability, $J$, or J factor, for DNA models having sequence-dependent bends or inhomogeneous bending flexibility. Within the last ten years, however, approaches based on harmonic analysis of semi-flexible polymer models have been introduced, which offer much greater computational efficiency than Monte Carlo techniques. These methods consider the ensemble of molecular conformations in terms of harmonic fluctuations about a well-defined elastic-energy minimum. However, the harmonic approximation is only applicable for small systems, because the accessible conformation space of larger systems is increasingly dominated by anharmonic contributions. In the case of computed values of the J factor, deviations of the harmonic approximation from the exact value of $J$ as a function of DNA length have not been characterized. Using a recent, numerically exact method that accounts for both anharmonic and harmonic contributions to $J$ for wormlike chains of arbitrary size, we report here the apparent error that results from neglecting anharmonic behavior. For wormlike chains having contour lengths less than four times the persistence length the error in $J$ arising from the harmonic approximation is generally small, amounting to free energies less than the thermal energy, $k_B T$. For larger systems, however, the deviations between harmonic and exact $J$ values increase approximately linearly with size.Comment: 23 pages, 6 figures. Typos corrected. Manuscript improve

Sequence Dependence of Transcription Factor-Mediated DNA Looping

DNA is subject to large deformations in a wide range of biological processes. Two key examples illustrate how such deformations influence the readout of the genetic information: the sequestering of eukaryotic genes by nucleosomes, and DNA looping in transcriptional regulation in both prokaryotes and eukaryotes. These kinds of regulatory problems are now becoming amenable to systematic quantitative dissection with a powerful dialogue between theory and experiment. Here we use a single-molecule experiment in conjunction with a statistical mechanical model to test quantitative predictions for the behavior of DNA looping at short length scales, and to determine how DNA sequence affects looping at these lengths. We calculate and measure how such looping depends upon four key biological parameters: the strength of the transcription factor binding sites, the concentration of the transcription factor, and the length and sequence of the DNA loop. Our studies lead to the surprising insight that sequences that are thought to be especially favorable for nucleosome formation because of high flexibility lead to no systematically detectable effect of sequence on looping, and begin to provide a picture of the distinctions between the short length scale mechanics of nucleosome formation and looping.Comment: Nucleic Acids Research (2012); Published version available at http://nar.oxfordjournals.org/cgi/content/abstract/gks473? ijkey=6m5pPVJgsmNmbof&keytype=re

Tops and Writhing DNA

The torsional elasticity of semiflexible polymers like DNA is of biological significance. A mathematical treatment of this problem was begun by Fuller using the relation between link, twist and writhe, but progress has been hindered by the non-local nature of the writhe. This stands in the way of an analytic statistical mechanical treatment, which takes into account thermal fluctuations, in computing the partition function. In this paper we use the well known analogy with the dynamics of tops to show that when subjected to stretch and twist, the polymer configurations which dominate the partition function admit a local writhe formulation in the spirit of Fuller and thus provide an underlying justification for the use of Fuller's "local writhe expression" which leads to considerable mathematical simplification in solving theoretical models of DNA and elucidating their predictions. Our result facilitates comparison of the theoretical models with single molecule micromanipulation experiments and computer simulations.Comment: 17 pages two figure

Slow-Fast Analysis of a Multi-Group Asset Flow Model with Implications for the Dynamics of Wealth

The multi-group asset flow model is a nonlinear dynamical system originally developed as a tool for understanding the behavioral foundations of market phenomena such as flash crashes and price bubbles. In this paper we use a modification of this model to analyze the dynamics of a single-asset market in situations when the trading rates of investors (i.e., their desire to exchange stock for cash) are prescribed ahead of time and independent of the state of the market. Under the assumption of fast trading compared to the time-rate of change in the prescribed trading rates we decompose the dynamics of the system to fast and slow components. We use the model to derive a variety of observations regarding the dynamics of price and investors’ wealth, and the dependence of these quantities on the prescribed trading rates. In particular, we show that strategies with constant trading rates, which represent the well-known constant-rebalanced portfolio (CRP) strategies, are optimal in the sense that they minimize investment risks. In contrast, we show that investors pursuing non-CRP strategies are at risk of loss of wealth, as a result of the slow system not being integrable in the sense that cyclic trading rates do not always result in periodic price variations

Lac repressor mediated DNA looping: Monte Carlo simulation of constrained DNA molecules complemented with current experimental results

Tethered particle motion (TPM) experiments can be used to detect time-resolved loop formation in a single DNA molecule by measuring changes in the length of a DNA tether. Interpretation of such experiments is greatly aided by computer simulations of DNA looping which allow one to analyze the structure of the looped DNA and estimate DNA-protein binding constants specific for the loop formation process. We here present a new Monte Carlo scheme for accurate simulation of DNA configurations subject to geometric constraints and apply this method to Lac repressor mediated DNA looping, comparing the simulation results with new experimental data obtained by the TPM technique. Our simulations, taking into account the details of attachment of DNA ends and fluctuations of the looped subsegment of the DNA, reveal the origin of the double-peaked distribution of RMS values observed by TPM experiments by showing that the average RMS value for anti-parallel loop types is smaller than that of parallel loop types. The simulations also reveal that the looping probabilities for the anti-parallel loop types are significantly higher than those of the parallel loop types, even for loops of length 600 and 900 base pairs, and that the correct proportion between the heights of the peaks in the distribution can only be attained when loops with flexible Lac repressor conformation are taken into account. Comparison of the in silico and in vitro results yields estimates for the dissociation constants characterizing the binding affinity between O1 and Oid DNA operators and the dimeric arms of the Lac repressor. © 2014 Biton et al

Nonlinear Dynamics and Stability In a Multigroup Asset Flow Model

The multigroup asset flow model for asset price dynamics incorporates distinct motivations, e. g., trend and fundamentals (value) and assessments of value by different groups of investors. The stability and bifurcation properties are established for the curve of equilibria. We prove that if all trader groups focus on fundamentals, then all equilibria are stable. For systems in which there is one fundamental and one momentum (trend) group, we establish conditions for stability. In particular, an equilibrium that is stable becomes unstable as the time scale on which momentum investors focus diminishes. The computations examine the excursions, which we define as the maximum deviation in price of the trajectory from its initial price located near the curve of equilibria

Interplay of Protein and DNA Structure Revealed in Simulations of the lac Operon

The E. coli Lac repressor is the classic textbook example of a protein that attaches to widely spaced sites along a genome and forces the intervening DNA into a loop. The short loops implicated in the regulation of the lac operon suggest the involvement of factors other than DNA and repressor in gene control. The molecular simulations presented here examine two likely structural contributions to the in-vivo looping of bacterial DNA: the distortions of the double helix introduced upon association of the highly abundant, nonspecific nucleoid protein HU and the large-scale deformations of the repressor detected in low-resolution experiments. The computations take account of the three-dimensional arrangements of nucleotides and amino acids found in crystal structures of DNA with the two proteins, the natural rest state and deformational properties of protein-free DNA, and the constraints on looping imposed by the conformation of the repressor and the orientation of bound DNA. The predicted looping propensities capture the complex, chain-length-dependent variation in repression efficacy extracted from gene expression studies and in vitro experiments and reveal unexpected chain-length-dependent variations in the uptake of HU, the deformation of repressor, and the folding of DNA. Both the opening of repressor and the presence of HU, at levels approximating those found in vivo, enhance the probability of loop formation. HU affects the global organization of the repressor and the opening of repressor influences the levels of HU binding to DNA. The length of the loop determines whether the DNA adopts antiparallel or parallel orientations on the repressor, whether the repressor is opened or closed, and how many HU molecules bind to the loop. The collective behavior of proteins and DNA is greater than the sum of the parts and hints of ways in which multiple proteins may coordinate the packaging and processing of genetic information. © 2013 Czapla et al

Can You Cash In on Sin? An Analysis of Sin Stock Performance in Developed Markets

This thesis addresses the debate in the literature regarding the existence of a sin premium in equity markets. Focusing on three categories of sin stocks- alcohol, tobacco and gambling- we analayse data from global developed markets spanning the period 2000 to 2023. Using monthly returns, we construct value-weighted portfolios of sin stocks and comparable non-sin stocks. Through regression analyses, we evaluate the risk-adjusted performance of these portfolios using the Fama-French three-factor model, the Carhart four-factor model, and the Fama-French five-factor model, both with and without momentum. To assess whether a sin premium exist and if it can be attributed to the unique characteristics of the sin stocks, we estimate and analyse alphas through a dual approach: (i) the excess return of the sin portfolio (RSin − Rf), and (ii) a long-short strategy by going long in the sin portfolio and short in the comparable portfolio (RSin −RComp). Our findings reveal no significant alphas, indicating that the excess returns of sin stocks can largely be explained by conventional risk factors rather than a sin effect. These results challenges the notion of a distinct sin premium and emphasize the efficiency of modern equity markets- reminding investors that even the most controversial assets rarely escape the fundamental tenets of rational pricing