Comment on "Why is the DNA denaturation transition first order?"

In this comment we argue that while the conclusions in the original paper (Y. Kafri, D. Mukamel and L. Peliti, Phys. Rev. Lett. 85, 4988 (2000)) are correct for asymptotically long DNA chains, they do not apply to the chains used in typical experiments. In the added last paragraph, we point out that for real DNA the average distance between denatured loops is not of the order of the persistence length of a single-stranded chain but much larger. This corroborates our reasoning that the double helix between loops is quite rigid, and thereby our conclusion.Comment: 1 page, REVTeX. Last paragraph adde

Exons, introns and DNA thermodynamics

The genes of eukaryotes are characterized by protein coding fragments, the exons, interrupted by introns, i.e. stretches of DNA which do not carry any useful information for the protein synthesis. We have analyzed the melting behavior of randomly selected human cDNA sequences obtained from the genomic DNA by removing all introns. A clear correspondence is observed between exons and melting domains. This finding may provide new insights in the physical mechanisms underlying the evolution of genes.Comment: 4 pages, 8 figures - Final version as published. See also Phys. Rev. Focus 15, story 1

Becoming a ‘Real’ Smoker: Cultural Capital in Young Women\u27s Accounts of Smoking and Other Substance Use

This paper draws from a qualitative study of tobacco use by young women in Toronto, Canada. Narrative interviews were used to understand the multiple roles and functions of smoking within the everyday lives of female adolescents. Guided by a Bourdieusian theoretical framework this study employed the core construct of cultural capital in order to position tobacco and other substance use as field‐specific capital that young women accumulate while navigating the social worlds of adolescence. Departing from the psychosocial or peer‐influence models that inform the majority of tobacco research with young people, this analysis provides a nuanced understanding of how smoking, drinking, using drugs are much more than simple forms of teenage experimentation or rebellion, but can also serve as key resources for defining the self, acquiring status and making social distinctions within adolescent social worlds. In this context it is also argued that initiation into substance use practices is a way that young women demonstrate and develop social and cultural competencies

Roles of stiffness and excluded volume in DNA denaturation

The nature and the universal properties of DNA thermal denaturation are investigated by Monte Carlo simulations. For suitable lattice models we determine the exponent c describing the decay of the probability distribution of denaturated loops of length l, $P \sim l^{-c}$. If excluded volume effects are fully taken into account, c= 2.10(4) is consistent with a first order transition. The stiffness of the double stranded chain has the effect of sharpening the transition, if it is continuous, but not of changing its order and the value of the exponent c, which is also robust with respect to inclusion of specific base-pair sequence heterogeneities.Comment: RevTeX 4 Pages and 4 PostScript figures included. Final version as publishe

Multiple timescales in a model for DNA denaturation dynamics

The denaturation dynamics of a long double-stranded DNA is studied by means of a model of the Poland-Scheraga type. We note that the linking of the two strands is a locally conserved quantity, hence we introduce local updates that respect this symmetry. Linking dissipation via untwist is allowed only at the two ends of the double strand. The result is a slow denaturation characterized by two time scales that depend on the chain length $L$. In a regime up to a first characteristic time $\tau_1\sim L^{2.15}$ the chain embodies an increasing number of small bubbles. Then, in a second regime, bubbles coalesce and form entropic barriers that effectively trap residual double-stranded segments within the chain, slowing down the relaxation to fully molten configurations, which takes place at $\tau_2\sim L^3$. This scenario is different from the picture in which the helical constraints are neglected.Comment: 9 pages, 5 figure

A stitch in time: Efficient computation of genomic DNA melting bubbles

Background: It is of biological interest to make genome-wide predictions of the locations of DNA melting bubbles using statistical mechanics models. Computationally, this poses the challenge that a generic search through all combinations of bubble starts and ends is quadratic. Results: An efficient algorithm is described, which shows that the time complexity of the task is O(NlogN) rather than quadratic. The algorithm exploits that bubble lengths may be limited, but without a prior assumption of a maximal bubble length. No approximations, such as windowing, have been introduced to reduce the time complexity. More than just finding the bubbles, the algorithm produces a stitch profile, which is a probabilistic graphical model of bubbles and helical regions. The algorithm applies a probability peak finding method based on a hierarchical analysis of the energy barriers in the Poland-Scheraga model. Conclusions: Exact and fast computation of genomic stitch profiles is thus feasible. Sequences of several megabases have been computed, only limited by computer memory. Possible applications are the genome-wide comparisons of bubbles with promotors, TSS, viral integration sites, and other melting-related regions.Comment: 16 pages, 10 figure

Stacking Interactions in Denaturation of DNA Fragments

A mesoscopic model for heterogeneous DNA denaturation is developed in the framework of the path integral formalism. The base pair stretchings are treated as one-dimensional, time dependent paths contributing to the partition function. The size of the paths ensemble, which measures the degree of cooperativity of the system, is computed versus temperature consistently with the model potential physical requirements. It is shown that the ensemble size strongly varies with the molecule backbone stiffness providing a quantitative relation between stacking and features of the melting transition. The latter is an overall smooth crossover which begins from the \emph{adenine-thymine} rich portions of the fragment. The harmonic stacking coupling shifts, along the $T$-axis, the occurrence of the multistep denaturation but it does not change the character of the crossover. The methods to compute the fractions of open base pairs versus temperature are discussed: by averaging the base pair displacements over the path ensemble we find that such fractions signal the multisteps of the transition in good agreement with the indications provided by the specific heat plots.Comment: European Physical Journal E (2011) in pres

Hysteresis in Pressure-Driven DNA Denaturation

In the past, a great deal of attention has been drawn to thermal driven denaturation processes. In recent years, however, the discovery of stress-induced denaturation, observed at the one-molecule level, has revealed new insights into the complex phenomena involved in the thermo-mechanics of DNA function. Understanding the effect of local pressure variations in DNA stability is thus an appealing topic. Such processes as cellular stress, dehydration, and changes in the ionic strength of the medium could explain local pressure changes that will affect the molecular mechanics of DNA and hence its stability. In this work, a theory that accounts for hysteresis in pressure-driven DNA denaturation is proposed. We here combine an irreversible thermodynamic approach with an equation of state based on the Poisson-Boltzmann cell model. The latter one provides a good description of the osmotic pressure over a wide range of DNA concentrations. The resulting theoretical framework predicts, in general, the process of denaturation and, in particular, hysteresis curves for a DNA sequence in terms of system parameters such as salt concentration, density of DNA molecules and temperature in addition to structural and configurational states of DNA. Furthermore, this formalism can be naturally extended to more complex situations, for example, in cases where the host medium is made up of asymmetric salts or in the description of the (helical-like) charge distribution along the DNA molecule. Moreover, since this study incorporates the effect of pressure through a thermodynamic analysis, much of what is known from temperature-driven experiments will shed light on the pressure-induced melting issue

Stochastic Modeling of B Lymphocyte Terminal Differentiation and Its Suppression by Dioxin

<p>Abstract</p> <p>Background</p> <p>Upon antigen encounter, naïve B lymphocytes differentiate into antibody-secreting plasma cells. This humoral immune response is suppressed by the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other dioxin-like compounds, which belong to the family of aryl hydrocarbon receptor (AhR) agonists.</p> <p>Results</p> <p>To achieve a better understanding of the immunotoxicity of AhR agonists and their associated health risks, we have used computer simulations to study the behavior of the gene regulatory network underlying B cell terminal differentiation. The core of this network consists of two coupled double-negative feedback loops involving transcriptional repressors Bcl-6, Blimp-1, and Pax5. Bifurcation analysis indicates that the feedback network can constitute a bistable system with two mutually exclusive transcriptional profiles corresponding to naïve B cells and plasma cells. Although individual B cells switch to the plasma cell state in an all-or-none fashion when stimulated by the polyclonal activator lipopolysaccharide (LPS), stochastic fluctuations in gene expression make the switching event probabilistic, leading to heterogeneous differentiation response among individual B cells. Moreover, stochastic gene expression renders the dose-response behavior of a population of B cells substantially graded, a result that is consistent with experimental observations. The steepness of the dose response curve for the number of plasma cells formed vs. LPS dose, as evaluated by the apparent Hill coefficient, is found to be inversely correlated to the noise level in Blimp-1 gene expression. Simulations illustrate how, through AhR-mediated repression of the AP-1 protein, TCDD reduces the probability of LPS-stimulated B cell differentiation. Interestingly, stochastic simulations predict that TCDD may destabilize the plasma cell state, possibly leading to a reversal to the B cell phenotype.</p> <p>Conclusion</p> <p>Our results suggest that stochasticity in gene expression, which renders a graded response at the cell population level, may have been exploited by the immune system to launch humoral immune response of a magnitude appropriately tuned to the antigen dose. In addition to suppressing the initiation of the humoral immune response, dioxin-like compounds may also disrupt the maintenance of the acquired immunity.</p

Mapping new theoretical and methodological terrain for knowledge translation: contributions from critical realism and the arts

Abstract Background Clinical practice guidelines have been a popular tool for the improvement of health care through the implementation of evidence from systematic research. Yet, it is increasingly clear that knowledge alone is insufficient to change practice. The social, cultural, and material contexts within which practice occurs may invite or reject innovation, complement or inhibit the activities required for success, and sustain or alter adherence to entrenched practices. However, knowledge translation (KT) models are limited in providing insight about how and why contextual contingencies interact, the causal mechanisms linking structural aspects of context and individual agency, and how these mechanisms influence KT. Another limitation of KT models is the neglect of methods to engage potential adopters of the innovation in critical reflection about aspects of context that influence practice, the relevance and meaning of innovation in the context of practice, and the identification of strategies for bringing about meaningful change. Discussion This paper presents a KT model, the Critical Realism and the Arts Research Utilization Model (CRARUM), that combines critical realism and arts-based methodologies. Critical realism facilitates understanding of clinical settings by providing insight into the interrelationship between its structures and potentials, and individual action. The arts nurture empathy, and can foster reflection on the ways in which contextual factors influence and shape clinical practice, and how they may facilitate or impede change. The combination of critical realism and the arts within the CRARUM model promotes the successful embedding of interventions, and greater impact and sustainability. Conclusion CRARUM has the potential to strengthen the science of implementation research by addressing the complexities of practice settings, and engaging potential adopters to critically reflect on existing and proposed practices and strategies for sustaining change.</p