A lattice polymer study of DNA renaturation dynamics

DNA renaturation is the recombination of two complementary single strands to form a double helix. It is experimentally known that renaturation proceeds through the formation of a double stranded nucleus of several base pairs (the rate limiting step) followed by a much faster zippering. We consider a lattice polymer model undergoing Rouse dynamics and focus on the nucleation of two diffusing strands. We study numerically the dependence of various nucleation rates on the strand lengths and on an additional local nucleation barrier. When the local barrier is sufficiently high, all renaturation rates considered scale with the length as predicted by Kramers' rate theory and are also in agreement with experiments: their scaling behavior is governed by exponents describing equilibrium properties of polymers. When the local barrier is lowered renaturation occurs in a regime of genuine non-equilibrium behavior and the scaling deviates from the rate theory prediction.Comment: 13 pages, 6 figures. To appear in Journal of Statistical Mechanic

Breakdown of thermodynamic equilibrium for DNA hybridization in microarrays

Test experiments of hybridization in DNA microarrays show systematic deviations from the equilibrium isotherms. We argue that these deviations are due to the presence of a partially hybridized long-lived state, which we include in a kinetic model. Experiments confirm the model predictions for the intensity vs. free energy behavior. The existence of slow relaxation phenomena has important consequences for the specificity of microarrays as devices for the detection of a target sequence from a complex mixture of nucleic acids.Comment: 4 pages, 4 figure

The computational complexity of distance functions of two-dimensional domains

AbstractWe study the computational complexity of the distance function associated with a polynomial-time computable two-dimensional domains, in the context of the Turing machine-based complexity theory of real functions. It is proved that the distance function is not necessarily computable even if a two-dimensional domain is polynomial-time recognizable. On the other hand, if both the domain and its complement are strongly polynomial-time recognizable, then the distance function is polynomial-time computable if and only if P=NP

Anomalous zipping dynamics and forced polymer translocation

We investigate by Monte Carlo simulations the zipping and unzipping dynamics of two polymers connected by one end and subject to an attractive interaction between complementary monomers. In zipping, the polymers are quenched from a high temperature equilibrium configuration to a low temperature state, so that the two strands zip up by closing up a "Y"-fork. In unzipping, the polymers are brought from a low temperature double stranded configuration to high temperatures, so that the two strands separate. Simulations show that the unzipping time, $\tau_u$, scales as a function of the polymer length as $\tau_u \sim L$, while the zipping is characterized by anomalous dynamics $\tau_z \sim L^\alpha$ with $\alpha = 1.37(2)$. This exponent is in good agreement with simulation results and theoretical predictions for the scaling of the translocation time of a forced polymer passing through a narrow pore. We find that the exponent $\alpha$ is robust against variations of parameters and temperature, whereas the scaling of $\tau_z$ as a function of the driving force shows the existence of two different regimes: the weak forcing ($\tau_z \sim 1/F$) and strong forcing ($\tau_z$ independent of $F$) regimes. The crossover region is possibly characterized by a non-trivial scaling in $F$, matching the prediction of recent theories of polymer translocation. Although the geometrical setup is different, zipping and translocation share thus the same type of anomalous dynamics. Systems where this dynamics could be experimentally investigated are DNA (or RNA) hairpins: our results imply an anomalous dynamics for the hairpins closing times, but not for the opening times.Comment: 15 pages, 9 figure

Fractional Brownian motion and the critical dynamics of zipping polymers

We consider two complementary polymer strands of length $L$ attached by a common end monomer. The two strands bind through complementary monomers and at low temperatures form a double stranded conformation (zipping), while at high temperature they dissociate (unzipping). This is a simple model of DNA (or RNA) hairpin formation. Here we investigate the dynamics of the strands at the equilibrium critical temperature $T=T_c$ using Monte Carlo Rouse dynamics. We find that the dynamics is anomalous, with a characteristic time scaling as $\tau \sim L^{2.26(2)}$, exceeding the Rouse time $\sim L^{2.18}$. We investigate the probability distribution function, the velocity autocorrelation function, the survival probability and boundary behaviour of the underlying stochastic process. These quantities scale as expected from a fractional Brownian motion with a Hurst exponent $H=0.44(1)$. We discuss similarities and differences with unbiased polymer translocation.Comment: 7 pages, 8 figure

Effects of Chronic Atrial Fibrillation on Active and Passive Force Generation in Human Atrial Myofibrils

Rationale: Chronic atrial fibrillation (cAF) is associated with atrial contractile dysfunction. Sarcomere remodeling may contribute to this contractile disorder. Objective: Here, we use single atrial myofibrils and fast solution switching techniques to directly investigate the impact of cAF on myofilament mechanical function eliminating changes induced by the arrhythmia in atrial myocytes membranes and extracellular components. Remodeling of sarcomere proteins potentially related to the observed mechanical changes is also investigated. Methods and Results: Myofibrils were isolated from atrial samples of 15 patients in sinus rhythm and 16 patients with cAF. Active tension changes following fast increase and decrease in [Ca2+] and the sarcomere length\u2013passive tension relation were determined in the 2 groups of myofibrils. Compared to sinus rhythm myofibrils, cAF myofibrils showed (1) a reduction in maximum tension and in the rates of tension activation and relaxation; (2) an increase in myofilament Ca2+ sensitivity; (3) a reduction in myofibril passive tension. The slow \u3b2-myosin heavy chain isoform and the more compliant titin isoform N2BA were up regulated in cAF myofibrils. Phosphorylation of multiple myofilament proteins was increased in cAF as compared to sinus rhythm atrial myocardium. Conclusions: Alterations in active and passive tension generation at the sarcomere level, explained by translational and post-translational changes of multiple myofilament proteins, are part of the contractile dysfunction of human cAF and may contribute to the self-perpetuation of the arrhythmia and the development of atrial dilatation

Alpha and beta myosin isoforms and human atrial and ventricular contraction.

Human atrial and ventricular contractions have distinct mechanical characteristics including speed of contraction, volume of blood delivered and the range of pressure generated. Notably, the ventricle expresses predominantly β-cardiac myosin while the atrium expresses mostly the α-isoform. In recent years exploration of the properties of pure α- & β-myosin isoforms have been possible in solution, in isolated myocytes and myofibrils. This allows us to consider the extent to which the atrial vs ventricular mechanical characteristics are defined by the myosin isoform expressed, and how the isoform properties are matched to their physiological roles. To do this we Outline the essential feature of atrial and ventricular contraction; Explore the molecular structural and functional characteristics of the two myosin isoforms; Describe the contractile behaviour of myocytes and myofibrils expressing a single myosin isoform; Finally we outline the outstanding problems in defining the differences between the atria and ventricles. This allowed us consider what features of contraction can and cannot be ascribed to the myosin isoforms present in the atria and ventricles

Histopathological comparison of intramural coronary artery remodeling and myocardial fibrosis in obstructive versus end-stage hypertrophic cardiomyopathy

Background: Although imaging techniques have demonstrated the existence of microvascular abnormalities in hypertrophic cardiomyopathy (HCM), a detailed histopathological assessment is lacking as well as a comparison between different phases of the disease. We aimed to compare microvasculopathy and myocardial fibrosis in hypertrophic obstructive cardiomyopathy (HOCM) versus end-stage (ES) HCM. Methods: 27 myectomy specimens of HOCM patients and 30 ES-HCM explanted hearts were analyzed. Myocardial fibrosis was quantitatively determined with dedicated software and qualitatively classified as scar-like or interstitial. Intramural coronary arteries were evaluated separately according to lumen diameter: 100–500 μ versus <100 μ. Microvasculopathy assessment included the description of medial and intimal abnormalities and stenosis grading. The two subgroups were compared considering only the anterobasal septum of ES explanted hearts. Results: Median value of fibrosis in the anterobasal septum of explanted hearts was 34.6% as opposed to 10.3% of myectomy specimens (p < 0.001). Scar-like fibrosis was widely found in ES hearts while interstitial fibrosis was distinctive of HOCM (p < 0.001). All slides showed 100–500 μ microvasculopathy without any differences between subgroups in terms of lumen narrowing, extent of the disease and type of parietal involvement. Among ES hearts these lesions were associated with scar-like fibrosis (p = 0.034). <100-μ microvasculopathy was also frequent with no differences between subgroups. Conclusions: Microvasculopathy is an intrinsic feature of HCM with similar characteristics across the natural phases of the disease. Conversely, myocardial fibrosis changes over time with ES hearts showing a three-fold greater amount, mainly scar-like. ES showed a closer association between microvasculopathy and replacement fibrosis