Topological effects in ring polymers: A computer simulation study

Unconcatenated, unknotted polymer rings in the melt are subject to strong interactions with neighboring chains due to the presence of topological constraints. We study this by computer simulation using the bond-fluctuation algorithm for chains with up to N=512 statistical segments at a volume fraction \Phi=0.5 and show that rings in the melt are more compact than gaussian chains. A careful finite size analysis of the average ring size R \propto N^{\nu} yields an exponent \nu \approx 0.39 \pm 0.03 in agreement with a Flory-like argument for the topologica interactions. We show (using the same algorithm) that the dynamics of molten rings is similar to that of linear chains of the same mass, confirming recent experimental findings. The diffusion constant varies effectively as D_{N} \propto N^{-1.22(3) and is slightly higher than that of corresponding linear chains. For the ring sizes considered (up to 256 statistical segments) we find only one characteristic time scale \tau_{ee} \propto N^{2.0(2); this is shown by the collapse of several mean-square displacements and correlation functions onto corresponding master curves. Because of the shrunken state of the chain, this scaling is not compatible with simple Rouse motion. It applies for all sizes of ring studied and no sign of a crossover to any entangled regime is found.Comment: 20 Pages,11 eps figures, Late

Volume Effects on the Glass Transition Dynamics

The role of jamming (steric constraints) and its relationship to the available volume is addressed by examining the effect that certain modifications of a glass-former have on the ratio of its isochoric and isobaric activation enthalpies. This ratio reflects the relative contribution of volume (density) and temperature (thermal energy) to the temperature-dependence of the relaxation times of liquids and polymers. We find that an increase in the available volume confers a stronger volume-dependence to the relaxation dynamics, a result at odds with free volume interpretations of the glass transition.Comment: 9 pages 5 figure

Evolution favors protein mutational robustness in sufficiently large populations

BACKGROUND: An important question is whether evolution favors properties such as mutational robustness or evolvability that do not directly benefit any individual, but can influence the course of future evolution. Functionally similar proteins can differ substantially in their robustness to mutations and capacity to evolve new functions, but it has remained unclear whether any of these differences might be due to evolutionary selection for these properties. RESULTS: Here we use laboratory experiments to demonstrate that evolution favors protein mutational robustness if the evolving population is sufficiently large. We neutrally evolve cytochrome P450 proteins under identical selection pressures and mutation rates in populations of different sizes, and show that proteins from the larger and thus more polymorphic population tend towards higher mutational robustness. Proteins from the larger population also evolve greater stability, a biophysical property that is known to enhance both mutational robustness and evolvability. The excess mutational robustness and stability is well described by existing mathematical theories, and can be quantitatively related to the way that the proteins occupy their neutral network. CONCLUSIONS: Our work is the first experimental demonstration of the general tendency of evolution to favor mutational robustness and protein stability in highly polymorphic populations. We suggest that this phenomenon may contribute to the mutational robustness and evolvability of viruses and bacteria that exist in large populations

Inferring stabilizing mutations from protein phylogenies : application to influenza hemagglutinin

One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution

Measurement of XUV-absorption spectra of ZnS radiatively heated foils

Time-resolved absorption of zinc sulfide (ZnS) and aluminum in the XUV-range has been measured. Thin foils in conditions close to local thermodynamic equilibrium were heated by radiation from laser-irradiated gold spherical cavities. Analysis of the aluminum foil radiative hydrodynamic expansion, based on the detailed atomic calculations of its absorption spectra, showed that the cavity emitted flux that heated the absorption foils corresponds to a radiation temperature in the range 55 60 eV. Comparison of the ZnS absorption spectra with calculations based on a superconfiguration approach identified the presence of species Zn6+ - Zn8+ and S5+ - S6+. Based on the validation of the radiative source simulations, experimental spectra were then compared to calculations performed by post-processing the radiative hydrodynamic simulations of ZnS. Satisfying agreement is found when temperature gradients are accounted for

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

On a Generalization of Zaslavsky's Theorem for Hyperplane Arrangements

We define arrangements of codimension-1 submanifolds in a smooth manifold which generalize arrangements of hyperplanes. When these submanifolds are removed the manifold breaks up into regions, each of which is homeomorphic to an open disc. The aim of this paper is to derive formulas that count the number of regions formed by such an arrangement. We achieve this aim by generalizing Zaslavsky's theorem to this setting. We show that this number is determined by the combinatorics of the intersections of these submanifolds.Comment: version 3: The title had a typo in v2 which is now fixed. Will appear in Annals of Combinatorics. Version. 2: 19 pages, major revision in terms of style and language, some results improved, contact information updated, final versio

DNA looping provides stability and robustness to the bacteriophage lambda switch

The bistable gene regulatory switch controlling the transition from lysogeny to lysis in bacteriophage lambda presents a unique challenge to quantitative modeling. Despite extensive characterization of this regulatory network, the origin of the extreme stability of the lysogenic state remains unclear. We have constructed a stochastic model for this switch. Using Forward Flux Sampling simulations, we show that this model predicts an extremely low rate of spontaneous prophage induction in a recA mutant, in agreement with experimental observations. In our model, the DNA loop formed by octamerization of CI bound to the O_L and O_R operator regions is crucial for stability, allowing the lysogenic state to remain stable even when a large fraction of the total CI is depleted by nonspecific binding to genomic DNA. DNA looping also ensures that the switch is robust to mutations in the order of the O_R binding sites. Our results suggest that DNA looping can provide a mechanism to maintain a stable lysogenic state in the face of a range of challenges including noisy gene expression, nonspecific DNA binding and operator site mutations.Comment: In press on PNAS. Single file contains supplementary inf

Correlation of gene expression and protein production rate - a system wide study

<p>Abstract</p> <p>Background</p> <p>Growth rate is a major determinant of intracellular function. However its effects can only be properly dissected with technically demanding chemostat cultivations in which it can be controlled. Recent work on <it>Saccharomyces cerevisiae </it>chemostat cultivations provided the first analysis on genome wide effects of growth rate. In this work we study the filamentous fungus <it>Trichoderma reesei </it>(<it>Hypocrea jecorina</it>) that is an industrial protein production host known for its exceptional protein secretion capability. Interestingly, it exhibits a low growth rate protein production phenotype.</p> <p>Results</p> <p>We have used transcriptomics and proteomics to study the effect of growth rate and cell density on protein production in chemostat cultivations of <it>T. reesei</it>. Use of chemostat allowed control of growth rate and exact estimation of the extracellular specific protein production rate (SPPR). We find that major biosynthetic activities are all negatively correlated with SPPR. We also find that expression of many genes of secreted proteins and secondary metabolism, as well as various lineage specific, mostly unknown genes are positively correlated with SPPR. Finally, we enumerate possible regulators and regulatory mechanisms, arising from the data, for this response.</p> <p>Conclusions</p> <p>Based on these results it appears that in low growth rate protein production energy is very efficiently used primarly for protein production. Also, we propose that flux through early glycolysis or the TCA cycle is a more fundamental determining factor than growth rate for low growth rate protein production and we propose a novel eukaryotic response to this i.e. the lineage specific response (LSR).</p