Efficient Estimators for Quantum Instanton Evaluation of theKinetic Isotope Effects: Application to the Intramolecular HydrogenTransfer in Pentadiene

The quantum instanton approximation is used to compute kinetic isotope effects for intramolecular hydrogen transfer in cis-1,3-pentadiene. Due to the importance of skeleton motions, this system with 13 atoms is a simple prototype for hydrogen transfer in enzymatic reactions. The calculation is carried out using thermodynamic integration with respect to the mass of the isotopes and a path integral Monte Carlo evaluation of relevant thermodynamic quantities. Efficient 'virial' estimators are derived for the logarithmic derivatives of the partition function and the delta-delta correlation functions. These estimators require significantly fewer Monte Carlo samples since their statistical error does not increase with the number of discrete time slices in the path integral. The calculation treats all 39 degrees of freedom quantum-mechanically and uses an empirical valence bond potential based on a modified general AMBER force field

Scanning tunneling microscopy and atomic force microscopy in the characterization of activated graphite electrodes

Sir: To date there have been many methods described to activate carbon electrodes, including electrochemical treatment (1-1 7), laser irradiation (18-21), radio-frequency (RF) plasma (22), and heat treatment (23-26). These methods were developed empirically, and only now is an understanding of parameters controlling surface activity beginning to emerge (20,27). Electrochemical treatment and laser irradiation are particularly attractive treatments because they are relatively inexpensive, are quick, and can be performed without removing the electrode from solution. Activation, common to these procedures, may be attributable to an increase in the exposed edge plane density, which has been associated with faster kinetics (14,20). Copper deposition in conjunction with scanning electron microscopy (SEM) has shown an increase in the density of localized defects on active surfaces (15); an increase in surface activity is associated with an increase in the density of the localized defects (15). Scanning tunneling microscopy (STM), phase detection microscopy, and SEM have also been used to study the effects of electrochemical treatment of highly oriented pyrolytic graphite (HOPG) (13) and glassy carbon (GC) (16,17). These studies have suggested an increase in surface roughness consistent with an increase in the density of exposed edge planes

Quasi-stationary States of Two-Dimensional Electron Plasma Trapped in Magnetic Field

We have performed numerical simulations on a pure electron plasma system under a strong magnetic field, in order to examine quasi-stationary states that the system eventually evolves into. We use ring states as the initial states, changing the width, and find that the system evolves into a vortex crystal state from a thinner-ring state while a state with a single-peaked density distribution is obtained from a thicker-ring initial state. For those quasi-stationary states, density distribution and macroscopic observables are defined on the basis of a coarse-grained density field. We compare our results with experiments and some statistical theories, which include the Gibbs-Boltzmann statistics, Tsallis statistics, the fluid entropy theory, and the minimum enstrophy state. From some of those initial states, we obtain the quasi-stationary states which are close to the minimum enstrophy state, but we also find that the quasi-stationary states depend upon initial states, even if the initial states have the same energy and angular momentum, which means the ergodicity does not hold.Comment: 9 pages, 7 figure

Genetic risk prediction of atrial fibrillation

Background—Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods—To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from <1x10-3 to <1x10-8 in a prior independent genetic association study. Results—Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13-1.46; P=1.5x10-4) to 1.67 (25 variants; 95%CI, 1.47-1.90; P=9.3x10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95%CI, 1.39-4.58; P=2.7x10-3). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20-4.40; P=0.01). Conclusions—Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms

Motion of Three Vortices near Collapse

A system of three point vortices in an unbounded plane has a special family of self-similarly contracting or expanding solutions: during the motion, vortex triangle remains similar to the original one, while its area decreases (grows) at a constant rate. A contracting configuration brings three vortices to a single point in a finite time; this phenomenon known as vortex collapse is of principal importance for many-vortex systems. Dynamics of close-to-collapse vortex configurations depends on the way the collapse conditions are violated. Using an effective potential representation, a detailed quantitative analysis of all the different types of near-collapse dynamics is performed when two of the vortices are identical. We discuss time and length scales, emerging in the problem, and their behavior as the initial vortex triangle is approaching to an exact collapse configuration. Different types of critical behaviors, such as logarithmic or power-law divergences are exhibited, which emphasizes the importance of the way the collapse is approached. Period asymptotics for all singular cases are presented as functions of the initial vortices configurations. Special features of passive particle mixing by a near-collapse flows are illustrated numerically.Comment: 45 pages, 22 figures Last version of the paper with all update

A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect siz

The Mre11-Rad50-Nbs1 complex mediates activation of TopBP1 by ATM

The activation of ATR-ATRIP in response to double-stranded DNA breaks (DSBs) depends upon ATM in human cells and Xenopus egg extracts. One important aspect of this dependency involves regulation of TopBP1 by ATM. In Xenopus egg extracts, ATM associates with TopBP1 and thereupon phosphorylates it on S1131. This phosphorylation enhances the capacity of TopBP1 to activate the ATR-ATRIP complex. We show that TopBP1 also interacts with the Mre11-Rad50-Nbs1 (MRN) complex in egg extracts in a checkpoint-regulated manner. This interaction involves the Nbs1 subunit of the complex. ATM can no longer interact with TopBP1 in Nbs1-depleted egg extracts, which suggests that the MRN complex helps to bridge ATM and TopBP1 together. The association between TopBP1 and Nbs1 involves the first pair of BRCT repeats in TopBP1. In addition, the two tandem BRCT repeats of Nbs1 are required for this binding. Functional studies with mutated forms of TopBP1 and Nbs1 suggested that the BRCT-dependent association of these proteins is critical for a normal checkpoint response to DSBs. These findings suggest that the MRN complex is a crucial mediator in the process whereby ATM promotes the TopBP1-dependent activation of ATR-ATRIP in response to DSBs

Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium

Background: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI).Methods: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49 066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17 672/31 394 with/without periodontitis); 68 761 participants with BMI and genotype data; and 57 871 participants (18 881/38 990 with/without periodontitis) with data on BMI and periodontitis.Results: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI:1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data.Conclusions: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals