Transition-state vibrational analysis and isotope effects for COMT-catalyzed methyl transfer

Isotopic partition-function ratios (IPFRs) computed for transition structures (TSs) of the methyl-transfer reaction catalyzed by catechol O-methyltransferase and modeled by hybrid QM/MM methods are analyzed. The ability of smaller Hessians to reproduce trends in α-3H3 and 14Cα IPFRs as obtained using the much larger subset QM/MM Hessians from which they are extracted is investigated critically. A 6-atom-extracted Hessian reproduces perfectly the α-T3 IPFR values from the full-subset Hessians of all the TSs but not the α-14CIPFRs. Average AM1/OPLS-AA harmonic frequencies and mean-square amplitudes are presented for the 12 normal modes of the α-CH3 moiety within the active site of several enzymic transition structures, together with QM/MM potential energy scans along each of these modes to assess the degree of anharmonicity. A novel investigation of ponderal effects upon IPFRs suggests that the value for α-14C tends toward a limiting minimum whereas that for α-T3 tends toward a limiting maximum as the mass of the rest of the system increases. The transition vector is dominated by motions of atoms within the donor and acceptor moieties and is very well described as a simple combination of Walden-inversion “umbrella” bending and asymmetric stretching of the SCα and CαO bonds. The contribution of atoms of the protein residues Met40, Tyr68, and Asp141 to the transition vector is extremely small. Average valence force constants for the COMT TS show significant differences from early BEBOVIB estimates which were used in support of the compression hypothesis for catalysis. There is no correlation between TS IPFRs and the nonbonded distances for close contacts between the S atom of SAM and Tyr68 or between any of the H atoms of the transferring methyl group and either Met40 or Asp141

Gender perspectives on views and preferences of older people on exercise to prevent falls: a systematic mixed studies review

Background: To offer fall prevention exercise programs that attract older people of both sexes there is a need to understand both womens and mens views and preferences regarding these programs. This paper aims to systematically review the literature to explore any underlying gender perspectives or gender interpretations on older peoples views or preferences regarding uptake and adherence to exercise to prevent falls. Methods: A review of the literature was carried out using a convergent qualitative design based on systematic searches of seven electronic databases (PubMed, CINAHL, Amed, PsycINFO, Scopus, PEDro, and OTseeker). Two investigators identified eligible studies. Each included article was read by at least two authors independently to extract data into tables. Views and preferences reported were coded and summarized in themes of facilitators and barriers using a thematic analysis approach. Results: Nine hundred and nine unique studies were identified. Twenty five studies met the criteria for inclusion. Only five of these contained a gender analysis of mens and womens views on fall prevention exercises. The results suggests that both women and men see women as more receptive to and in more need of fall prevention messages. The synthesis from all 25 studies identified six themes illustrating facilitators and six themes describing barriers for older people either starting or adhering to fall prevention exercise. The facilitators were: support from professionals or family; social interaction; perceived benefits; a supportive exercise context; feelings of commitment; and having fun. Barriers were: practical issues; concerns about exercise; unawareness; reduced health status; lack of support; and lack of interest. Considerably more women than men were included in the studies. Conclusion: Although there is plenty of information on the facilitators and barriers to falls prevention exercise in older people, there is a distinct lack of studies investigating differences or similarities in older womens and mens views regarding fall prevention exercise. In order to ensure that fall prevention exercise is appealing to both sexes and that the inclusion of both men and women are encouraged, more research is needed to find out whether gender differences exists and whether practitioners need to offer a range of opportunities and support strategies to attract both women and men to falls prevention exercise.Funding Agencies|Swedish Research Council [2015-03481]; Strategic Research Programme in Care Sciences, Umea University; Karolinska Institute, Sweden; Umea University</p

Introducing SpatialGridBuilder: A new system for creating geo-coded datasets

Researchers in the conflict research community have become increasingly aware that we can no longer depend on state-aggregated data. Numerous factors at the substate level affect the nature of human interactions, so if we really want to understand conflict, we need to find more appropriate units of analysis. However, while many conflict researchers have realized this, actually taking the next step and performing data analysis on spatial data grids has remained a rather elusive goal for many because of the difficulty of learning the new techniques to perform such analyses. This paper introduces SpatialGridBuilder, a new, freely available, open-source system with the goal of empowering conflict researchers with no background in GIS methods to start their own spatial analyses. SpatialGridBuilder allows the researcher to: (a) create entirely new spatial datasets, based on the needs of their own research; (b) import their own spatial data; (c) easily add a range of important variables to the datasets, including commonly used conflict variables, plus new variables that have not been presented before; and (d) visualize graphical renderings of this data. Having done this, SpatialGridBuilder will then export the dataset for the researcher to analyse using conventional statistical methods. This article introduces the new program, and demonstrates how it can be used to set up such a statistical analysis. It also shows how different results can be achieved by building grids of different resolutions, thereby encouraging researchers to choose grid resolutions appropriate to their research questions and data. The article also introduces a novel means of determining infrastructure complexity, using Google maps

Cellulose acetate phthalate, a common pharmaceutical excipient, inactivates HIV-1 and blocks the coreceptor binding site on the virus envelope glycoprotein gp120

BACKGROUND: Cellulose acetate phthalate (CAP), a pharmaceutical excipient used for enteric film coating of capsules and tablets, was shown to inhibit infection by the human immunodeficiency virus type 1 (HIV-1) and several herpesviruses. CAP formulations inactivated HIV-1, herpesvirus types 1 (HSV-1) and 2 (HSV-2) and the major nonviral sexually transmitted disease (STD) pathogens and were effective in animal models for vaginal infection by HSV-2 and simian immunodeficiency virus. METHODS: Enzyme-linked immunoassays and flow cytometry were used to demonstrate CAP binding to HIV-1 and to define the binding site on the virus envelope. RESULTS: 1) CAP binds to HIV-1 virus particles and to the envelope glycoprotein gp120; 2) this leads to blockade of the gp120 V3 loop and other gp120 sites resulting in diminished reactivity with HIV-1 coreceptors CXCR4 and CCR5; 3) CAP binding to HIV-1 virions impairs their infectivity; 4) these findings apply to both HIV-1 IIIB, an X4 virus, and HIV-1 BaL, an R5 virus. CONCLUSIONS: These results provide support for consideration of CAP as a topical microbicide of choice for prevention of STDs, including HIV-1 infection

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

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

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

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 &lt;1x10-3 to &lt;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

FTO, Type 2 Diabetes, and Weight Gain Throughout Adult Life: A Meta-Analysis of 41,504 Subjects From the Scandinavian HUNT, MDC, and MPP Studies

OBJECTIVE—FTO is the most important polygene identified for obesity. We aimed to investigate whether a variant in FTO affects type 2 diabetes risk entirely through its effect on BMI and how FTO influences BMI across adult life span. RESEARCH DESIGN AND METHODS—Through regression models, we assessed the relationship between the FTO single nucleotide polymorphisms rs9939609, type 2 diabetes, and BMI across life span in subjects from the Norwegian population-based HUNT study using cross-sectional and longitudinal perspectives. For replication and meta-analysis, we used data from the Malmö Diet and Cancer (MDC) and Malmö Preventive Project (MPP) cohorts, comprising a total sample of 41,504 Scandinavians.RESULTS—The meta-analysis revealed a highly significant association for rs9939609 with both type 2 diabetes (OR 1.13; P = 4.5 3 1028) and the risk to develop incident type 2 diabetes (OR 1.16; P = 3.2 3 1028). The associations remained also after correction for BMI and other anthropometric measures. Furthermore, we confirmed the strong effect on BMI (0.28 kg/m2 per risk allele; P = 2.0 3 10226), with no heterogeneity between different age-groups. We found no differences in change of BMI over time according to rs9939609 risk alleles, neither overall (ΔBMI = 0.0[20.05, 0.05]) nor in any individual age stratum, indicating no further weight gain attributable to FTO genotype in adults. CONCLUSIONS—We have identified that a variant in FTO alters type 2 diabetes risk partly independent of its observed effect on BMI. The additional weight gain as a result of the FTO risk variant seems to occur before adulthood, and the BMI difference remains stable thereafter