179 research outputs found
Simulating Supersonic Turbulence in Magnetized Molecular Clouds
We present results of large-scale three-dimensional simulations of weakly
magnetized supersonic turbulence at grid resolutions up to 1024^3 cells. Our
numerical experiments are carried out with the Piecewise Parabolic Method on a
Local Stencil and assume an isothermal equation of state. The turbulence is
driven by a large-scale isotropic solenoidal force in a periodic computational
domain and fully develops in a few flow crossing times. We then evolve the flow
for a number of flow crossing times and analyze various statistical properties
of the saturated turbulent state. We show that the energy transfer rate in the
inertial range of scales is surprisingly close to a constant, indicating that
Kolmogorov's phenomenology for incompressible turbulence can be extended to
magnetized supersonic flows. We also discuss numerical dissipation effects and
convergence of different turbulence diagnostics as grid resolution refines from
256^3 to 1024^3 cells.Comment: 10 pages, 3 figures, to appear in the proceedings of the DOE/SciDAC
2009 conferenc
Deuterium isotope effects on 15N backbone chemical shifts in proteins
Quantum mechanical calculations are presented that predict that one-bond deuterium isotope effects on the 15N chemical shift of backbone amides of proteins, 1Î15N(D), are sensitive to backbone conformation and hydrogen bonding. A quantitative empirical model for 1Î15N(D) including the backbone dihedral angles, Ί and Κ, and the hydrogen bonding geometry is presented for glycine and amino acid residues with aliphatic side chains. The effect of hydrogen bonding is rationalized in part as an electric-field effect on the first derivative of the nuclear shielding with respect to NâH bond length. Another contributing factor is the effect of increased anharmonicity of the NâH stretching vibrational state upon hydrogen bonding, which results in an altered NâH/NâD equilibrium bond length ratio. The NâH stretching anharmonicity contribution falls off with the cosine of the NâH···O bond angle. For residues with uncharged side chains a very good prediction of isotope effects can be made. Thus, for proteins with known secondary structures, 1Î15N(D) can provide insights into hydrogen bonding geometries
Selective 13C labeling of nucleotides for large RNA NMR spectroscopy using an E. coli strain disabled in the TCA cycle
Escherichia coli (E. coli) is an ideal organism to tailor-make labeled nucleotides for biophysical studies of RNA. Recently, we showed that adding labeled formate enhanced the isotopic enrichment at protonated carbon sites in nucleotides. In this paper, we show that growth of a mutant E. coli strain DL323 (lacking succinate and malate dehydrogenases) on 13C-2-glycerol and 13C-1,3-glycerol enables selective labeling at many useful sites for RNA NMR spectroscopy. For DL323 E. coli grown in 13C-2-glycerol without labeled formate, all the ribose carbon atoms are labeled except the C3âČ and C5âČ carbon positions. Consequently the C1âČ, C2âČ and C4âČ positions remain singlet. In addition, only the pyrimidine base C6 atoms are substantially labeled to ~96% whereas the C2 and C8 atoms of purine are labeled to ~5%. Supplementing the growth media with 13C-formate increases the labeling at C8 to ~88%, but not C2. Not unexpectedly, addition of exogenous formate is unnecessary for attaining the high enrichment levels of ~88% for the C2 and C8 purine positions in a 13C-1,3-glycerol based growth. Furthermore, the ribose ring is labeled in all but the C4âČ carbon position, such that the C2âČ and C3âČ positions suffer from multiplet splitting but the C5âČ position remains singlet and the C1âČ position shows a small amount of residual C1âČâC2âČ coupling. As expected, all the protonated base atoms, except C6, are labeled to ~90%. In addition, labeling with 13C-1,3-glycerol affords an isolated methylene ribose with high enrichment at the C5âČ position (~90%) that makes it particularly attractive for NMR applications involving CH2-TROSY modules without the need for decoupling the C4âČ carbon. To simulate the tumbling of large RNA molecules, perdeuterated glycerol was added to a mixture of the four nucleotides, and the methylene TROSY experiment recorded at various temperatures. Even under conditions of slow tumbling, all the expected carbon correlations were observed, which indicates this approach of using nucleotides obtained from DL323 E. coli will be applicable to high molecular weight RNA systems
Preventing foot ulceration in diabetes:systematic review and meta-analyses of RCT data
Aims/hypothesis:
Foot ulceration is a serious complication for people with diabetes that results in high levels of morbidity for individuals and significant costs for health and social care systems. Nineteen systematic reviews of preventative interventions have been published, but none provides a reliable numerical summary of treatment effects. The aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to make the best possible use of the currently available data.
Methods:
We conducted a systematic review and meta-analysis of RCTs of preventative interventions for foot ulceration. OVID MEDLINE and EMBASE were searched to February 2019 and the Cochrane Central Register of Controlled Trials to October 2018. RCTs of interventions to prevent foot ulcers in people with diabetes who were free from foot ulceration at trial entry were included. Two independent reviewers read the full-text articles and extracted data. The quality of trial reporting was assessed using the Cochrane Risk of Bias tool. The primary outcome of foot ulceration was summarised using pooled relative risks in meta-analyses.
Results:
Twenty-two RCTs of eight interventions were eligible for analysis. One trial of digital silicone devices (RR 0.07 [95% CI 0.01, 0.55]) and meta-analyses of dermal infrared thermometry (RR 0.41 [95% CI 0.19, 0.86]), complex interventions (RR 0.59 [95% CI 0.38, 0.90], and custom-made footwear and offloading insoles (RR 0.53 [95% CI 0.33, 0.85]) showed beneficial effects for these interventions.
Conclusions/interpretation:
Four interventions were identified as being effective in preventing foot ulcers in people with diabetes, but uncertainty remains about what works and who is most likely to benefit
Peptide Conformer Acidity Analysis of Protein Flexibility Monitored by Hydrogen Exchangeâ
ABSTRACT: The amide hydrogens that are exposed to solvent in the high-resolution X-ray structures of ubiquitin, FK506-binding protein, chymotrypsin inhibitor 2, and rubredoxin span a billion-fold range in hydroxide-catalyzed exchange rates which are predictable by continuum dielectric methods. To facilitate analysis of transiently accessible amides, the hydroxide-catalyzed rate constants for every backbone amide of ubiquitin were determined under near physiological conditions. With the previously reported NMR-restrained molecular dynamics ensembles of ubiquitin (PDB codes 2NR2 and 2K39) used as representations of the Boltzmann-weighted conformational distribution, nearly all of the exchange rates for the highly exposed amides were more accurately predicted than by use of the high-resolution X-ray structure. More strikingly, predictions for the amide hydrogens of the NMR relaxation-restrained ensemble that become exposed to solvent in more than one but less than half of the 144 protein conformations in this ensemble were almost as accurate. In marked contrast, the exchange rates for many of the analogous amides in the residual dipolar coupling-restrained ubiquitin ensemble are substantially overestimated, as was particularly evident for the Ile 44 to Lys 48 segment which constitutes the primary interaction site for the proteasome targeting enzymes involved in polyubiquitylation. For both ensembles, âexcited state â conformers in this active site region having markedly elevated peptide acidities are represented at a population level that is 102 to 103 abov
Suicidality in primary care patients who present with sadness and anhedonia: a prospective European study
Background: Sadness and anhedonia (loss of interest in activities) are central symptoms of major depression.
However, not all people with these symptoms meet diagnostic criteria for major depression. We aimed to assess
the importance of suicidality in the outcomes for primary care patients who present with sadness and anhedonia.
Method: Cohort study of 2,599 unselected primary care attenders in six European countries followed up at 6 and
12 months.
Results: 1) In patients with sadness and/or anhedonia who were not depressed at entry to the study, suicide plans
(OR = 3.05; 95 % CI = 1.50â6.24; p = 0.0022) and suicide attempts (OR = 9.08; 95 % CI = 2.57â32.03; p = 0.0006) were
significant predictors of developing new onset depression at 6 or 12 months. 2) In patients with sadness and/or
anhedonia who met CIDI criteria for major depression at entry, suicidal ideation (OR = 2.93; 95 % CI = 1.70â5.07;
p = 0.0001), suicide plans (OR = 3.70; 95 % CI = 2.08â6.57; p < 0.0001), and suicide attempts (OR = 3.33; 95 %
CI = 1.47â7.54; p = 0.0040) were significant predictors of persistent depression at 6 or 12 months.
Conclusions: Three questions on suicidality could help primary care professionals to assess such patients more closely
without necessarily establishing whether they meet criteria for major depression.This research was funded by a grant from The European Commission,
referencePREDICT-QL4-CT2002-00683. We are also grateful for part support in
Europe from: the Estonian Scientific Foundation (grant number 5696); the
Slovenian Ministry for Research (grant No.4369-1027); the Spanish Ministry of
Health (grant FIS references: PI041980, PI041771, PI042450) and the Spanish
Network of Primary Care Research, redIAPP (ISCIII-RETICS RD06/0018) and
SAMSERAP group; and the UK NHS Research and Development office for
providing service support costs in the UK. We are also grateful for the support
from the University of Malaga (Spain) and to Carlos GarcĂa from Loyola
AndalucĂa University (Spain)
CASA: An Efficient Automated Assignment of Protein Mainchain NMR Data Using an Ordered Tree Search Algorithm
Rapid analysis of protein structure, interaction, and dynamics requires fast and automated assignments of 3D protein backbone triple-resonance NMR spectra. We introduce a new depth-first ordered tree search method of automated assignment, CASA, which uses hand-edited peak-pick lists of a flexible number of triple resonance experiments. The computer program was tested on 13 artificially simulated peak lists for proteins up to 723 residues, as well as on the experimental data for four proteins. Under reasonable tolerances, it generated assignments that correspond to the ones reported in the literature within a few minutes of CPU time. The program was also tested on the proteins analyzed by other methods, with both simulated and experimental peaklists, and it could generate good assignments in all relevant cases. The robustness was further tested under various situations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43050/1/10858_2005_Article_4079.pd
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