697 research outputs found
Investigation into the role of an extracellular loop in mediating proton-evoked inhibition of voltage-gated sodium channels
Proton-evoked activation of sensory neurons is counteracted by inhibition of voltage-gated Na+ channels, and the low acid-sensitivity of sensory neuron of the African naked mole-rat (ANMr) was reported to be due to a strong proton-evoked block of ANMrNav1.7. Here we aimed to reevaluate the role of the suggested negatively-charged motif in the ANMrNav1.7 domain IV P-loop for inhibition by protons. Patch clamp recordings were performed on the recombinant α-subunits Nav1.2–1.8. The insertion of the negatively charged motif (EKE) of ANMrNav1.7 into human Nav1.7 results in an increased proton-evoked tonic inhibition, but also in a reduced channel function. While the voltage-dependency of fast inactivation is changed in hNav1.7-EKE, pH 6.4 fails to induce a significant shift in both constructs. Proton-evoked inhibition of other channel α-subunits reveals a discrete differential inhibition among α-subunits with hNav1.7 displaying the lowest proton-sensitivity. The mutant hNav1.7-EKE displays a similar proton-sensitivity as Nav1.2, Nav1.3, Nav1.6 and Nav1.8. Overall, a correlation between proton-evoked inhibition and motif charge was not evident. Accordingly, a homology model of hNav1.7 shows that the EKE motif residues do not contribute to the pore lumen. Our data confirms that a negative charge of a postulated proton-motif encodes for a high proton-sensitivity when inserted into hNav1.7. However, a negatively charged motif is not a reliable predictor for a high proton-sensitivity in other α-subunits. Given the distance of the proton-motif from the pore mouth it seems unlikely that a blocking mechanism involving direct obstruction of the pore underlies the observed proton-evoked channel inhibition
MultiPhen: Joint Model of Multiple Phenotypes Can Increase Discovery in GWAS
The genome-wide association study (GWAS) approach has discovered hundreds of genetic variants associated with diseases and quantitative traits. However, despite clinical overlap and statistical correlation between many phenotypes, GWAS are generally performed one-phenotype-at-a-time. Here we compare the performance of modelling multiple phenotypes jointly with that of the standard univariate approach. We introduce a new method and software, MultiPhen, that models multiple phenotypes simultaneously in a fast and interpretable way. By performing ordinal regression, MultiPhen tests the linear combination of phenotypes most associated with the genotypes at each SNP, and thus potentially captures effects hidden to single phenotype GWAS. We demonstrate via simulation that this approach provides a dramatic increase in power in many scenarios. There is a boost in power for variants that affect multiple phenotypes and for those that affect only one phenotype. While other multivariate methods have similar power gains, we describe several benefits of MultiPhen over these. In particular, we demonstrate that other multivariate methods that assume the genotypes are normally distributed, such as canonical correlation analysis (CCA) and MANOVA, can have highly inflated type-1 error rates when testing case-control or non-normal continuous phenotypes, while MultiPhen produces no such inflation. To test the performance of MultiPhen on real data we applied it to lipid traits in the Northern Finland Birth Cohort 1966 (NFBC1966). In these data MultiPhen discovers 21% more independent SNPs with known associations than the standard univariate GWAS approach, while applying MultiPhen in addition to the standard approach provides 37% increased discovery. The most associated linear combinations of the lipids estimated by MultiPhen at the leading SNPs accurately reflect the Friedewald Formula, suggesting that MultiPhen could be used to refine the definition of existing phenotypes or uncover novel heritable phenotypes
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Amplified surface temperature response of cold, deep lakes to inter-annual air temperature variability
Summer lake surface water temperatures (LSWTs) have previously been shown to respond more rapidly to climatic warming compared to local summer surface air temperatures (SATs). In a global- scale analysis, we explore the factors underpinning the observation of an amplified response of summer LSWT to SAT variability using 20 years of satellite-derived temperatures from 144 lakes. We demonstrate that the degree of amplification in inter-annual summer LSWT is variable, and is greater for cold lakes (e.g. high latitude and high altitude), which are characterised by a short warming season, and deep lakes, that exhibit long correlation timescales of temperature anomalies due to increased thermal inertia. Such lakes are more likely to display responses in excess of local inter-annual summer SAT variability. Climatic modification of LSWT has numerous consequences for water quality and lake ecosystems, so quantifying this amplified response at a global scale is important
All-sky search for periodic gravitational waves in LIGO S4 data
We report on an all-sky search with the LIGO detectors for periodic
gravitational waves in the frequency range 50-1000 Hz and with the frequency's
time derivative in the range -1.0E-8 Hz/s to zero. Data from the fourth LIGO
science run (S4) have been used in this search. Three different semi-coherent
methods of transforming and summing strain power from Short Fourier Transforms
(SFTs) of the calibrated data have been used. The first, known as "StackSlide",
averages normalized power from each SFT. A "weighted Hough" scheme is also
developed and used, and which also allows for a multi-interferometer search.
The third method, known as "PowerFlux", is a variant of the StackSlide method
in which the power is weighted before summing. In both the weighted Hough and
PowerFlux methods, the weights are chosen according to the noise and detector
antenna-pattern to maximize the signal-to-noise ratio. The respective
advantages and disadvantages of these methods are discussed. Observing no
evidence of periodic gravitational radiation, we report upper limits; we
interpret these as limits on this radiation from isolated rotating neutron
stars. The best population-based upper limit with 95% confidence on the
gravitational-wave strain amplitude, found for simulated sources distributed
isotropically across the sky and with isotropically distributed spin-axes, is
4.28E-24 (near 140 Hz). Strict upper limits are also obtained for small patches
on the sky for best-case and worst-case inclinations of the spin axes.Comment: 39 pages, 41 figures An error was found in the computation of the C
parameter defined in equation 44 which led to its overestimate by 2^(1/4).
The correct values for the multi-interferometer, H1 and L1 analyses are 9.2,
9.7, and 9.3, respectively. Figure 32 has been updated accordingly. None of
the upper limits presented in the paper were affecte
All-sky LIGO Search for Periodic Gravitational Waves in the Early S5 Data
We report on an all-sky search with the LIGO detectors for periodic
gravitational waves in the frequency range 50--1100 Hz and with the frequency's
time derivative in the range -5.0E-9 Hz/s to zero. Data from the first eight
months of the fifth LIGO science run (S5) have been used in this search, which
is based on a semi-coherent method (PowerFlux) of summing strain power.
Observing no evidence of periodic gravitational radiation, we report 95%
confidence-level upper limits on radiation emitted by any unknown isolated
rotating neutron stars within the search range. Strain limits below 1.E-24 are
obtained over a 200-Hz band, and the sensitivity improvement over previous
searches increases the spatial volume sampled by an average factor of about 100
over the entire search band. For a neutron star with nominal equatorial
ellipticity of 1.0E-6, the search is sensitive to distances as great as 500
pc--a range that could encompass many undiscovered neutron stars, albeit only a
tiny fraction of which would likely be rotating fast enough to be accessible to
LIGO. This ellipticity is at the upper range thought to be sustainable by
conventional neutron stars and well below the maximum sustainable by a strange
quark star.Comment: 6 pages, 1 figur
Search for gravitational waves from binary inspirals in S3 and S4 LIGO data
We report on a search for gravitational waves from the coalescence of compact
binaries during the third and fourth LIGO science runs. The search focused on
gravitational waves generated during the inspiral phase of the binary
evolution. In our analysis, we considered three categories of compact binary
systems, ordered by mass: (i) primordial black hole binaries with masses in the
range 0.35 M(sun) < m1, m2 < 1.0 M(sun), (ii) binary neutron stars with masses
in the range 1.0 M(sun) < m1, m2 < 3.0 M(sun), and (iii) binary black holes
with masses in the range 3.0 M(sun)< m1, m2 < m_(max) with the additional
constraint m1+ m2 < m_(max), where m_(max) was set to 40.0 M(sun) and 80.0
M(sun) in the third and fourth science runs, respectively. Although the
detectors could probe to distances as far as tens of Mpc, no gravitational-wave
signals were identified in the 1364 hours of data we analyzed. Assuming a
binary population with a Gaussian distribution around 0.75-0.75 M(sun), 1.4-1.4
M(sun), and 5.0-5.0 M(sun), we derived 90%-confidence upper limit rates of 4.9
yr^(-1) L10^(-1) for primordial black hole binaries, 1.2 yr^(-1) L10^(-1) for
binary neutron stars, and 0.5 yr^(-1) L10^(-1) for stellar mass binary black
holes, where L10 is 10^(10) times the blue light luminosity of the Sun.Comment: 12 pages, 11 figure
Search for Gravitational Wave Bursts from Soft Gamma Repeaters
We present the results of a LIGO search for short-duration gravitational
waves (GWs) associated with Soft Gamma Repeater (SGR) bursts. This is the first
search sensitive to neutron star f-modes, usually considered the most efficient
GW emitting modes. We find no evidence of GWs associated with any SGR burst in
a sample consisting of the 27 Dec. 2004 giant flare from SGR 1806-20 and 190
lesser events from SGR 1806-20 and SGR 1900+14 which occurred during the first
year of LIGO's fifth science run. GW strain upper limits and model-dependent GW
emission energy upper limits are estimated for individual bursts using a
variety of simulated waveforms. The unprecedented sensitivity of the detectors
allows us to set the most stringent limits on transient GW amplitudes published
to date. We find upper limit estimates on the model-dependent isotropic GW
emission energies (at a nominal distance of 10 kpc) between 3x10^45 and 9x10^52
erg depending on waveform type, detector antenna factors and noise
characteristics at the time of the burst. These upper limits are within the
theoretically predicted range of some SGR models.Comment: 6 pages, 1 Postscript figur
Search for Gravitational Waves Associated with 39 Gamma-Ray Bursts Using Data from the Second, Third, and Fourth LIGO Runs
We present the results of a search for short-duration gravitational-wave
bursts associated with 39 gamma-ray bursts (GRBs) detected by gamma-ray
satellite experiments during LIGO's S2, S3, and S4 science runs. The search
involves calculating the crosscorrelation between two interferometer data
streams surrounding the GRB trigger time. We search for associated
gravitational radiation from single GRBs, and also apply statistical tests to
search for a gravitational-wave signature associated with the whole sample. For
the sample examined, we find no evidence for the association of gravitational
radiation with GRBs, either on a single-GRB basis or on a statistical basis.
Simulating gravitational-wave bursts with sine-gaussian waveforms, we set upper
limits on the root-sum-square of the gravitational-wave strain amplitude of
such waveforms at the times of the GRB triggers. We also demonstrate how a
sample of several GRBs can be used collectively to set constraints on
population models. The small number of GRBs and the significant change in
sensitivity of the detectors over the three runs, however, limits the
usefulness of a population study for the S2, S3, and S4 runs. Finally, we
discuss prospects for the search sensitivity for the ongoing S5 run, and beyond
for the next generation of detectors.Comment: 24 pages, 10 figures, 14 tables; minor changes to text and Fig. 2;
accepted by Phys. Rev.
First LIGO search for gravitational wave bursts from cosmic (super)strings
We report on a matched-filter search for gravitational wave bursts from
cosmic string cusps using LIGO data from the fourth science run (S4) which took
place in February and March 2005. No gravitational waves were detected in 14.9
days of data from times when all three LIGO detectors were operating. We
interpret the result in terms of a frequentist upper limit on the rate of
gravitational wave bursts and use the limits on the rate to constrain the
parameter space (string tension, reconnection probability, and loop sizes) of
cosmic string models.Comment: 11 pages, 3 figures. Replaced with version submitted to PR
Posttraumatic Stress Disorder Prevalence and Risk of Recurrence in Acute Coronary Syndrome Patients: A Meta-analytic Review
BACKGROUND:Acute coronary syndromes (ACS; myocardial infarction or unstable angina) can induce posttraumatic stress disorder (PTSD), and ACS-induced PTSD may increase patients' risk for subsequent cardiac events and mortality. OBJECTIVE:To determine the prevalence of PTSD induced by ACS and to quantify the association between ACS-induced PTSD and adverse clinical outcomes using systematic review and meta-analysis. DATA SOURCES:Articles were identified by searching Ovid MEDLINE, PsycINFO, and Scopus, and through manual search of reference lists. METHODOLOGY/PRINCIPAL FINDINGS:Observational cohort studies that assessed PTSD with specific reference to an ACS event at least 1 month prior. We extracted estimates of the prevalence of ACS-induced PTSD and associations with clinical outcomes, as well as study characteristics. We identified 56 potentially relevant articles, 24 of which met our criteria (N = 2383). Meta-analysis yielded an aggregated prevalence estimate of 12% (95% confidence interval [CI], 9%-16%) for clinically significant symptoms of ACS-induced PTSD in a random effects model. Individual study prevalence estimates varied widely (0%-32%), with significant heterogeneity in estimates explained by the use of a screening instrument (prevalence estimate was 16% [95% CI, 13%-20%] in 16 studies) vs a clinical diagnostic interview (prevalence estimate was 4% [95% CI, 3%-5%] in 8 studies). The aggregated point estimate for the magnitude of the relationship between ACS-induced PTSD and clinical outcomes (ie, mortality and/or ACS recurrence) across the 3 studies that met our criteria (N = 609) suggested a doubling of risk (risk ratio, 2.00; 95% CI, 1.69-2.37) in ACS patients with clinically significant PTSD symptoms relative to patients without PTSD symptoms. CONCLUSIONS/SIGNIFICANCE:This meta-analysis suggests that clinically significant PTSD symptoms induced by ACS are moderately prevalent and are associated with increased risk for recurrent cardiac events and mortality. Further tests of the association of ACS-induced PTSD and clinical outcomes are needed
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