359 research outputs found
Quaternary structure of a G-protein coupled receptor heterotetramer in complex with Gi and Gs
Background: G-protein-coupled receptors (GPCRs), in the form of monomers or homodimers that bind heterotrimeric G proteins, are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways. Different GPCRs may also interact to form heteromers that are novel signaling units. Despite the exponential growth in the number of solved GPCR crystal structures, the structural properties of heteromers remain unknown. Results: We used single-particle tracking experiments in cells expressing functional adenosine A1-A2A receptors fused to fluorescent proteins to show the loss of Brownian movement of the A1 receptor in the presence of the A2A receptor, and a preponderance of cell surface 2:2 receptor heteromers (dimer of dimers). Using computer modeling, aided by bioluminescence resonance energy transfer assays to monitor receptor homomerization and heteromerization and G-protein coupling, we predict the interacting interfaces and propose a quaternary structure of the GPCR tetramer in complex with two G proteins. Conclusions: The combination of results points to a molecular architecture formed by a rhombus-shaped heterotetramer, which is bound to two different interacting heterotrimeric G proteins (Gi and Gs). These novel results constitute an important advance in understanding the molecular intricacies involved in GPCR function
Direct-acting Antivirals for the Treatment of Kidney Transplant Patients With Chronic Hepatitis C Virus Infection in Spain: A Long-term Prospective Observational Study
Background: Direct-acting antivirals (DAA) allow effective and safe eradication of hepatitis C virus (HCV) in most patients. There are limited data on the long-term effects of all-oral, interferon-free DAA combination therapies in kidney transplant (KT) patients infected with HCV. Here we evaluated the long-term tolerability, efficacy, and safety of DAA combination therapies in KT patients with chronic HCV infection. Methods: Clinical data from KT patients treated with DAA were collected before, during, and after the treatment, including viral response, immunosuppression regimens, and kidney and liver function. Results: Patients (N = 226) were mostly male (65.9%) aged 56.1 +/- 10.9 years, with a median time from KT to initiation of DAA therapy of 12.7 years and HCV genotype 1b (64.6%). Most patients were treated with sofosbuvir-based therapies. Rapid virological response at 1 month was achieved by 89.4% of the patients and sustained virological response by week 12 by 98.1%. Liver function improved significantly after DAA treatment. Tacrolimus dosage increased 37% from the beginning of treatment (2.5 +/- 1.7 mg/d) to 1 year after the start of DAA treatment (3.4 +/- 1.9 mg/d, P < 0.001). Median follow-up was 37.0 months (interquartile range, 28.4-41.9) and death-censored graft survival was 91.1%. Adverse events resulting from DAA treatment, especially anemia, were reported for 31.0% of the patients. Conclusions: Chronic HCV infection can be treated efficiently and safely with DAA therapy in KT patients. Most patients retained stable kidney function and improved liver function. Tacrolimus dose had to be increased in most patients, potentially as a result of better liver function
Planck intermediate results. XLI. A map of lensing-induced B-modes
The secondary cosmic microwave background (CMB) -modes stem from the
post-decoupling distortion of the polarization -modes due to the
gravitational lensing effect of large-scale structures. These lensing-induced
-modes constitute both a valuable probe of the dark matter distribution and
an important contaminant for the extraction of the primary CMB -modes from
inflation. Planck provides accurate nearly all-sky measurements of both the
polarization -modes and the integrated mass distribution via the
reconstruction of the CMB lensing potential. By combining these two data
products, we have produced an all-sky template map of the lensing-induced
-modes using a real-space algorithm that minimizes the impact of sky masks.
The cross-correlation of this template with an observed (primordial and
secondary) -mode map can be used to measure the lensing -mode power
spectrum at multipoles up to . In particular, when cross-correlating with
the -mode contribution directly derived from the Planck polarization maps,
we obtain lensing-induced -mode power spectrum measurement at a significance
level of , which agrees with the theoretical expectation derived
from the Planck best-fit CDM model. This unique nearly all-sky
secondary -mode template, which includes the lensing-induced information
from intermediate to small () angular scales, is
delivered as part of the Planck 2015 public data release. It will be
particularly useful for experiments searching for primordial -modes, such as
BICEP2/Keck Array or LiteBIRD, since it will enable an estimate to be made of
the lensing-induced contribution to the measured total CMB -modes.Comment: 20 pages, 12 figures; Accepted for publication in A&A; The B-mode map
is part of the PR2-2015 Cosmology Products; available as Lensing Products in
the Planck Legacy Archive http://pla.esac.esa.int/pla/#cosmology; and
described in the 'Explanatory Supplement'
https://wiki.cosmos.esa.int/planckpla2015/index.php/Specially_processed_maps#2015_Lensing-induced_B-mode_ma
Numerical Approaches to Spacetime Singularities
This Living Review updates a previous version which its itself an update of a
review article. Numerical exploration of the properties of singularities could,
in principle, yield detailed understanding of their nature in physically
realistic cases. Examples of numerical investigations into the formation of
naked singularities, critical behavior in collapse, passage through the Cauchy
horizon, chaos of the Mixmaster singularity, and singularities in spatially
inhomogeneous cosmologies are discussed.Comment: 51 pages, 6 figures may be found in online version: Living Rev.
Relativity 2002-1 at www.livingreviews.or
Minigene-like inhibition of protein synthesis mediated by hungry codons near the start codon
Rare AGA or AGG codons close to the initiation codon inhibit protein synthesis by a tRNA-sequestering mechanism as toxic minigenes do. To further understand this mechanism, a parallel analysis of protein synthesis and peptidyl-tRNA accumulation was performed using both a set of lacZ constructs where AGAAGA codons were moved codon by codon from +2, +3 up to +7, +8 positions and a series of 3–8 codon minigenes containing AGAAGA codons before the stop codon. β-Galactosidase synthesis from the AGAAGA lacZ constructs (in a Pth defective in vitro system without exogenous tRNA) diminished as the AGAAGA codons were closer to AUG codon. Likewise, β-galactosidase expression from the reporter +7 AGA lacZ gene (plus tRNA, 0.25 μg/μl) waned as the AGAAGAUAA minigene shortened. Pth counteracted both the length-dependent minigene effect on the expression of β-galactosidase from the +7 AGA lacZ reporter gene and the positional effect from the AGAAGA lacZ constructs. The +2, +3 AGAAGA lacZ construct and the shortest +2, +3 AGAAGAUAA minigene accumulated the highest percentage of peptidyl-tRNAArg4. These observations lead us to propose that hungry codons at early positions, albeit with less strength, inhibit protein synthesis by a minigene-like mechanism involving accumulation of peptidyl-tRNA
First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data
Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of
continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a
fully coherent search, based on matched filtering, which uses the position and rotational parameters
obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto-
noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch
between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have
been developed, allowing a fully coherent search for gravitational waves from known pulsars over a
fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of
11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial
outliers, further studies show no significant evidence for the presence of a gravitational wave signal.
Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of
the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for
the first time. For an additional 3 targets, the median upper limit across the search bands is below the
spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried
out so far
Search for the standard model Higgs boson decaying to a pair in events with no charged leptons and large missing transverse energy using the full CDF data set
We report on a search for the standard model Higgs boson produced in
association with a vector boson in the full data set of proton-antiproton
collisions at TeV recorded by the CDF II detector at the
Tevatron, corresponding to an integrated luminosity of 9.45 fb. We
consider events having no identified charged lepton, a transverse energy
imbalance, and two or three jets, of which at least one is consistent with
originating from the decay of a quark. We place 95% credibility level upper
limits on the production cross section times standard model branching fraction
for several mass hypotheses between 90 and . For a Higgs
boson mass of , the observed (expected) limit is 6.7
(3.6) times the standard model prediction.Comment: Accepted by Phys. Rev. Let
Search for the standard model Higgs boson decaying to a bb pair in events with one charged lepton and large missing transverse energy using the full CDF data set
We present a search for the standard model Higgs boson produced in
association with a W boson in sqrt(s) = 1.96 TeV p-pbar collision data
collected with the CDF II detector at the Tevatron corresponding to an
integrated luminosity of 9.45 fb-1. In events consistent with the decay of the
Higgs boson to a bottom-quark pair and the W boson to an electron or muon and a
neutrino, we set 95% credibility level upper limits on the WH production cross
section times the H->bb branching ratio as a function of Higgs boson mass. At a
Higgs boson mass of 125 GeV/c2 we observe (expect) a limit of 4.9 (2.8) times
the standard model value.Comment: Submitted to Phys. Rev. Lett (v2 contains clarifications suggested by
PRL
Search for the standard model Higgs boson decaying to a bb pair in events with two oppositely-charged leptons using the full CDF data set
We present a search for the standard model Higgs boson produced in
association with a Z boson in data collected with the CDF II detector at the
Tevatron, corresponding to an integrated luminosity of 9.45/fb. In events
consistent with the decay of the Higgs boson to a bottom-quark pair and the Z
boson to electron or muon pairs, we set 95% credibility level upper limits on
the ZH production cross section times the H -> bb branching ratio as a function
of Higgs boson mass. At a Higgs boson mass of 125 GeV/c^2 we observe (expect) a
limit of 7.1 (3.9) times the standard model value.Comment: To be submitted to Phys. Rev. Let
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