359 research outputs found
PIONIER: a visitor instrument for the VLTI
PIONIER is a 4-telescope visitor instrument for the VLTI, planned to see its
first fringes in 2010. It combines four ATs or four UTs using a pairwise ABCD
integrated optics combiner that can also be used in scanning mode. It provides
low spectral resolution in H and K band. PIONIER is designed for imaging with a
specific emphasis on fast fringe recording to allow closure-phases and
visibilities to be precisely measured. In this work we provide the detailed
description of the instrument and present its updated status.Comment: Proceedings of SPIE conference Optical and Infrared Interferometry II
(Conference 7734) San Diego 201
Swift follow-up observations of candidate gravitational-wave transient events
We present the first multi-wavelength follow-up observations of two candidate
gravitational-wave (GW) transient events recorded by LIGO and Virgo in their
2009-2010 science run. The events were selected with low latency by the network
of GW detectors and their candidate sky locations were observed by the Swift
observatory. Image transient detection was used to analyze the collected
electromagnetic data, which were found to be consistent with background.
Off-line analysis of the GW data alone has also established that the selected
GW events show no evidence of an astrophysical origin; one of them is
consistent with background and the other one was a test, part of a "blind
injection challenge". With this work we demonstrate the feasibility of rapid
follow-ups of GW transients and establish the sensitivity improvement joint
electromagnetic and GW observations could bring. This is a first step toward an
electromagnetic follow-up program in the regime of routine detections with the
advanced GW instruments expected within this decade. In that regime
multi-wavelength observations will play a significant role in completing the
astrophysical identification of GW sources. We present the methods and results
from this first combined analysis and discuss its implications in terms of
sensitivity for the present and future instruments.Comment: Submitted for publication 2012 May 25, accepted 2012 October 25,
published 2012 November 21, in ApJS, 203, 28 (
http://stacks.iop.org/0067-0049/203/28 ); 14 pages, 3 figures, 6 tables;
LIGO-P1100038; Science summary at
http://www.ligo.org/science/Publication-S6LVSwift/index.php ; Public access
area to figures, tables at
https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=p110003
Comparison of general practitioners and rheumatologists' prescription patterns for patients with knee osteoarthritis
Lambda and Sigma0 Pair Production in Two-Photon Collisions at LEP
Strange baryon pair production in two-photon collisions is studied with the
L3 detector at LEP. The analysis is based on data collected at e+e-
centre-of-mass energies from 91 GeV to 208 GeV, corresponding to an integrated
luminosity of 844 pb-1. The processes gamma gamma -> Lambda Anti-lambda and
gamma gamma -> Sigma0 Anti-sigma0 are identified. Their cross sections as a
function of the gamma gamma centre-of-mass energy are measured and results are
compared to predictions of the quark-diquark model
Search for Single Top Production at LEP
Single top production in e+e- annihilations is searched for in data collected
by the L3 detector at centre-of-mass energies from 189 to 209 GeV,
corresponding to a total integrated luminosity of 634 pb-1. Investigating
hadronic and semileptonic top decays, no evidence of single top production at
LEP is obtained and upper limits on the single top cross section as a function
of the centre-of-mass energy are derived. Limits on possible anomalous
couplings, as well as on the scale of contact interactions responsible for
single top production are determined
MYC Cooperates with AKT in Prostate Tumorigenesis and Alters Sensitivity to mTOR Inhibitors
MYC and phosphoinositide 3-kinase (PI3K)-pathway deregulation are common in human prostate cancer. Through examination of 194 human prostate tumors, we observed statistically significant co-occurrence of MYC amplification and PI3K-pathway alteration, raising the possibility that these two lesions cooperate in prostate cancer progression. To investigate this, we generated bigenic mice in which both activated human AKT1 and human MYC are expressed in the prostate (MPAKT/Hi-MYC model). In contrast to mice expressing AKT1 alone (MPAKT model) or MYC alone (Hi-MYC model), the bigenic phenotype demonstrates accelerated progression of mouse prostate intraepithelial neoplasia (mPIN) to microinvasive disease with disruption of basement membrane, significant stromal remodeling and infiltration of macrophages, B- and T-lymphocytes, similar to inflammation observed in human prostate tumors. In contrast to the reversibility of mPIN lesions in young MPAKT mice after treatment with mTOR inhibitors, Hi-MYC and bigenic MPAKT/Hi-MYC mice were resistant. Additionally, older MPAKT mice showed reduced sensitivity to mTOR inhibition, suggesting that additional genetic events may dampen mTOR dependence. Since increased MYC expression is an early feature of many human prostate cancers, these data have implications for treatment of human prostate cancers with PI3K-pathway alterations using mTOR inhibitors
Caenorhabditis elegans Myotubularin MTM-1 Negatively Regulates the Engulfment of Apoptotic Cells
During programmed cell death, apoptotic cells are recognized and rapidly engulfed by phagocytes. Although a number of genes have been identified that promote cell corpse engulfment, it is not well understood how phagocytosis of apoptotic cells is negatively regulated. Here we have identified Caenorhabditis elegans myotubularin MTM-1 as a negative regulator of cell corpse engulfment. Myotubularins (MTMs) constitute a large, highly conserved family of lipid phosphatases. MTM gene mutations are associated with various human diseases, but the cellular functions of MTM proteins are not clearly defined. We found that inactivation of MTM-1 caused significant reduction in cell corpses in strong loss-of-function mutants of ced-1, ced-6, ced-7, and ced-2, but not in animals deficient in the ced-5, ced-12, or ced-10 genes. In contrast, overexpression of MTM-1 resulted in accumulation of cell corpses. This effect is dependent on the lipid phosphatase activity of MTM-1. We show that loss of mtm-1 function accelerates the clearance of cell corpses by promoting their internalization. Importantly, the reduction of cell corpses caused by mtm-1 RNAi not only requires the activities of CED-5, CED-12, and CED-10, but also needs the functions of the phosphatidylinositol 3-kinases (PI3Ks) VPS-34 and PIKI-1. We found that MTM-1 localizes to the plasma membrane in several known engulfing cell types and may modulate the level of phosphatidylinositol 3-phosphate (PtdIns(3)P) in vivo. We propose that MTM-1 negatively regulates cell corpse engulfment through the CED-5/CED-12/CED-10 module by dephosphorylating PtdIns(3)P on the plasma membrane
Conformational Changes and Slow Dynamics through Microsecond Polarized Atomistic Molecular Simulation of an Integral Kv1.2 Ion Channel
Structure and dynamics of voltage-gated ion channels, in particular the motion of
the S4 helix, is a highly interesting and hotly debated topic in current
membrane protein research. It has critical implications for insertion and
stabilization of membrane proteins as well as for finding how transitions occur
in membrane proteins—not to mention numerous applications in drug
design. Here, we present a full 1 µs atomic-detail molecular dynamics
simulation of an integral Kv1.2 ion channel, comprising 120,000 atoms. By
applying 0.052 V/nm of hyperpolarization, we observe structural rearrangements,
including up to 120° rotation of the S4 segment, changes in
hydrogen-bonding patterns, but only low amounts of translation. A smaller
rotation (∼35°) of the extracellular end of all S4 segments is
present also in a reference 0.5 µs simulation without applied field,
which indicates that the crystal structure might be slightly different from the
natural state of the voltage sensor. The conformation change upon
hyperpolarization is closely coupled to an increase in 310 helix
contents in S4, starting from the intracellular side. This could support a model
for transition from the crystal structure where the hyperpolarization
destabilizes S4–lipid hydrogen bonds, which leads to the helix
rotating to keep the arginine side chains away from the hydrophobic phase, and
the driving force for final relaxation by downward translation is partly
entropic, which would explain the slow process. The coordinates of the
transmembrane part of the simulated channel actually stay closer to the recently
determined higher-resolution Kv1.2 chimera channel than the starting structure
for the entire second half of the simulation (0.5–1 µs).
Together with lipids binding in matching positions and significant thinning of
the membrane also observed in experiments, this provides additional support for
the predictive power of microsecond-scale membrane protein simulations
Repertoire of Intensive Care Unit Pneumonia Microbiota
Despite the considerable number of studies reported to date, the causative agents of pneumonia are not completely identified. We comprehensively applied modern and traditional laboratory diagnostic techniques to identify microbiota in patients who were admitted to or developed pneumonia in intensive care units (ICUs). During a three-year period, we tested the bronchoalveolar lavage (BAL) of patients with ventilator-associated pneumonia, community-acquired pneumonia, non-ventilator ICU pneumonia and aspiration pneumonia, and compared the results with those from patients without pneumonia (controls). Samples were tested by amplification of 16S rDNA, 18S rDNA genes followed by cloning and sequencing and by PCR to target specific pathogens. We also included culture, amoeba co-culture, detection of antibodies to selected agents and urinary antigen tests. Based on molecular testing, we identified a wide repertoire of 160 bacterial species of which 73 have not been previously reported in pneumonia. Moreover, we found 37 putative new bacterial phylotypes with a 16S rDNA gene divergence ≥98% from known phylotypes. We also identified 24 fungal species of which 6 have not been previously reported in pneumonia and 7 viruses. Patients can present up to 16 different microorganisms in a single BAL (mean ± SD; 3.77±2.93). Some pathogens considered to be typical for ICU pneumonia such as Pseudomonas aeruginosa and Streptococcus species can be detected as commonly in controls as in pneumonia patients which strikingly highlights the existence of a core pulmonary microbiota. Differences in the microbiota of different forms of pneumonia were documented
Convergence of Free Energy Profile of Coumarin in Lipid Bilayer
Atomistic molecular dynamics (MD) simulations of druglike
molecules
embedded in lipid bilayers are of considerable interest as models
for drug penetration and positioning in biological membranes. Here
we analyze partitioning of coumarin in dioleoylphosphatidylcholine
(DOPC) bilayer, based on both multiple, unbiased 3 μs MD simulations
(total length) and free energy profiles along the bilayer normal calculated
by biased MD simulations (∼7 μs in total). The convergences
in time of free energy profiles calculated by both umbrella sampling
and z-constraint techniques are thoroughly analyzed. Two sets of starting
structures are also considered, one from unbiased MD simulation and
the other from “pulling” coumarin along the bilayer
normal. The structures obtained by pulling simulation contain water
defects on the lipid bilayer
surface, while those acquired from unbiased simulation have no membrane
defects. The free energy profiles converge more rapidly when starting
frames from unbiased simulations are used. In addition, z-constraint
simulation leads to more rapid convergence than umbrella sampling,
due to quicker relaxation of membrane defects. Furthermore, we show
that the choice of RESP, PRODRG, or Mulliken charges considerably
affects the resulting free energy profile of our model drug along
the bilayer normal. We recommend using z-constraint biased MD simulations
based on starting geometries acquired from unbiased MD simulations
for efficient calculation of convergent free energy profiles of druglike
molecules along bilayer normals. The calculation of free energy profile
should start with an unbiased simulation, though the polar molecules
might need a slow pulling afterward. Results obtained with the recommended
simulation protocol agree well with available experimental data for
two coumarin derivatives
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