190 research outputs found
Granulocyte-derived extracellular vesicles activate monocytes and are associated with mortality in intensive care unit patients
Photometric observations of selected, optically bright quasars for Space Interferometry Mission and other future celestial reference frames
Photometric observations of 235 extragalactic objects that are potential
targets for the Space Interferometry Mission (SIM) are presented. Mean B, V, R,
I magnitudes at the 5% level are obtained at 1 - 4 epochs between 2005 and 2007
using the 1-m telescopes at Cerro Tololo Inter-American Observatory and Naval
Observatory Flagstaff Station. Of the 134 sources which have V magnitudes in
the Veron & Veron-Cetty catalog a difference of over 1.0 mag is found for the
observed-catalog magnitudes for about 36% of the common sources, and 10 sources
show over 3 mag difference. Our first set of observations presented here form
the basis of a long-term photometric variability study of the selected
reference frame sources to assist in mission target selection and to support in
general QSO multi-color photometric variability studies.Comment: 40 pages, 13 figures, 4 table
A Conformation Change in the Extracellular Domain that Accompanies Desensitization of Acid-sensing Ion Channel (ASIC) 3
Acid-sensing ion channels (ASICs) are thought to trigger some forms of acid-induced pain and taste, and to contribute to stroke-induced neural damage. After activation by low extracellular pH, different ASICs undergo desensitization on time scales from 0.1 to 10 s. Consistent with a substantial conformation change, desensitization slows dramatically when temperature drops (Askwith, C.C., C.J. Benson, M.J. Welsh, and P.M. Snyder. 2001. PNAS. 98:6459–6463). The nature of this conformation change is unknown, but two studies showed that desensitization rate is altered by mutations on or near the first transmembrane domain (TM1) (Coric, T., P. Zhang, N. Todorovic, and C.M. Canessa. 2003. J. Biol. Chem. 278:45240–45247; Pfister, Y., I. Gautschi, A.-N. Takeda, M. van Bemmelen, S. Kellenberger, and L. Schild. 2006. J. Biol. Chem. 281:11787–11791). Here we show evidence of a specific conformation change associated with desensitization. When mutated from glutamate to cysteine, residue 79, which is some 20 amino acids extracellular to TM1, can be altered by cysteine-modifying reagents when the channel is closed, but not when it is desensitized; thus, desensitization appears to conceal the residue from the extracellular medium. D78 and E79 are a pair of adjacent acidic amino acids that are highly conserved in ASICs yet absent from epithelial Na+ channels, their acid-insensitive relatives. Despite large effects on desensitization by mutations at positions 78 and 79—including a shift to 10-fold lower proton concentration with the E79A mutant—there are not significant effects on activation
Safety of paclitaxel-coated balloon angioplasty for femoropopliteal peripheral artery disease
OBJECTIVES: The aim of this study was to assess safety outcomes of femoropopliteal drug-coated balloon (DCB) angioplasty using patient-level data from the Lutonix clinical program.
BACKGROUND: A recent systematic review and meta-analysis of heterogenous trials and summary-level data identified increased long-term mortality in patients treated with paclitaxel-coated balloons and stents.
METHODS: We evaluated DCB angioplasty (n = 1,093) and uncoated balloon angioplasty (percutaneous transluminal angioplasty [PTA]) (n = 250) outcomes in LEVANT 1 (The Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis), LEVANT 2 (Moxy Drug Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Femoropopliteal Arteries), and the LEVANT Japan Clinical Trial. Hazard ratios (HRs) were calculated with Cox proportional hazards modeling.
RESULTS: There were no significant differences in mortality rates between DCB angioplasty and PTA. The 5-year HR was 1.01 (95% confidence interval [CI]: 0.68 to 1.52) in the aggregated LEVANT trials. The 2-year HR after DCB angioplasty was 0.99 (95% CI: 0.25 to 3.95) in LEVANT 1, 1.40 (95% CI: 0.62 to 3.14) in LEVANT 2, and 0.32 (95% CI: 0.05 to 1.92) in the LEVANT Japan Clinical Trial. The 5-year HR was 1.60 (95% CI: 0.94 to 2.72) in LEVANT 2. Adverse events and causes of death were balanced, without clustering between DCB angioplasty and PTA. Patients who underwent paclitaxel or nonpaclitaxel reinterventions had higher survival rates than those who did not undergo reinterventions. Baseline covariates predicting mortality included, among others, age (HR: 1.03 per year; p \u3c 0.0001), prior treatment of target lesion (HR: 1.67; p = 0.022), arrhythmia (HR: 1.65; p = 0.031), and diabetes (HR: 1.18; p = 0.047), without differences between the 2 arms. No dose-response relationship was identified when adjusted for key predictors of mortality.
CONCLUSIONS: Analyses of patient-level data identified no mortality differences between DCB angioplasty and PTA. Furthermore, the lack of dose-response relationships or clustering of causes of death argues against a causal relationship between paclitaxel and mortality. (LEVANT 1, The Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis [LEVANT 1], NCT00930813; Moxy Drug Coated Balloon vs. Standard Balloon Angioplasty for the Treatment of Femoropopliteal Arteries [LEVANT 2], NCT01412541; LEVANT 2 Continued Access Registry, NCT01628159; LEVANT Japan Clinical Trial, NCT01816412)
WMAP5 and the Cluster Mass Function
The recently revised cosmological constraints from the Five-Year WMAP data
ameliorate previous tension between cosmological constraints from the microwave
background and from cluster abundances. We demonstrate that the revised
estimates of cosmological parameters are in excellent agreement with the mass
function of X-ray clusters in the Sloan Digital Sky Survey. Velocity
segregation between galaxies and the underlying dark matter could cause virial
mass estimates to be biased, causing the mass scale of the mass function to be
offset from the true value. Modest velocity segregation
(=1.13) is sufficient to match the
mass function to the Five-Year WMAP results. When the new WMAP results are
combined with constraints from supernovae and baryon acoustic oscillations,
there is no need for velocity segregation
(=1.050.05). This result agrees with
expectations for velocity segregation from state-of-the-art numerical
simulations of clusters. Together with the improved agreement between the new
WMAP results and recent cosmic shear measurements, this result demonstrates
that the amplitude of large-scale structure in the nearby universe matches that
predicted from the structure seen in the microwave background. The new
constraint we place on velocity segregation in clusters indicates that virial
mass estimates for clusters are reasonably accurate. This result suggests that
future cluster surveys will be able to probe both cosmological parameters and
fundamental cluster physics.Comment: 4 pages, 2 color figures, submitted to ApJ Letter
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The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing.
Transcriptional regulation in eukaryotes occurs at promoter-proximal regions wherein transcriptionally engaged RNA polymerase II (Pol II) pauses before proceeding toward productive elongation. The role of chromatin in pausing remains poorly understood. Here, we demonstrate that the histone deacetylase SIRT6 binds to Pol II and prevents the release of the negative elongation factor (NELF), thus stabilizing Pol II promoter-proximal pausing. Genetic depletion of SIRT6 or its chromatin deficiency upon glucose deprivation causes intragenic enrichment of acetylated histone H3 at lysines 9 (H3K9ac) and 56 (H3K56ac), activation of cyclin-dependent kinase 9 (CDK9)-that phosphorylates NELF and the carboxyl terminal domain of Pol II-and enrichment of the positive transcription elongation factors MYC, BRD4, PAF1, and the super elongation factors AFF4 and ELL2. These events lead to increased expression of genes involved in metabolism, protein synthesis, and embryonic development. Our results identified SIRT6 as a Pol II promoter-proximal pausing-dedicated histone deacetylase
Infall Regions and Scaling Relations of X-ray Selected Groups
We use the Fifth Data Release of the Sloan Digital Sky Survey to study
X-ray-selected galaxy groups and compare their properties to clusters. We
search for infall patterns around the groups and use these to measure group
mass profiles to large radii. In previous work, we analyzed infall patterns for
an X-ray-selected sample of 72 clusters from the ROSAT All-Sky Survey. Here, we
extend this approach to a sample of systems with smaller X-ray fluxes selected
from the 400 Square Degree serendipitous survey of clusters and groups in ROSAT
pointed observations. We identify 16 groups with SDSS DR5 spectroscopy, search
for infall patterns, and compute mass profiles out to 2-6 Mpc from the group
centers with the caustic technique. No other mass estimation methods are
currently available at such large radii for these low-mass groups, because the
virial estimate requires dynamical equilibrium and the gravitational lensing
signal is too weak. Despite the small masses of these groups, most display
recognizable infall patterns. We use caustic and virial mass estimates to
measure the scaling relations between different observables, extending these
relations to smaller fluxes and luminosities than many previous surveys. Close
inspection reveals that three of the groups are subclusters in the outskirts of
larger clusters. A fourth group is apparently undergoing a group-group merger.
These four merging groups represent the most extreme outliers in the scaling
relations. Excluding these groups, we find ,
consistent with previous determinations for both clusters and groups.
Understanding cluster and group scaling relations is crucial for measuring
cosmological parameters from clusters.Comment: published in AJ Feb 2010, significantly revised in response to
referee report, title edite
A behavioral database for masked form priming
Reading involves a process of matching an orthographic input with stored representations in lexical memory. The masked priming paradigm has become a standard tool for investigating this process. Use of existing results from this paradigm can be limited by the precision of the data and the need for cross-experiment comparisons that lack normal experimental controls. Here, we present a single, large, high-precision, multicondition experiment to address these problems. Over 1,000 participants from 14 sites responded to 840 trials involving 28 different types of orthographically related primes (e.g., castfe–CASTLE) in a lexical decision task, as well as completing measures of spelling and vocabulary. The data were indeed highly sensitive to differences between conditions: After correction for multiple comparisons, prime type condition differences of 2.90 ms and above reached significance at the 5% level. This article presents the method of data collection and preliminary findings from these data, which included replications of the most widely agreed-upon differences between prime types, further evidence for systematic individual differences in susceptibility to priming, and new evidence regarding lexical properties associated with a target word’s susceptibility to priming. These analyses will form a basis for the use of these data in quantitative model fitting and evaluation and for future exploration of these data that will inform and motivate new experiments
Distinct Mechanisms for Induction and Tolerance Regulate the Immediate Early Genes Encoding Interleukin 1β and Tumor Necrosis Factor α
Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators. © 2013 Adamik et al
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