Abstract
Objective: Oxidative stress is implicated in the initiation and progression of congestive heart failure, but the putative reactive species and cellular targets involved remain undefined. We ...have previously shown that peroxynitrite (ONOO−, an aggressive biological oxidant and nitrating agent) potently inhibits myofibrillar creatine kinase (MM-CK), a critical controller of contractility known to be impaired during heart failure. Here we hypothesized that nitration and inhibition of MM-CK participate in cardiac failure in vivo. Methods: Heart failure was induced in rats by myocardial infarction (left coronary artery ligation) and confirmed by histological analysis at 8 weeks postinfarct (1.3±1.4 vs. 37.7±3.2% left ventricular circumference; sham control vs. CHF, n = 10 each). Results: Immunohistochemistry demonstrated significantly increased protein nitration in failing myocardium compared to control (optical density: 0.58±0.06 vs. 0.93±0.09, sham vs. CHF, P<0.05). Significant decreases in MM-CK activity and content were observed in failing hearts (MM-CK k
cat: 6.0±0.4 vs. 3.0±0.3 μmol/nM M-CK/min, P<0.05; 6.8±1.3 vs. 4.7±1.2% myofibrillar protein, P<0.05), with no change in myosin ATPase activity. In separate experiments, isolated rat cardiac myofibrils were exposed to ONOO− (2-250 μM) and enzyme studies were conducted. Identical to in vivo studies, selective reductions in MM-CK were observed at ONOO− concentrations as low as 2 μM (IC50=92.5±6.0 μM); myosin ATPase was unaffected with ONOO− concentrations as high as 250 μM. Concentration dependent nitration of MM-CK occurred and extent of nitration was statistically correlated to extent of CK inhibition (P<0.001). Immunoprecipitation of MM-CK from failing left ventricle yielded significant evidence of tyrosine nitration. Conclusion: These data demonstrate that cardiac ONOO− formation and perturbation of myofibrillar energetic controllers occur during experimental heart failure; MM-CK may be a critical cellular target in this setting.
We present measurements of the ep->ep pi^0 cross section extracted at two values of four-momentum transfer Q^2=1.9 GeV^2 and Q^2=2.3 GeV^2 at Jefferson Lab Hall A. The kinematic range allows to study ...the evolution of the extracted hadronic tensor as a function of Q^2 and W. Results will be confronted with Regge inspired calculations and GPD predictions. An intepretation of our data within the framework of semi-inclusive deep inelastic scattering has also been attempted.
The CLAS12 drift chamber system Mestayer, M.D.; Adhikari, K.; Bennett, R.P. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
04/2020, Letnik:
959, Številka:
C
Journal Article
Recenzirano
Odprti dostop
The CEBAF Large Acceptance Spectrometer at 12 GeV (CLAS12) is located in Hall B, one of the experimental halls at Jefferson Lab. The forward part of CLAS12 is built around a superconducting toroidal ...magnet. The six coils of the toroid divide the detector azimuthally into six sectors. Each sector contains three multi-layer drift chambers for reconstructing the trajectories of charged particles originating from a fixed target.
Each of the 18 planar chambers has two “superlayers” of six layers each, with the wires in the two adjacent superlayers oriented at ±6° stereo angles. Each layer has 112 hexagonal cells spanning a range from about 5° to 40° in polar angle. The six-layer structure provides redundancy in track segment finding and good tracking efficiency even in the presence of some individual wire inefficiency. The design, construction, operation, and calibration methods are described, and estimates of the efficiency and resolution are presented from in-beam measurements.
High-precision 1H(e,e'p)pi(0) measurements at Q2 = 0.126 (GeV/c)2 are reported, which allow the determination of quadrupole amplitudes in the gamma*N-->Delta transition; they simultaneously test the ...reliability of electroproduction models. The derived quadrupole-to-dipole ( I = 3/2) amplitude ratios, R(SM) = (-6.5+/-0.2(stat+sys)+/-2.5(mod))% and R(EM) = (-2.1+/-0.2(stat+sys)+/-2.0(mod))%, are dominated by model error. Previous R(SM) and R(EM) results should be reconsidered after the model uncertainties associated with the method of their extraction are taken into account.
We present the results of the search for gravitational waves (GWs) associated with γ-ray bursts detected during the first observing run of the Advanced Laser Interferometer Gravitational-Wave ...Observatory (LIGO). We find no evidence of a GW signal for any of the 41 γ-ray bursts for which LIGO data are available with sufficient duration. For all γ-ray bursts, we place lower bounds on the distance to the source using the optimistic assumption that GWs with an energy of were emitted within the - Hz band, and we find a median 90% confidence limit of 71 Mpc at 150 Hz. For the subset of 19 short/hard γ-ray bursts, we place lower bounds on distance with a median 90% confidence limit of 90 Mpc for binary neutron star (BNS) coalescences, and 150 and 139 Mpc for neutron star-black hole coalescences with spins aligned to the orbital angular momentum and in a generic configuration, respectively. These are the highest distance limits ever achieved by GW searches. We also discuss in detail the results of the search for GWs associated with GRB 150906B, an event that was localized by the InterPlanetary Network near the local galaxy NGC 3313, which is at a luminosity distance of Mpc (z = 0.0124). Assuming the γ-ray emission is beamed with a jet half-opening angle , we exclude a BNS and a neutron star-black hole in NGC 3313 as the progenitor of this event with confidence >99%. Further, we exclude such progenitors up to a distance of 102 Mpc and 170 Mpc, respectively.
We present the results of targeted searches for gravitational-wave transients associated with gamma-ray bursts during the second observing run of Advanced LIGO and Advanced Virgo, which took place ...from 2016 November to 2017 August. We have analyzed 98 gamma-ray bursts using an unmodeled search method that searches for generic transient gravitational waves and 42 with a modeled search method that targets compact-binary mergers as progenitors of short gamma-ray bursts. Both methods clearly detect the previously reported binary merger signal GW170817, with p-values of <9.38 × 10−6 (modeled) and 3.1 × 10−4 (unmodeled). We do not find any significant evidence for gravitational-wave signals associated with the other gamma-ray bursts analyzed, and therefore we report lower bounds on the distance to each of these, assuming various source types and signal morphologies. Using our final modeled search results, short gamma-ray burst observations, and assuming binary neutron star progenitors, we place bounds on the rate of short gamma-ray bursts as a function of redshift for z ≤ 1. We estimate 0.07-1.80 joint detections with Fermi-GBM per year for the 2019-20 LIGO-Virgo observing run and 0.15-3.90 per year when current gravitational-wave detectors are operating at their design sensitivities.
Background
The aim was to evaluate long‐term effectiveness and safety of lanadelumab in patients ≥12 y old with hereditary angioedema (HAE) 1/2 (NCT02741596).
Methods
Rollover patients completing the ...HELP Study and continuing into HELP OLE received one lanadelumab 300 mg dose until first attack (dose‐and‐wait period), then 300 mg q2wks (regular dosing stage). Nonrollovers (newly enrolled) received lanadelumab 300 mg q2wks from day 0. Baseline attack rate for rollovers: ≥1 attack/4 weeks (based on run‐in period attack rate during HELP Study); for nonrollovers: historical attack rate ≥1 attack/12 weeks. The planned treatment period was 33 months.
Results
212 patients participated (109 rollovers, 103 nonrollovers); 81.6% completed ≥30 months on study (mean SD, 29.6 8.2 months). Lanadelumab markedly reduced mean HAE attack rate (reduction vs baseline: 87.4% overall). Patients were attack free for a mean of 97.7% of days during treatment; 81.8% and 68.9% of patients were attack free for ≥6 and ≥12 months, respectively. Angioedema Quality‐of‐Life total and domain scores improved from day 0 to end of study. Treatment‐emergent adverse events (TEAEs) (excluding HAE attacks) were reported by 97.2% of patients; most commonly injection site pain (47.2%) and viral upper respiratory tract infection (42.0%). Treatment‐related TEAEs were reported by 54.7% of patients. Most injection site reactions resolved within 1 hour (70.2%) or 1 day (92.6%). Six (2.8%) patients discontinued due to TEAEs. No treatment‐related serious TEAEs or deaths were reported. Eleven treatment‐related TEAEs of special interest were reported by seven (3.3%) patients.
Conclusion
Lanadelumab demonstrated sustained efficacy and acceptable tolerability with long‐term use in HAE patients.
Lanadelumab markedly reduced mean HAE attack rates versus baseline. Most patients were exposed to lanadelumab for an extended time and experienced prolonged attack‐free intervals. The final results from the HELP OLE further support the long‐term tolerability of lanadelumab 300 mg q2wks previously shown in the HELP Study and confirm the sustained benefit of treatment for long‐term prevention of HAE attacks.
Abbreviations: HAE, hereditary angioedema; q2wks,every 2 weeks, OLE, open label extension
Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene ...expression. The computational method PrediXcan uses
cis
-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (
n
= 169) and whole blood (
n
= 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with
TRIM4
(discovery
P
= 2.2 × 10
− 4
, replication
P
= 0.01), and
PYGL
(discovery
P
= 2.3 × 10
− 4
, replication
P
= 6.7 × 10
− 4
). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (
P
< 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus,
CXCR1
and
CXCR2
, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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