The Rad9-Rad1-Hus1 checkpoint clamp activates the DNA damage response and promotes DNA repair. DNA loading on the central channel of the Rad9-Rad1-Hus1 complex is required to execute its biological ...functions. Because Rad9A has the highest DNA affinity among the three subunits, we determined the domains and functional residues of human Rad9A that are critical for DNA interaction. The N-terminal globular domain (residues 1-133) had 3.7-fold better DNA binding affinity than the C-terminal globular domain (residues 134-266) of Rad9A.sup.1-266 . Rad9A.sup.1-266 binds DNA 16-, 60-, and 30-fold better than Rad9A.sup.1-133, Rad9A.sup.134-266, and Rad9A.sup.94-266, respectively, indicating that different regions cooperatively contribute to DNA binding. We show that basic residues including K11, K15, R22, K78, K220, and R223 are important for DNA binding. The reductions on DNA binding of Ala substituted mutants of these basic residues show synergistic effect and are dependent on their residential Rad9A deletion constructs. Interestingly, deletion of a loop (residues 160-163) of Rad9A.sup.94-266 weakens DNA binding activity by 4.1-fold as compared to wild-type (WT) Rad9A.sup.94-266 . Cellular sensitivity to genotoxin of rad9A knockout cells is restored by expressing WT-Rad9A.sup.full . However, rad9A knockout cells expressing Rad9A mutants defective in DNA binding are more sensitive to H.sub.2 O.sub.2 as compared to cells expressing WT-Rad9A.sup.full . Only the rad9A knockout cells expressing loop-deleted Rad9A mutant are more sensitive to hydroxyurea than cells expressing WT-Rad9A. In addition, Rad9A-DNA interaction is required for DNA damage signaling activation. Our results indicate that DNA association by Rad9A is critical for maintaining cell viability and checkpoint activation under stress.
Asthma is a chronic inflammatory airway disease accounting for severe morbidity and mortality in children. To determine the characteristics of traditional Chinese medicine (TCM) used to treat ...pediatric asthma, we conducted a nationwide population‐based study by analyzing a cohort of one million randomly sampled patients from the beneficiaries of the National Health Insurance Program in Taiwan from 2002 to 2010. Children under 18 years of age with newly diagnosed asthma (ICD‐9‐CM code: 493, N = 45 833) were enrolled, and 57.95% (N = 26 585) of them had used TCM. The number of TCM users was significantly more than that of non‐TCM users in school‐age children. The most commonly prescribed TCM formula is Ding‐chuan‐tang, or Xing‐ren (Semen Armeniacae Amarum) for the single herb. Our study is the first to reveal characteristics and prescription patterns of the use of TCM in children with asthma. Further research is needed to elucidate the efficacy and safety of these Chinese herbal products.
Short gamma-ray bursts within 200 Mpc Dichiara, S; Troja, E; O’Connor, B ...
Monthly notices of the Royal Astronomical Society,
03/2020, Letnik:
492, Številka:
4
Journal Article
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ABSTRACT
We present a systematic search for short-duration gamma-ray bursts (GRBs) in the local Universe based on 14 yr of observations with the Neil Gehrels Swift Observatory. We cross-correlate the ...GRB positions with the GLADE catalogue of nearby galaxies, and find no event at a distance ≲100 Mpc and four plausible candidates in the range 100 Mpc ≲ D ≲ 200 Mpc. Although affected by low statistics, this number is higher than the one expected for chance alignments to random galaxies, and possibly suggests a physical association between these bursts and nearby galaxies. By assuming a local origin, we use these events to constrain the range of properties for X-ray counterparts of neutron star mergers. Optical upper limits place tight constraints on the onset of a blue kilonova, and imply either low masses ($\lesssim 10^{-3}\, \mathrm{M}_{\odot }$) of lanthanide-poor ejecta or unfavorable orientations (θobs ≳ 30 deg). Finally, we derive that the all-sky rate of detectable short GRBs within 200 Mpc is $1.3^{+1.7}_{-0.8}$ yr−1 (68 per cent confidence interval), and discuss the implications for the GRB outflow structure. If these candidates are instead of cosmological origin, we set a upper limit of ≲2.0 yr−1 (90 per cent confidence interval) to the rate of nearby events detectable with operating gamma-ray observatories, such as Swift and Fermi.
The Afterglow and Kilonova of the Short GRB 160821B Troja, E.; Castro-Tirado, A. J.; Gonzalez, J Becerra ...
Monthly notices of the Royal Astronomical Society,
08/2019, Letnik:
489, Številka:
2
Journal Article
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GRB 160821B is a short duration gamma-ray burst (GRB) detected and localized by the Neil Gehrels Swift Observatory in the outskirts of a spiral galaxy at z = 0.1613, at a projected physical offset of ...16 kpc from the galaxy’s center. We present X-ray, optical/nIR, and radio observations of its counterpart and model them with two distinct components of emission: a standard afterglow, arising from the interaction of the relativistic jet with the surrounding medium, and a kilonova, powered by the radioactive decay of the sub-relativistic ejecta. Broadband modelling of the afterglow data reveals a weak reverse shock propagating backward into the jet, and a likely jet-break at 3.5 d. This is consistent with a structured jet seen slightly off-axis (θview ∼ θcore) while expanding into a low-density medium (n ≈ 10−3 cm−3). Analysis of the kilonova properties suggests a rapid evolution towards red colours, similar toAT2017gfo, and a low-nIR luminosity, possibly due to the presence of a long-lived neutron star. The global properties of the environment, the inferred low mass (Mej <~ 0.006 Msun) and velocities (vej >~ 0.05c) of lanthanide-rich ejecta are consistent with a binary neutron star merger progenitor.
ABSTRACT We report the results of our observing campaign on GRB 140903A, a nearby (z = 0.351) short-duration (T90 ∼ 0.3 s) gamma-ray burst discovered by Swift. We monitored the X-ray afterglow with ...Chandra up to 15 days after the burst and detected a steeper decay of the X-ray flux after tj 1 day. Continued monitoring at optical and radio wavelengths showed a similar decay in flux at nearly the same time, and we interpret it as evidence of a narrowly collimated jet. By using the standard fireball model to describe the afterglow evolution, we derive a jet opening angle θj 5° and a collimation-corrected total energy release E 2 erg. We further discuss the nature of the GRB progenitor system. Three main lines disfavor a massive star progenitor: the properties of the prompt gamma-ray emission, the age and low star formation rate of the host galaxy, and the lack of a bright supernova. We conclude that this event likely originated from a compact binary merger.
The largest glitch observed in the Crab pulsar Shaw, B; Lyne, A G; Stappers, B W ...
Monthly notices of the Royal Astronomical Society,
08/2018, Letnik:
478, Številka:
3
Journal Article
Postoperative residual neuromuscular block is a frequent occurrence. Recent surveys of clinical practice in Europe suggest that neuromuscular blocking drugs are often administered without appropriate ...monitoring. No comparable survey has been undertaken in the United States (US). From this survey, we compared current clinical neuromuscular practice and attitudes between anesthesia practitioners in the US and Europe.
We conducted an Internet-based survey among anesthesia practitioners in the US and Europe. The Anesthesia Patient Safety Foundation and the European Society of Anaesthesiology e-mailed all of their active members, inviting them to anonymously answer a series of questions on a dedicated Internet Protocol address-sensitive website. The survey was available online for 60 days. The chi(2) test and Fisher's exact test were used to compare clinical survey items between the 2 cohorts.
A total of 2636 completed surveys were received. Most respondents from the US (64.1%) and Europe (52.2%) estimated the incidence of clinically significant postoperative residual neuromuscular weakness to be <1% (P < 0.0001). Routine pharmacologic reversal was less common in Europe than in the US (18% vs 34.2%, respectively; P < 0.0001), and quantitative monitors were available to fewer clinicians in the US (22.7%) than in Europe (70.2%) (P < 0.0001). However, 19.3% of Europeans and 9.4% of Americans never use neuromuscular monitors. Most respondents reported that neither conventional nerve stimulators nor quantitative train-of-four monitors should be part of minimum monitoring standards.
Our results suggest a lack of agreement among anesthesia providers about the best way to monitor neuromuscular function. Efforts to improve awareness by developing formal training programs and/or publishing official guidelines on best practices to reduce the incidence of postoperative neuromuscular weakness and patient morbidity are warranted.
Abstract
We study the high-energy properties of GRB 181123B, a short gamma-ray burst (sGRB) at redshift
z
≈ 1.75. We show that, despite its nominal short duration with
T
90
< 2 s, this burst displays ...evidence of a temporally extended emission (EE) at high energies and that the same trend is observed in the majority of sGRBs at
z
≳ 1. We discuss the impact of instrumental selection effects on the GRB classification, stressing that the measured
T
90
is not an unambiguous indicator of the burst physical origin. By examining their environment (e.g., stellar mass, star formation, offset distribution), we find that these high-
z
sGRBs share many properties of long GRBs at a similar distance and are consistent with a short-lived progenitor system. If produced by compact binary mergers, these sGRBs with EE may be easier to localize at large distances and herald a larger population of sGRBs in the early universe.
Kinases perform phosphoryl-transfer reactions in milliseconds; without enzymes, these reactions would take about 8,000 years under physiological conditions. Despite extensive studies, a comprehensive ...understanding of kinase energy landscapes, including both chemical and conformational steps, is lacking. Here we scrutinize the microscopic steps in the catalytic cycle of adenylate kinase, through a combination of NMR measurements during catalysis, pre-steady-state kinetics, molecular-dynamics simulations and crystallography of active complexes. We find that the Mg(2+) cofactor activates two distinct molecular events: phosphoryl transfer (>10(5)-fold) and lid opening (10(3)-fold). In contrast, mutation of an essential active site arginine decelerates phosphoryl transfer 10(3)-fold without substantially affecting lid opening. Our results highlight the importance of the entire energy landscape in catalysis and suggest that adenylate kinases have evolved to activate key processes simultaneously by precise placement of a single, charged and very abundant cofactor in a preorganized active site.
•MYH knockdown human cells are more sensitive to H2O2 than the control cells.•hMYH knockdown cells have altered DNA signaling activation in response to oxidative stress.•hMYH knockdown cells contain ...higher levels of 8-oxoG lesions than the control cells following H2O2 treatment.•Human cells with overexpression of mouse Myh are more resistant to killing by oxidative stress than control cells.•MYH protects cell from oxidative DNA damage and is critical for proper cellular response to DNA damage.
MutY DNA glycosylase homologs (MYH or MUTYH) reduce G:C to T:A mutations by removing misincorporated adenines or 2-hydroxyadenines paired with guanine or 8-oxo-7,8-dihydroguanine (8-oxo-G). Mutations in the human MYH (hMYH) gene are associated with the colorectal cancer predisposition syndrome MYH-associated polyposis. To examine the function of MYH in human cells, we regulated MYH gene expression by knockdown or overproduction. MYH knockdown human HeLa cells are more sensitive to the killing effects of H2O2 than the control cells. In addition, hMYH knockdown cells have altered cell morphology, display enhanced susceptibility to apoptosis, and have altered DNA signaling activation in response to oxidative stress. The cell cycle progression of hMYH knockdown cells is also different from that of the control cells following oxidative stress. Moreover, hMYH knockdown cells contain higher levels of 8-oxo-G lesions than the control cells following H2O2 treatment. Although MYH does not directly remove 8-oxo-G, MYH may generate favorable substrates for other repair enzymes. Overexpression of mouse Myh (mMyh) in human mismatch repair defective HCT15 cells makes the cells more resistant to killing and refractory to apoptosis by oxidative stress than the cells transfected with vector. In conclusion, MYH is a vital DNA repair enzyme that protects cells from oxidative DNA damage and is critical for a proper cellular response to DNA damage.
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