The PARP-1 inhibitor Olaparib causes retention of γ-H2AX foci in BRCA1 heterozygote cells following exposure to gamma radiation

This article is made available through the Brunel Open Access Publishing Fund. Copyright © 2013 Emma C. Bourton et al. This is an open access article distributed under the Creative Commons Attribution Li-cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A novel treatment for cancer patients with homozygous deletions of BRCA1 and BRCA2 is to use drugs that inhibit the enzyme poly(ADP-ribose) polymerase (PARP). Specific inhibition of PARP-1 can induce synthetic lethality in irradi- ated cancer cells while theoretically leaving normal tissue unaffected. We recently demonstrated in a cell survival assay that lymphoblastoid cells with mono-allelic mutations of BRCA1 were hypersensitive to gamma radiation in the pres- ence of the PARP-1 inhibitor Olaparib compared to normal cells and mono-allelic BRCA2 cells. To determine if the enhanced radiation sensitivity was due to a persistence of DNA strand breaks, we performed γ-H2AX foci analysis in cells derived from two normal individuals, three heterozygous BRCA1 and three heterozygous BRCA2 cell lines. Cells were exposed to 2 Gy gamma radiation in the presence or absence of 5 μM Olaparib. Using immunofluorescence and imaging flow cytometry, foci were measured in untreated cells and at 0.5, 3, 5 and 24 hours post-irradiation. In all lymphoblastoid cells treated with 2 Gy gamma radiation, there was a predictable induction of DNA strand breaks, with a modest but significant retention of foci over 24 hours in irradiated cells treated with Olaparib (ANOVA P < 0.05). However, in mono-allelic BRCA1 cells, there was a failure to fully repair DNA double-strand breaks (DSB) in the pres- ence of Olaparib, evidenced by a significant retention of foci at 24 hours’ post irradiation (t-Test P < 0.05). These data show that the cellular hypersensitivity of mono-allelic BRCA1 lymphoblastoid cells to gamma radiation in the presence of the Olaparib is due to the retention of DNA DSB. These data may indicate that patients with inherited mutations in the BRCA1 gene treated with radiotherapy and PARP-1 inhibitors may experience elevated radiation-associated normal tissue toxicity.Vidal Sassoon Foundation of America

Observation of Excess J/ψ Yield at Very Low Transverse Momenta in Au+Au Collisions at sqrt[s_{NN}]=200 GeV and U+U Collisions at sqrt[s_{NN}]=193 GeV.

We report on the first measurements of J/ψ production at very low transverse momentum (p_{T}&lt;0.2  GeV/c) in hadronic Au+Au collisions at sqrt[s_{NN}]=200  GeV and U+U collisions at sqrt[s_{NN}]=193  GeV. Remarkably, the inferred nuclear modification factor of J/ψ at midrapidity in Au+Au (U+U) collisions reaches about 24 (52) for p_{T}&lt;0.05  GeV/c in the 60%-80% collision centrality class. This noteworthy enhancement cannot be explained by hadronic production accompanied by cold and hot medium effects. In addition, the dN/dt distribution of J/ψ for the very low p_{T} range is presented for the first time. The distribution is consistent with that expected from the Au nucleus and shows a hint of interference. Comparison of the measurements to theoretical calculations of coherent production shows that the excess yield can be described reasonably well and reveals a partial disruption of coherent production in semicentral collisions, perhaps due to the violent hadronic interactions. Incorporating theoretical calculations, the results strongly suggest that the dramatic enhancement of J/ψ yield observed at extremely low p_{T} originates from coherent photon-nucleus interactions. In particular, coherently produced J/ψ's in violent hadronic collisions may provide a novel probe of the quark-gluon plasma

Measurement of inclusive J/ψ suppression in Au+Au collisions at sNN=200 GeV through the dimuon channel at STAR

J/ψ suppression has long been considered a sensitive signature of the formation of the Quark-Gluon Plasma (QGP) in relativistic heavy-ion collisions. In this letter, we present the first measurement of inclusive J/ψ production at mid-rapidity through the dimuon decay channel in Au+Au collisions at sNN=200 GeV with the STAR experiment. These measurements became possible after the installation of the Muon Telescope Detector was completed in 2014. The J/ψ yields are measured in a wide transverse momentum (pT) range of 0.15 GeV/c to 12 GeV/c from central to peripheral collisions. They extend the kinematic reach of previous measurements at RHIC with improved precision. In the 0-10% most central collisions, the J/ψ yield is suppressed by a factor of approximately 3 for pT&gt;5 GeV/c relative to that in p+p collisions scaled by the number of binary nucleon-nucleon collisions. The J/ψ nuclear modification factor displays little dependence on pT in all centrality bins. Model calculations can qualitatively describe the data, providing further evidence for the color-screening effect experienced by J/ψ mesons in the QGP

Charge-dependent pair correlations relative to a third particle in p + Au and d + Au collisions at RHIC

Quark interactions with topological gluon configurations can induce chirality imbalance and local parity violation in quantum chromodynamics. This can lead to electric charge separation along the strong magnetic field in relativistic heavy-ion collisions – the chiral magnetic effect (CME). We report measurements by the STAR collaboration of a CME-sensitive observable in p+Au and d+Au collisions at 200 GeV, where the CME is not expected, using charge-dependent pair correlations relative to a third particle. We observe strong charge-dependent correlations similar to those measured in heavy-ion collisions. This bears important implications for the interpretation of the heavy-ion data

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

Measurements of the transverse-momentum-dependent cross sections of J /ψ production at mid-rapidity in proton+proton collisions at s =510 and 500 GeV with the STAR detector

We present measurements of the differential cross sections of inclusive J/ψ meson production as a function of transverse momentum (pTJ/ψ) using the μ+μ- and e+e- decay channels in proton+proton collisions at center-of-mass energies of 510 and 500 GeV, respectively, recorded by the STAR detector at the Relativistic Heavy Ion Collider. The measurement from the μ+μ- channel is for

Bulk properties of the system formed in Au+Au collisions at sNN =14.5 GeV at the BNL STAR detector

We report systematic measurements of bulk properties of the system created in Au+Au collisions at sNN=14.5 GeV recorded by the STAR detector at the Relativistic Heavy Ion Collider (RHIC). The transverse momentum spectra of π±, K±, and p(p) are studied at midrapidity (|y|&lt;0.1) for nine centrality intervals. The centrality, transverse momentum (pT), and pseudorapidity (η) dependence of inclusive charged particle elliptic flow (v2), and rapidity-odd charged particles directed flow (v1) results near midrapidity are also presented. These measurements are compared with the published results from Au+Au collisions at other energies, and from Pb+Pb collisions at sNN=2.76 TeV. The results at sNN=14.5 GeV show similar behavior as established at other energies and fit well in the energy dependence trend. These results are important as the 14.5-GeV energy fills the gap in μB, which is of the order of 100 MeV, between sNN=11.5 and 19.6 GeV. Comparisons of the data with UrQMD and AMPT models show poor agreement in general

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente