349 research outputs found
MCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex.
MCM8-9 complex is required for homologous recombination (HR)-mediated repair of double-strand breaks (DSBs). Here we report that MCM8-9 is required for DNA resection by MRN (MRE11-RAD50-NBS1) at DSBs to generate ssDNA. MCM8-9 interacts with MRN and is required for the nuclease activity and stable association of MRN with DSBs. The ATPase motifs of MCM8-9 are required for recruitment of MRE11 to foci of DNA damage. Homozygous deletion of the MCM9 found in various cancers sensitizes a cancer cell line to interstrand-crosslinking (ICL) agents. A cancer-derived point mutation or an SNP on MCM8 associated with premature ovarian failure (POF) diminishes the functional activity of MCM8. Therefore, the MCM8-9 complex facilitates DNA resection by the MRN complex during HR repair, genetic or epigenetic inactivation of MCM8 or MCM9 are seen in human cancers, and genetic inactivation of MCM8 may be the basis of a POF syndrome
Environment-mediated structure, surface redox activity and reactivity of ceria nanoparticles
Nanomaterials, with potential application as bio-medicinal agents, exploit the chemical properties of a solid, with the ability to be transported (like a molecule) to a variety of bodily compartments. However, the chemical environment can change significantly the structure and hence properties of a nanomaterial. Accordingly, its surface reactivity is critically dependent upon the nature of the (biological) environment in which it resides. Here, we use Molecular Dynamics (MD) simulation, Density Functional Theory (DFT) and aberration corrected TEM to predict and rationalise differences in structure and hence surface reactivity of ceria nanoparticles in different environments. In particular we calculate reactivity 'fingerprints' for unreduced and reduced ceria nanoparticles immersed in water and in vacuum. Our simulations predict higher activities of ceria nanoparticles, towards oxygen release, when immersed in water because the water quenches the coordinative unsaturation of surface ions. Conversely, in vacuum, surface ions relax into the body of the nanoparticle to relieve coordinative unsaturation, which increases the energy barriers associated with oxygen release. Our simulations also reveal that reduced ceria nanoparticles are more active towards surface oxygen release compared to unreduced nanoceria. In parallel, experiment is used to explore the activities of ceria nanoparticles that have suffered a change in environment. In particular, we compare the ability of ceria nanoparticles, in an aqueous environment, to scavenge superoxide radicals compared to the same batch of nanoparticles, which have first been dried and then rehydrated. The latter show a distinct reduction in activity, which we correlate to a change in the redox chemistry associated with moving between different environments. The reactivity of ceria nanoparticles is therefore not only environment dependent, but is also influenced by the transport pathway or history required to reach the particular environment in which its reactivity is to be exploited. Ă© 2013 The Royal Society of Chemistry
Radiative multipole moments of integer-spin fields in curved spacetime
Radiative multipole moments of scalar, electromagnetic, and linearized
gravitational fields in Schwarzschild spacetime are computed to third order in
v in a weak-field, slow-motion approximation, where v is a characteristic
velocity associated with the motion of the source. To zeroth order in v, a
radiative moment of order l is given by the corresponding source moment
differentiated l times with respect to retarded time. At second order in v,
additional terms appear inside the spatial integrals. These are near-zone
corrections which depend on the detailed behavior of the source. At third order
in v, the correction terms occur outside the spatial integrals, so that they do
not depend on the detailed behavior of the source. These are wave-propagation
corrections which are heuristically understood as arising from the scattering
of the radiation by the spacetime curvature surrounding the source. Our
calculations show that the wave-propagation corrections take a universal form
which is independent of multipole order and field type. We also show that in
general relativity, temporal and spatial curvatures contribute equally to the
wave-propagation corrections.Comment: 34 pages, ReVTe
Gravitational Radiation from Coalescing Binary Neutron Stars
We calculate the gravitational radiation produced by the merger and
coalescence of inspiraling binary neutron stars using 3-dimensional numerical
simulations. The stars are modeled as polytropes and start out in the
point-mass limit at wide separation. The hydrodynamic integration is performed
using smooth particle hydrodynamics (SPH) with Newtonian gravity, and the
gravitational radiation is calculated using the quadrupole approximation. We
have run several simulations, varying both the neutron star radius and the
equation of state. The resulting gravitational wave energy spectra are
rich in information about the hydrodynamics of merger and coalescence. In
particular, our results demonstrate that detailed information on both
and the equation of state can in principle be extracted from the spectrum.Comment: 33 pages, LaTex with RevTex macros; 21 figures available in
compressed PostScript format via anonymous ftp to
ftp://zonker.drexel.edu/papers/ns_coll_1 ; in press, Phys. Rev. D (Nov 15,
1994 issue
A flow cytometry-based method to simplify the analysis and quantification of protein association to chromatin in mammalian cells.
Protein accumulation on chromatin has traditionally been studied using immunofluorescence microscopy or biochemical cellular fractionation followed by western immunoblot analysis. As a way to improve the reproducibility of this kind of analysis, to make it easier to quantify and to allow a streamlined application in high-throughput screens, we recently combined a classical immunofluorescence microscopy detection technique with flow cytometry. In addition to the features described above, and by combining it with detection of both DNA content and DNA replication, this method allows unequivocal and direct assignment of cell cycle distribution of protein association to chromatin without the need for cell culture synchronization. Furthermore, it is relatively quick (takes no more than a working day from sample collection to quantification), requires less starting material compared with standard biochemical fractionation methods and overcomes the need for flat, adherent cell types that are required for immunofluorescence microscopy.Research in our laboratory is funded by Cancer Research UK (CRUK; programme grant C6/A11224), the European Research Council and the European Community Seventh Framework Programme (grant agreement no. HEALTHÂŹâF2ÂŹâ2010ÂŹâ259893 (DDResponse)). Core funding is provided by Cancer Research UK (C6946/A14492) and the Wellcome Trust (WT092096). J.V.F. is funded by Cancer Research UK programme grant C6/A11224 and the Ataxia Telangiectasia Society. S.P.J. receives his salary from the University of Cambridge, supplemented by CRUK.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nprot.2015.06
Mast cells partly contribute to allergic enteritis development: Findings in two different mast cell-deficient mice
Allergic enteritis (AE) is a gastrointestinal form of food allergy. The presence of mast cells and granulocytes has been detected in the inflamed tissues in AE. In this study, we aimed to elucidate the role of mast cells in AE development using two mast cell-deficient mouse strains: KIT(W-sh/W-sh) bearing the W-sash (W(sh)) inversion mutation and Cpa3Cre/+, which lack mast cells due to Cre-mediated mast cell eradication, were used in an AE experimental model. The development of clinical symptoms (e.g. drop in body temperature and weight loss) were abolished in both strains, whereas inflammatory levels of AE (e.g. villous atrophy, edema, and granulocyte accumulation) were reduced mainly in KITW-sh/W-sh mice. FACS analysis of the KITW-sh/W-sh intestinal lamina propria, showed a reduction in the eosinophil (CD45+CD11b+SiglecF+cells) and neutrophil (CD45+CD11b+SiglecFâLy6G+ cells) accumulation. Cpa3Cre/+ mice showed reduced eosinophil (CD45+CD11b+SiglecF+cells) accumulation, but neutrophil (CD45+CD11b+SiglecFâLy6G+ cells) accumulation was retained at AE sites. The concentrations of CC chemokine ligand 1 (CCL1), a known CC chemokine receptor 8 ligand leading to eosinophil recruitment, was reduced in intestinal homogenates of both mast cell-deficient mouse strains. These results suggest that mast cells play a role in AE development in part by expressing CCL1 and contributing to eosinophil accumulation at AE. This study offers implications for establishing AE treatments that target infiltrating leucocytes in AE tissues.Fil: Blanco PĂ©rez, Frank. No especifĂca;Fil: Gonzalez Menendez, Irene. No especifĂca;Fil: Stassen, Michael. Johannes Gutenberg Universitat Mainz; AlemaniaFil: Kato, Yoichiro. Tokyo Women's Medical University; JapĂłnFil: Laiño, Jonathan Emiliano. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - TucumĂĄn. Centro de Referencia para Lactobacilos; ArgentinaFil: Kirberg, Jörg. No especifĂca;Fil: Krause, Maren. No especifĂca;Fil: Martella, Manuela. No especifĂca;Fil: Shibata, Noriyuki. Tokyo Women's Medical University; JapĂłnFil: Quintanilla-Martinez, Leticia. No especifĂca;Fil: Feyerabend, Thorsten B.. No especifĂca;Fil: Rodewald, Hans Reimer. No especifĂca;Fil: Galli, Stephen J.. University of Stanford; Estados UnidosFil: Vieths, Stefan. No especifĂca;Fil: Scheurer, Stephan. No especifĂca;Fil: Toda, Masako. No especifĂca
Gravitational Radiation from the Coalescence of Binary Neutron Stars: Effects Due to the Equation of State, Spin, and Mass Ratio
We calculate the gravitational radiation produced by the coalescence of
inspiraling binary neutron stars in the Newtonian regime using 3-dimensional
numerical simulations. The stars are modeled as polytropes and start out in the
point-mass regime at wide separation. The hydrodynamic integration is performed
using smooth particle hydrodynamics (SPH) with Newtonian gravity, and the
gravitational radiation is calculated using the quadrupole approximation. We
have run a number of simulations varying the neutron star radii, equations of
state, spins, and mass ratio. The resulting gravitational waveforms and spectra
are rich in information about the hydrodynamics of coalescence, and show
characteristic dependence on GM/Rc^2, the equation of state, and the mass
ratio.Comment: 39 pages, uses Latex 2.09. To be published in the Dec. 15, 1996 issue
of Physical Review D. 16 Figures (bitmapped). Originals available in
compressed Postscript format at ftp://zonker.drexel.edu/papers/PAPER2
Moon Shadow by Cosmic Rays under the Influence of Geomagnetic Field and Search for Antiprotons at Multi-TeV Energies
We have observed the shadowing of galactic cosmic ray flux in the direction
of the moon, the so-called moon shadow, using the Tibet-III air shower array
operating at Yangbajing (4300 m a.s.l.) in Tibet since 1999. Almost all cosmic
rays are positively charged; for that reason, they are bent by the geomagnetic
field, thereby shifting the moon shadow westward. The cosmic rays will also
produce an additional shadow in the eastward direction of the moon if cosmic
rays contain negatively charged particles, such as antiprotons, with some
fraction. We selected 1.5 x10^{10} air shower events with energy beyond about 3
TeV from the dataset observed by the Tibet-III air shower array and detected
the moon shadow at level. The center of the moon was detected
in the direction away from the apparent center of the moon by 0.23 to
the west. Based on these data and a full Monte Carlo simulation, we searched
for the existence of the shadow produced by antiprotons at the multi-TeV energy
region. No evidence of the existence of antiprotons was found in this energy
region. We obtained the 90% confidence level upper limit of the flux ratio of
antiprotons to protons as 7% at multi-TeV energies.Comment: 13pages,4figures; Accepted for publication in Astroparticle Physic
Theory of Pseudomodes in Quantum Optical Processes
This paper deals with non-Markovian behaviour in atomic systems coupled to a
structured reservoir of quantum EM field modes, with particular relevance to
atoms interacting with the field in high Q cavities or photonic band gap
materials. In cases such as the former, we show that the pseudo mode theory for
single quantum reservoir excitations can be obtained by applying the Fano
diagonalisation method to a system in which the atomic transitions are coupled
to a discrete set of (cavity) quasimodes, which in turn are coupled to a
continuum set of (external) quasimodes with slowly varying coupling constants
and continuum mode density. Each pseudomode can be identified with a discrete
quasimode, which gives structure to the actual reservoir of true modes via the
expressions for the equivalent atom-true mode coupling constants. The quasimode
theory enables cases of multiple excitation of the reservoir to now be treated
via Markovian master equations for the atom-discrete quasimode system.
Applications of the theory to one, two and many discrete quasimodes are made.
For a simple photonic band gap model, where the reservoir structure is
associated with the true mode density rather than the coupling constants, the
single quantum excitation case appears to be equivalent to a case with two
discrete quasimodes
Tumor immune infiltration estimated from gene expression profiles predicts colorectal cancer relapse
A substantial fraction of patients with stage I-III colorectal adenocarcinoma (CRC) experience disease relapse after surgery with curative intent. However, biomarkers for predicting the likelihood of CRC relapse have not been fully explored. Therefore, we assessed the association between tumor infiltration by a broad array of innate and adaptive immune cell types and CRC relapse risk. We implemented a discovery-validation design including a discovery dataset from Moffitt Cancer Center (MCC; Tampa, FL) and three independent validation datasets: (1) GSE41258 (2) the Molecular Epidemiology of Colorectal Cancer (MECC) study, and (3) GSE39582. Infiltration by 22 immune cell types was inferred from tumor gene expression data, and the association between immune infiltration by each cell type and relapse-free survival was assessed using Cox proportional hazards regression. Within each of the four independent cohorts, CD4+ memory activated T cell (HR: 0.93, 95% CI: 0.90-0.96; FDR = 0.0001) infiltration was associated with longer time to disease relapse, independent of stage, microsatellite instability, and adjuvant therapy. Based on our meta-analysis across the four datasets, 10 innate and adaptive immune cell types associated with disease relapse of which 2 were internally validated using multiplex immunofluorescence. Moreover, immune cell type infiltration was a better predictors of disease relapse than Consensus Molecular Subtype (CMS) and other expression-based biomarkers (Immune-AICMCC:238.1-238.9; CMS-AICMCC: 241.0). These data suggest that transcriptome-derived immune profiles are prognostic indicators of CRC relapse and quantification of both innate and adaptive immune cell types may serve as candidate biomarkers for predicting prognosis and guiding frequency and modality of disease surveillance
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