Cytosine residues in the sequence 5′CpG (cytosine-guanine) are often postsynthetically methylated in animal genomes. CpG methylation is involved in long-term silencing of certain genes during ...mammalian development, and in repression of viral genomes,. The methyl-CpG-binding proteins MeCP1 (ref. 5) and MeCP2 (ref. 6) interact specifically with methylated DNA and mediate transcriptional repression. Here we study the mechanism of repression by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis. MeCP2 binds tightly to chromosomes in a methylation-dependent manner,. It contains a transcriptional-repression domain (TRD) that can function at a distance in vitro and in vivo. We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. Transcriptional repression in vivo is relieved by the deacetylase inhibitor trichostatin A, indicating that deacetylation of histones (and/or of other proteins) is an essential component of this repression mechanism. The data suggest that two global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by MeCP2.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Protein lysine methyltransferases G9a and GLP modulate the transcriptional repression of a variety of genes via dimethylation of Lys9 on histone H3 (H3K9me2) as well as dimethylation of non-histone ...targets. Here we report the discovery of UNC0638, an inhibitor of G9a and GLP with excellent potency and selectivity over a wide range of epigenetic and non-epigenetic targets. UNC0638 treatment of a variety of cell lines resulted in lower global H3K9me2 levels, equivalent to levels observed for small hairpin RNA knockdown of G9a and GLP with the functional potency of UNC0638 being well separated from its toxicity. UNC0638 markedly reduced the clonogenicity of MCF7 cells, reduced the abundance of H3K9me2 marks at promoters of known G9a-regulated endogenous genes and disproportionately affected several genomic loci encoding microRNAs. In mouse embryonic stem cells, UNC0638 reactivated G9a-silenced genes and a retroviral reporter gene in a concentration-dependent manner without promoting differentiation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A joint determination of the reactor antineutrino spectra resulting from the fission of 235U and 239Pu has been carried out by the Daya Bay and PROSPECT Collaborations. This Letter reports the level ...of consistency of 235U spectrum measurements from the two experiments and presents new results from a joint analysis of both data sets. Here, the measurements are found to be consistent. The combined analysis reduces the degeneracy between the dominant 235U and 239Pu isotopes and improves the uncertainty of the 235U spectral shape to about 3%. The 235U and 239Pu antineutrino energy spectra are unfolded from the jointly deconvolved reactor spectra using the Wiener-SVD unfolding method, providing a data-based reference for other reactor antineutrino experiments and other applications. This is the first measurement of the 235U and 239Pu spectra based on the combination of experiments at low- and highly enriched uranium reactors.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
The responses of species to environmental changes will determine future community composition and ecosystem function. Many syntheses of global change experiments examine the magnitude of treatment ...effect sizes, but we lack an understanding of how plant responses to treatments compare to ongoing changes in the unmanipulated (ambient or background) system. We used a database of long‐term global change studies manipulating CO2, nutrients, water, and temperature to answer three questions: (a) How do changes in plant species abundance in ambient plots relate to those in treated plots? (b) How does the magnitude of ambient change in species‐level abundance over time relate to responsiveness to global change treatments? (c) Does the direction of species‐level responses to global change treatments differ from the direction of ambient change? We estimated temporal trends in plant abundance for 791 plant species in ambient and treated plots across 16 long‐term global change experiments yielding 2,116 experiment–species–treatment combinations. Surprisingly, for most species (57%) the magnitude of ambient change was greater than the magnitude of treatment effects. However, the direction of ambient change, whether a species was increasing or decreasing in abundance under ambient conditions, had no bearing on the direction of treatment effects. Although ambient communities are inherently dynamic, there is now widespread evidence that anthropogenic drivers are directionally altering plant communities in many ecosystems. Thus, global change treatment effects must be interpreted in the context of plant species trajectories that are likely driven by ongoing environmental changes.
Across 16 long‐term global change experiments, we found strong patterns of change in plant species abundance in ambient plots. Experimental treatment effects were smaller than ambient change in magnitude for most species and only rarely reversed the direction of ambient change.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Reactor neutrino experiments have seen major improvements in precision in recent years. With the experimental uncertainties becoming lower than those from theory, carefully considering all sources of ...ν¯e is important when making theoretical predictions. One source of ν¯e that is often neglected arises from the irradiation of the nonfuel materials in reactors. The ν¯e rates and energies from these sources vary widely based on the reactor type, configuration, and sampling stage during the reactor cycle and have to be carefully considered for each experiment independently. In this article, we present a formalism for selecting the possible ν¯e sources arising from the neutron captures on reactor and target materials. We apply this formalism to the High Flux Isotope Reactor (HFIR) at Oak Ridge National Laboratory, the ν¯e source for the the Precision Reactor Oscillation and Spectrum Measurement (PROSPECT) experiment. Overall, we observe that the nonfuel ν¯e contributions from HFIR to PROSPECT amount to 1% above the inverse β decay threshold with a maximum contribution of 9% in the 1.8–2.0 MeV range. Nonfuel contributions can be particularly high for research reactors like HFIR because of the choice of structural and reflector material in addition to the intentional irradiation of target material for isotope production. We show that typical commercial pressurized water reactors fueled with low-enriched uranium will have significantly smaller nonfuel ν¯e contribution.
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Background radiation measurements at high power research reactors Ashenfelter, J.; Balantekin, B.; Baldenegro, C.X. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
01/2016, Volume:
806
Journal Article
Peer reviewed
Open access
Research reactors host a wide range of activities that make use of the intense neutron fluxes generated at these facilities. Recent interest in performing measurements with relatively low event ...rates, e.g. reactor antineutrino detection, at these facilities necessitates a detailed understanding of background radiation fields. Both reactor-correlated and naturally occurring background sources are potentially important, even at levels well below those of importance for typical activities. Here we describe a comprehensive series of background assessments at three high-power research reactors, including γ-ray, neutron, and muon measurements. For each facility we describe the characteristics and identify the sources of the background fields encountered. The general understanding gained of background production mechanisms and their relationship to facility features will prove valuable for the planning of any sensitive measurement conducted therein.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Pharmacological ascorbate (i.e., intravenous infusions of vitamin C reaching ~ 20 mM in plasma) is under active investigation as an adjuvant to standard of care anti-cancer treatments due to its dual ...redox roles as an antioxidant in normal tissues and as a prooxidant in malignant tissues. Immune checkpoint inhibitors (ICIs) are highly promising therapies for many cancer patients but face several challenges including low response rates, primary or acquired resistance, and toxicity. Ascorbate modulates both innate and adaptive immune functions and plays a key role in maintaining the balance between pro and anti-inflammatory states. Furthermore, the success of pharmacological ascorbate as a radiosensitizer and a chemosensitizer in pre-clinical studies and early phase clinical trials suggests that it may also enhance the efficacy and expand the benefits of ICIs.
The Rho-family of small GTPase specific guanine nucleotide exchange factor, GEFT, is expressed at high levels in adult human excitable tissues including the brain, heart, and skeletal muscle. ...Previously, we demonstrated that GEFT is specifically expressed in the adult mouse hippocampus and cerebellum, and that overexpression of this protein can result in neurite and dendrite remodeling. This finding prompted us to explore the expression of GEFT in other tissues, which share common developmental ancestry to the nervous system, specifically the ocular system. Using immunohistochemical analysis specific for GEFT protein expression, we observed the highest ocular expression of GEFT occurring in the neuroblastic layer and differentiating lens fibers of the late-stage mouse embryo, and in the postnatal corneal epithelium, lens epithelium, and throughout the retina. Exogenous expression of GEFT in N/N1003A rabbit lens epithelial cells induced lens fiber differentiation as reflected by cell elongation and lentoid formation, as well as a strong increase in β-crystallin and filensin expression. Moreover, transfection of lens epithelial cells with GEFT resulted in a Rac-1 mediated up-regulation of αA-, αB-, βB-, γC-, or γF-crystallin promoter activities that is in part dependent on the nuclear localization of Rac1. Furthermore, pharmacological inhibition of Rac1 blocked GEFT-induced N/N1003A lens fiber differentiation and βB-crystallin expression in ex vivo mouse lens explants. These results demonstrate for the first time a role for GEFT in lens cell differentiation and mouse eye development. Moreover, GEFT regulation of lens differentiation and eye development occurs through a Rac1-dependent mechanism.
Anchovy Engraulis encrasicolus is economically important and ecologically critical to the structure and function of the Benguela Current ecosystem, as it transfers energy from plankton to piscivorous ...fishes, seabirds, and marine mammals. Like other small pelagic fishes, annual recruitment strength varies substantially, but the drivers of these fluctuations are not well understood. To address this issue, we investigated the relationship between 30 yr of anchovy recruitment estimates derived from acoustic survey data and a new coastal upwelling index for the Southern Benguela defined as the monthly sum of offshore Ekman transport over the region 29–36° S. Cumulative December–March upwelling was significantly and positively related to recruitment, and this relationship was improved by integrating the upwelling index over multiple years (i.e. adding autocorrelation). A threshold-generalized additive model further showed that the slope of the linear regression between integrated upwelling and recruitment increased when anchovy spawner biomass on the west coast of South Africa in the preceding year exceeded ∼0.74 million tonnes. By combining these 2 simple linear regressions into a single model, we were able to account for 82% of the variability in anchovy recruitment from 1985 to 2014. The biomass threshold in the upwelling–recruitment relationship could relate to the presence of a strong spawner–recruit relationship, or to a shift in the dominant driver of recruitment variability as adult biomass increases, such as effective transport of eggs, larvae retention in coastal habitats, and primary productivity.
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