Physical interaction between MYCN oncogene and polycomb repressive complex 2 (PRC2) in neuroblastoma: Functional and therapeutic implications

This article is made available through the Brunel Open Access Publishing Fund. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.CLU (clusterin) is a tumor suppressor gene that we have previously shown to be negatively modulated by the MYCN proto-oncogene, but the mechanism of repression was unclear. Here, we show that MYCN inhibits the expression of CLU by direct interaction with the non-canonical E box sequence CACGCG in the 5′-flanking region. Binding of MYCN to the CLU gene induces bivalent epigenetic marks and recruitment of repressive proteins such as histone deacetylases and Polycomb members. MYCN physically binds in vitro and in vivo to EZH2, a component of the Polycomb repressive complex 2, required to repress CLU. Notably, EZH2 interacts with the Myc box domain 3, a segment of MYC known to be essential for its transforming effects. The expression of CLU can be restored in MYCN-amplified cells by epigenetic drugs with therapeutic results. Importantly, the anticancer effects of the drugs are ablated if CLU expression is blunted by RNA interference. Our study implies that MYC tumorigenesis can be effectively antagonized by epigenetic drugs that interfere with the recruitment of chromatin modifiers at repressive E boxes of tumor suppressor genes such as CLU.SPARKS, The Neuroblastoma Society, a Wellcome Trust grant (to A. S.), and the Italian Association for Cancer Research

Stretching magnetism with an electric field in a nitride semiconductor

By direct magnetization measurements, performed employing a new detection scheme, we demonstrate an electrical control of magnetization in wurtzite (Ga,Mn)N. In this dilute magnetic insulator the Fermi energy is pinned by Mn ions in the mid-gap region, and the Mn3+ ions show strong single-ion anisotropy. We establish that (Ga,Mn)N sustains an electric field up to at least 5 MV/cm, indicating that Mn doping turns GaN into a worthwhile semi-insulating material. Under these conditions, the magnetoelectric coupling may be driven by the inverse piezoelectric effect that stretches the elementary cell along the c axis and, thus, affects the magnitude of magnetic anisotropy. We develop a corresponding theory and show that it describes the experimentally determined dependence of magnetization on the electric field quantitatively with no adjustable parameters as a function of the magnetic field and temperature. In this way, our work bridges two research domains developed so far independently: piezoelectricity of wurtzite semiconductors and electrical control of magnetization in hybrid and composite magnetic structures containing piezoelectric components.Comment: 11 pages, 10 figures, version after revisio

The relationship between successional vascular plant assemblages and associated microbial communities on coal mine spoil heaps

The aim of the study was to investigate the relationships between the vascular plant species and the associated soil microbial properties at various stages of vegetation development on unclaimed hard coal mine spoil heaps in Upper Silesia (south Poland). The spontaneous vegetation, soil chemistry as well as the activity and structure of microbial communities were recorded on this specific habitat. The colliery heaps were divided into four age classes and the plant species composition and cover abundance were recorded on established plots (2 m × 2 m). The soil microbial activity under the vegetation patches was assessed using fluorescein diacetate hydrolytic activity (FDHA) and the soil microbial biomass and community composition were determined by phospholipid fatty acid (PLFA) biomarkers. Total microbial biomass in soils from the older vegetation plots was significantly higher than those in soils from the younger plots. In all studied samples, microbial communities consisted primarily of bacteria with the dominance of Gram negative bacteria over Gram positive and aerobic microorganisms were more dominant than anaerobic ones. Statistical analysis revealed a correlation between the type of vegetation and microbial community structure

Emissions from pre-Hispanic metallurgy in the South American atmosphere

This is the final version of the article. Available from Public Library of Science via the DOI in this record.Metallurgical activities have been undertaken in northern South America (NSA) for millennia. However, it is still unknown how far atmospheric emissions from these activities have been transported. Since the timing of metallurgical activities is currently estimated from scarce archaeological discoveries, the availability of reliable and continuous records to refine the timing of past metal deposition in South America is essential, as it provides an alternative to discontinuous archives, as well as evidence for global trace metal transport. We show in a peat record from Tierra del Fuego that anthropogenic metals likely have been emitted into the atmosphere and transported from NSA to southern South America (SSA) over the last 4200 yrs. These findings are supported by modern time back-trajectories from NSA to SSA. We further show that apparent anthropogenic Cu and Sb emissions predate any archaeological evidence for metallurgical activities. Lead and Sn were also emitted into the atmosphere as by-products of Inca and Spanish metallurgy, whereas local coal-gold rushes and the industrial revolution contributed to local contamination. We suggest that the onset of pre-Hispanic metallurgical activities is earlier than previously reported from archaeological records and that atmospheric emissions of metals were transported from NSA to SSA.This research is supported by a Young Researcher Grant of the Agence Nationale de la Recherche (ANR) to F. De Vleeschouwer (Project ANR-2011-JS56-006-01 “PARAD”). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Dzieci sieci 2.0

S\u142owa kluczowe: kompetencje komunikacyjne m\u142odzie\u17cy, edukacja medialna - gimnazjum, szkolne programy nauczania, netnografia, internet a uczniowie gimnazj\uf3

Disorder suppression and precise conductance quantization in constrictions of PbTe quantum wells

Conductance quantization was measured in submicron constrictions of PbTe, patterned into narrow,12 nm wide quantum wells deposited between Pb$_{0.92}$Eu$_{0.08}$Te barriers. Because the quantum confinement imposed by the barriers is much stronger than the lateral one, the one-dimensional electron energy level structure is very similar to that usually met in constrictions of AlGaAs/GaAs heterostructures. However, in contrast to any other system studied so far, we observe precise conductance quantization in $2e^2/h$ units, {\it despite of significant amount of charged defects in the vicinity of the constriction}. We show that such extraordinary results is a consequence of the paraelectric properties of PbTe, namely, the suppression of long-range tails of the Coulomb potentials due to the huge dielectric constant.Comment: 7 pages, 6 figures, submitted to Phys. Rev.

Histone arginine methylation regulates pluripotency in the early mouse embryo

It has been generally accepted that the mammalian embryo starts its development with all cells identical, and only when inside and outside cells form do differences between cells first emerge. However, recent findings show that cells in the mouse embryo can differ in their developmental fate and potency as early as the four-cell stage1,2,3,4. These differences depend on the orientation and order of the cleavage divisions that generated them2,5. Because epigenetic marks are suggested to be involved in sustaining pluripotency6,7, we considered that such developmental properties might be achieved through epigenetic mechanisms. Here we show that modification of histone H3, through the methylation of specific arginine residues, is correlated with cell fate and potency. Levels of H3 methylation at specific arginine residues are maximal in four-cell blastomeres that will contribute to the inner cell mass (ICM) and polar trophectoderm and undertake full development when combined together in chimaeras. Arginine methylation of H3 is minimal in cells whose progeny contributes more to the mural trophectoderm and that show compromised development when combined in chimaeras. This suggests that higher levels of H3 arginine methylation predispose blastomeres to contribute to the pluripotent cells of the ICM. We confirm this prediction by overexpressing the H3-specific arginine methyltransferase CARM1 in individual blastomeres and show that this directs their progeny to the ICM and results in a dramatic upregulation of Nanog and Sox2. Thus, our results identify specific histone modifications as the earliest known epigenetic marker contributing to development of ICM and show that manipulation of epigenetic information influences cell fate determination

LOFAR MSSS: Flattening low-frequency radio continuum spectra of nearby galaxies

Accepted for publication in Astronomy and AstrophysicsAims. The shape of low-frequency radio continuum spectra of normal galaxies is not well understood, the key question being the role of physical processes such as thermal absorption in shaping them. In this work we take advantage of the LOFAR Multifrequency Snapshot Sky Survey (MSSS) to investigate such spectra for a large sample of nearby star-forming galaxies. Methods. Using the measured 150 MHz flux densities from the LOFAR MSSS survey and literature flux densities at various frequencies we have obtained integrated radio spectra for 106 galaxies characterised by different morphology and star formation rate. The spectra are explained through the use of a three-dimensional model of galaxy radio emission, and radiation transfer dependent on the galaxy viewing angle and absorption processes. Results. Our galaxies' spectra are generally flatter at lower compared to higher frequencies: the median spectral index α low measured between ≈ 50 MHz and 1.5 GHz is -0.57 ± 0.01 while the high-frequency one α high, calculated between 1.3 GHz and 5 GHz, is -0.77 ± 0.03. As there is no tendency for the highly inclined galaxies to have more flattened low-frequency spectra, we argue that the observed flattening is not due to thermal absorption, contradicting the suggestion of Israel & Mahoney (1990, ApJ, 352, 30). According to our modelled radio maps for M 51-like galaxies, the free-free absorption effects can be seen only below 30 MHz and in the global spectra just below 20 MHz, while in the spectra of starburst galaxies, like M 82, the flattening due to absorption is instead visible up to higher frequencies of about 150 MHz. Starbursts are however scarce in the local Universe, in accordance with the weak spectral curvature seen in the galaxies of our sample. Locally, within galactic disks, the absorption effects are distinctly visible in M 51-like galaxies as spectral flattening around 100-200 MHz in the face-on objects, and as turnovers in the edge-on ones, while in M 82-like galaxies there are strong turnovers at frequencies above 700 MHz, regardless of viewing angle. Conclusions. Our modelling of galaxy spectra suggests that the weak spectral flattening observed in the nearby galaxies studied here results principally from synchrotron spectral curvature due to cosmic ray energy losses and propagation effects. We predict much stronger effects of thermal absorption in more distant galaxies with high star formation rates. Some influence exerted by the Milky Way's foreground on the spectra of all external galaxies is also expected at very low frequencies.Peer reviewedFinal Accepted Versio

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance