411 research outputs found

    Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader

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    Protein degradation via the use of bivalent chemical degraders provides an alternative strategy to block protein function and assess the biological roles of putative drug targets. This approach capitalizes on the advantages of small-molecule inhibitors while moving beyond the restrictions of traditional pharmacology. Here, we report a chemical degrader (UNC6852) that targets polycomb repressive complex 2 (PRC2). UNC6852 contains an EED226-derived ligand and a ligand for VHL which bind to the WD40 aromatic cage of EED and CRL2VHL, respectively, to induce proteasomal degradation of PRC2 components, EED, EZH2, and SUZ12. Degradation of PRC2 with UNC6852 blocks the histone methyltransferase activity of EZH2, decreasing H3K27me3 levels in HeLa cells and diffuse large B cell lymphoma (DLBCL) cells containing EZH2 gain-of-function mutations. UNC6852 degrades both wild-type and mutant EZH2, and additionally displays anti-proliferative effects in this cancer model system. Using an EED-targeted chemical degrader, Potjewyd et al. demonstrate successful degradation of the PRC2 complex. UNC6852 provides a unique tool to study PRC2 function and downregulation of PRC2 activity in cancer and demonstrates the feasibility of developing PRC2-targeted degraders as potential therapeutics

    Photometric Observation And Period Study of GO Cygni

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    Photometric observations of GO Cyg were performed during the July-October 2002, in B and V bands of Johnson system. Based on Wilson's model, the light curve analysis were carried out to find the photometric elements of the system. The O-C diagram which is based on new observed times of minima suggests a negative rate of period variation (dP/dt<0) for the system.Comment: 12 pages, 6 figures, 4 tables, submitted to Ap&S

    The age, origin and emplacement of the Tsiknias Ophiolite, Tinos, Greece

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    The Tsiknias Ophiolite, exposed at the highest structural levels of Tinos, Greece, represents a thrust sheet of Tethyan oceanic crust and upper mantle emplaced onto the Attic‐Cycladic Massif. We present new field observations and a new geological map of Tinos, integrated with petrology, THERMOCALC phase diagram modelling, U–Pb geochronology and whole rock geochemistry, resulting in a tectono‐thermal model that describes the formation and emplacement of the Tsiknias Ophiolite and newly identified underlying metamorphic sole. The ophiolite comprises a succession of partially dismembered and structurally repeated ultramafic and gabbroic rocks that represent the Moho Transition Zone. A plagiogranite dated by U‐Pb zircon at 161.9 ± 2.8 Ma, reveals that the Tsiknias Ophiolite formed in a supra‐subduction zone setting, comparable to the “East‐Vardar Ophiolites”, and was intruded by gabbros at 144.4 ± 5.6 Ma. Strongly sheared metamorphic sole rocks show a condensed and inverted metamorphic gradient, from partially anatectic amphibolites at P–T conditions of ca. 8.5 kbar 850‐600 °C, down‐structural section to greenschist‐facies oceanic metasediments over ~250 m. Leucosomes generated by partial melting of the uppermost sole amphibolite, yielded a U–Pb zircon protolith age of ca. 190 Ma and a high‐grade metamorphic‐anatectic age of 74.0 ± 3.5 Ma associated with ophiolite emplacement. The Tsiknias Ophiolite was therefore obducted ~90 Myrs after it formed during initiation of a NE‐dipping intra‐oceanic subduction zone to the northeast of the Cyclades that coincides with Africa's plate motion changing from transcurrent to convergent. Continued subduction resulted in high‐pressure metamorphism of the Cycladic continental margin ~25 Myrs later

    Le magmatisme de la rĂ©gion de Kwyjibo, Province\ud du Grenville (Canada) : intĂ©rĂȘt pour les\ud minĂ©ralisations de type fer-oxydes associĂ©es

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    The granitic plutons located north of the Kwyjibo property in Quebec’s Grenville Province are of\ud Mesoproterozoic age and belong to the granitic Canatiche Complex . The rocks in these plutons are calc-alkalic, K-rich,\ud and meta- to peraluminous. They belong to the magnetite series and their trace element characteristics link them to\ud intraplate granites. They were emplaced in an anorogenic, subvolcanic environment, but they subsequently underwent\ud significant ductile deformation. The magnetite, copper, and fluorite showings on the Kwyjibo property are polyphased\ud and premetamorphic; their formation began with the emplacement of hydraulic, magnetite-bearing breccias, followed by\ud impregnations and veins of chalcopyrite, pyrite, and fluorite, and ended with a late phase of mineralization, during\ud which uraninite, rare earths, and hematite were emplaced along brittle structures. The plutons belong to two families:\ud biotite-amphibole granites and leucogranites. The biotite-amphibole granites are rich in iron and represent a potential\ud heat and metal source for the first, iron oxide phase of mineralization. The leucogranites show a primary enrichment in\ud REE (rare-earth elements), F, and U, carried mainly in Y-, U-, and REE-bearing niobotitanates. They are metamict and\ud underwent a postmagmatic alteration that remobilized the uranium and the rare earths. The leucogranites could also be\ud a source of rare earths and uranium for the latest mineralizing events

    Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

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    A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3â€Č-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

    Measurement of CP observables in B± → D(⁎)K± and B± → D(⁎)π± decays

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    Measurements of CP observables in B ± →D (⁎) K ± and B ± →D (⁎) π ± decays are presented, where D (⁎) indicates a neutral D or D ⁎ meson that is an admixture of D (⁎)0 and DÂŻ (⁎)0 states. Decays of the D ⁎ meson to the Dπ 0 and DÎł final states are partially reconstructed without inclusion of the neutral pion or photon, resulting in distinctive shapes in the B candidate invariant mass distribution. Decays of the D meson are fully reconstructed in the K ± π ∓ , K + K − and π + π − final states. The analysis uses a sample of charged B mesons produced in pp collisions collected by the LHCb experiment, corresponding to an integrated luminosity of 2.0, 1.0 and 2.0 fb −1 taken at centre-of-mass energies of s=7, 8 and 13 TeV, respectively. The study of B ± →D ⁎ K ± and B ± →D ⁎ π ± decays using a partial reconstruction method is the first of its kind, while the measurement of B ± →DK ± and B ± →Dπ ± decays is an update of previous LHCb measurements. The B ± →DK ± results are the most precise to date

    Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

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    The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR
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