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

Novel synthetic approach to heteroatom doped polycyclic aromatic hydrocarbons: Optimizing the bottom-up approach to atomically precise doped nanographenes

The success of the rational bottom-up approach to nanostructured carbon materials and the discovery of the importance of their doping with heteroatoms puts under the spotlight all synthetic organic approaches to polycyclic aromatic hydrocarbons. The construction of atomically precise heteroatom doped nanographenes has evidenced the importance of controlling its geometry and the position of the doping heteroatoms, since these parameters influence their chemical–physical properties and their applications. The growing interest towards this research topic is testified by the large number of works published in this area, which have transformed a once “fundamental research” into applied research at the cutting edge of technology. This review analyzes the most recent synthetic approaches to this class of compounds

Spinfoams in the holomorphic representation

We study a holomorphic representation for spinfoams. The representation is obtained via the Ashtekar-Lewandowski-Marolf-Mour\~ao-Thiemann coherent state transform. We derive the expression of the 4d spinfoam vertex for Euclidean and for Lorentzian gravity in the holomorphic representation. The advantage of this representation rests on the fact that the variables used have a clear interpretation in terms of a classical intrinsic and extrinsic geometry of space. We show how the peakedness on the extrinsic geometry selects a single exponential of the Regge action in the semiclassical large-scale asymptotics of the spinfoam vertex.Comment: 10 pages, 1 figure, published versio

On the Ultraviolet Behaviour of Newton's constant

We clarify a point concerning the ultraviolet behaviour of the Quantum Field Theory of gravity, under the assumption of the existence of an ultraviolet Fixed Point. We explain why Newton's constant should to scale like the inverse of the square of the cutoff, even though it is technically inessential. As a consequence of this behaviour, the existence of an UV Fixed Point would seem to imply that gravity has a built-in UV cutoff when described in Planck units, but not necessarily in other units.Comment: 8 pages; CQG class; minor changes and rearrangement

Mechanical Behaviour of the Short Models of LHC Main Dipole Magnets

A series of single and twin aperture 1 metre magnet models has been built and tested in the framework of the R&D program of main superconducting dipole magnets for the Large Hadron Collider project. The se models, designed for a nominal field of 8.3 T at 1.8 K, have been constructed to test the performance of SC coils and to optimise various design options for the full length 15 metre long dipoles. T he models have been extensively equipped with a specially developed mechanical instrumentation, enabling both the control of main assembly parameters - like coil azimuthal and axial pre-load, stress i n the outer shrinking cylinder - and also the monitoring of magnet behaviour during cooling and energising, under the action of electromagnetic forces. The instrumentation used, mainly based on strain gauge transducers, is described and the results of mechanical measurements obtained during power tests of the models are discussed and compared with the design predictions based on Finite Element calc ulations

Contraints on Matter from Asymptotic Safety

Recent studies of the ultraviolet behaviour of pure gravity suggest that it admits a non-Gaussian attractive fixed point, and therefore that the theory is asymptotically safe. We consider the effect on this fixed point of massless minimally coupled matter fields. The existence of a UV attractive fixed point puts bounds on the type and number of such fields.Comment: 5 pages, 2 figures, revtex4; introduction expande

Asymptotics of LQG fusion coefficients

The fusion coefficients from SO(3) to SO(4) play a key role in the definition of spin foam models for the dynamics in Loop Quantum Gravity. In this paper we give a simple analytic formula of the EPRL fusion coefficients. We study the large spin asymptotics and show that they map SO(3) semiclassical intertwiners into $SU(2)_L\times SU(2)_R$ semiclassical intertwiners. This non-trivial property opens the possibility for an analysis of the semiclassical behavior of the model.Comment: 14 pages, minor change

State of the Short Dipole Model Program for the LHC

Superconducting single and twin aperture 1-m long dipole magnets are currently being fabricated at CERN at a rate of about one per month in the framework of the short dipole model program for the LHC. The program allows to study performance improvements coming from refinements in design, components and assembly options and to accumulate statistics based on a small-scale production. The experience thus gained provides in turn feedback into the long magnet program in industry. In recent models initial quenching fields above 9 T have been obtained and after a short training the conductor limit at 2 K is reached, resulting in a central bore field exceeding 10 T. The paper describes the features of recent single aperture models, the results obtained during cold tests and the plans to ensure the continuation of a vigorous model program providing input for the fabrication of the main LHC dipoles

Present State of the Single and Twin Aperture Short Dipole Model Program for the LHC

The LHC model program for main dipoles is based on the design, fabrication and testing at CERN of a number of single and twin aperture 1m long magnets. So far, a number of single aperture models, each with specific characteristics, were tested at 2 K at a rate of about one per month. These magnets are the main tool used to check coil performance as a function of design and assembly options in view of optimizing and finalizing choices of components and procedures. Initial quenching field levels of 8.8 T were obtained and the short sample limit of the cable at 1.9 K was reached corresponding to a central bore field of 10 T. A few twin aperture dipole models were also built and tested, using the same structural components as for the long magnets which are now being built in industry. The paper discusses the main characteristics of the models built so far, the instrumentation developed to date and the experience obtained. Finally it describes the plans aimed at continuing a vigorous program to provide input to the long magnet program in industry

Status of the Short Dipole Model Program for the LHC

The model program for the LHC main dipoles is dedicated to the study and validation of design variants and assembly parameters to achieve reproducible performance and optimise components and assembly costs. The topics investigated in the last year include the material of the coil end spacers, the use of polyimide films from different manufacturers, the definition of optimum azimuthal and longitudinal coil pre-stress values, shimming of coil ends, collaring around the "cold bore" and different layouts of the yoke ends. This paper presents the main characteristics of such recent models, the results obtained during cold tests and the plans for the final phase of the model program for the LHC dipoles