Identification of methotrexate as a heterochromatin-promoting drug.

Heterochromatin is a tightly packed form of DNA involved in gene silencing, chromosome segregation, and protection of genome stability. Heterochromatin is becoming more recognized in tumor suppression and may thus serve as a potential target for cancer therapy. However, to date there are no drugs that are well established to specifically promote heterochromatin formation. Here, we describe a screening method using Drosophila to identify small molecule compounds that promote heterochromatin formation, with the purpose of developing epigenetic cancer therapeutics. We took advantage of a Drosophila strain with a variegated eye color phenotype that is sensitive to heterochromatin levels, and screened a library of 97 FDA approved oncology drugs. This screen identified methotrexate as the most potent small molecule drug, among the 97 oncology drugs screened, in promoting heterochromatin formation. Interestingly, methotrexate has been identified as a JAK/STAT inhibitor in a functional screen, causing reduced phosphorylation of STAT proteins. These findings are in line with our previous observation that unphosphorylated STAT (uSTAT) promotes heterochromatin formation in both Drosophila and human cells and suppresses tumor growth in mouse xenografts. Thus, Drosophila with variegated eye color phenotypes could be an effective tool for screening heterochromatin-promoting compounds that could be candidates as cancer therapeutics

Cassini in situ observations of long duration magnetic reconnection in Saturn’s magnetotail

Magnetic reconnection is a fundamental process in solar system and astrophysical plasmas, through which stored magnetic energy associated with current sheets is converted into thermal, kinetic and wave energy1, 2, 3, 4. Magnetic reconnection is also thought to be a key process involved in shedding internally produced plasma from the giant magnetospheres at Jupiter and Saturn through topological reconfiguration of the magnetic field5, 6. The region where magnetic fields reconnect is known as the diffusion region and in this letter we report on the first encounter of the Cassini spacecraft with a diffusion region in Saturn’s magnetotail. The data also show evidence of magnetic reconnection over a period of 19?h revealing that reconnection can, in fact, act for prolonged intervals in a rapidly rotating magnetosphere. We show that reconnection can be a significant pathway for internal plasma loss at Saturn6. This counters the view of reconnection as a transient method of internal plasma loss at Saturn5, 7. These results, although directly relating to the magnetosphere of Saturn, have applications in the understanding of other rapidly rotating magnetospheres, including that of Jupiter and other astrophysical bodies

Polar Mapper: a computational tool for integrated visualization of protein interaction networks and mRNA expression data

Polar Mapper is a computational application for exposing the architecture of protein interaction networks. It facilitates the system-level analysis of mRNA expression data in the context of the underlying protein interaction network. Preliminary analysis of a human protein interaction network and comparison of yeast oxidative stress and heat shock gene expression responses are addressed as case studies

States for phase estimation in quantum interferometry

Ramsey interferometry allows the estimation of the phase $\phi$ of rotation of the pseudospin vector of an ensemble of two-state quantum systems. For $\phi$ small, the noise-to-signal ratio scales as the spin-squeezing parameter $\xi$, with $\xi<1$ possible for an entangled ensemble. However states with minimum $\xi$ are not optimal for single-shot measurements of an arbitrary phase. We define a phase-squeezing parameter, $\zeta$, which is an appropriate figure-of-merit for this case. We show that (unlike the states that minimize $\xi$), the states that minimize $\zeta$ can be created by evolving an unentangled state (coherent spin state) by the well-known 2-axis counter-twisting Hamiltonian. We analyse these and other states (for example the maximally entangled state, analogous to the optical "NOON" state $|\psi> = (|N,0>+|0,N>)/\sqrt{2}$) using several different properties, including $\xi$, $\zeta$, the coefficients in the pseudo angular momentum basis (in the three primary directions) and the angular Wigner function $W(\theta,\phi)$. Finally we discuss the experimental options for creating phase squeezed states and doing single-shot phase estimation.Comment: 8 pages and 5 figure

Nodal domains of Maass forms I

This paper deals with some questions that have received a lot of attention since they were raised by Hejhal and Rackner in their 1992 numerical computations of Maass forms. We establish sharp upper and lower bounds for the $L^2$-restrictions of these forms to certain curves on the modular surface. These results, together with the Lindelof Hypothesis and known subconvex $L^\infty$-bounds are applied to prove that locally the number of nodal domains of such a form goes to infinity with its eigenvalue.Comment: To appear in GAF

New insights into the enzymatic mechanism of human chitotriosidase (CHIT1) catalytic domain by atomic resolution X-ray diffraction and hybrid QM/MM

Chitotriosidase (CHIT1) is a human chitinase belonging to the highly conserved glycosyl hydrolase family 18 (GH18). GH18 enzymes hydrolyze chitin, an N-acetylglucosamine polymer synthesized by lower organisms for structural purposes. Recently, CHIT1 has attracted attention owing to its upregulation in immune-system disorders and as a marker of Gaucher disease. The 39 kDa catalytic domain shows a conserved cluster of three acidic residues, Glu140, Asp138 and Asp136, involved in the hydrolysis reaction. Under an excess concentration of substrate, CHIT1 and other homologues perform an additional activity, transglycosylation. To understand the catalytic mechanism of GH18 chitinases and the dual enzymatic activity, the structure and mechanism of CHIT1 were analyzed in detail. The resolution of the crystals of the catalytic domain was improved from 1.65 Å (PDB entry 1waw ) to 0.95-1.10 Å for the apo and pseudo-apo forms and the complex with chitobiose, allowing the determination of the protonation states within the active site. This information was extended by hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. The results suggest a new mechanism involving changes in the conformation and protonation state of the catalytic triad, as well as a new role for Tyr27, providing new insights into the hydrolysis and transglycosylation activities.Fil: Fadel, Firas. Centre National de la Recherche Scientifique; Francia. Institut de Génétique et de Biologie Moléculaire et Cellulaire; FranciaFil: Zhao, Yuguang. University of Oxford; Reino UnidoFil: Cachau, Raul. Frederick National Laboratory for Cancer Research; Estados UnidosFil: Cousido Siah, Alexandra. Centre National de la Recherche Scientifique; Francia. Institut de Génétique et de Biologie Moléculaire et Cellulaire; FranciaFil: Ruiz, Francesc X.. Centre National de la Recherche Scientifique; Francia. Institut de Génétique et de Biologie Moléculaire et Cellulaire; FranciaFil: Harlos, Karl. University of Oxford; Reino UnidoFil: Howard, Eduardo Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Centre National de la Recherche Scientifique; Francia. Institut de Génétique et de Biologie Moléculaire et Cellulaire; FranciaFil: Mitschler, Andre. Centre National de la Recherche Scientifique; Francia. Institut de Génétique et de Biologie Moléculaire et Cellulaire; FranciaFil: Podjarny, Alberto Daniel. Centre National de la Recherche Scientifique; Francia. Institut de Génétique et de Biologie Moléculaire et Cellulaire; Franci

NIKA2: a mm camera for cluster cosmology

Galaxy clusters constitute a major cosmological probe. However, Planck 2015 results have shown a weak tension between CMB-derived and cluster-derived cosmological parameters. This tension might be due to poor knowledge of the cluster mass and observable relationship. As for now, arcmin resolution Sunyaev-Zeldovich (SZ) observations ({\it e.g.} SPT, ACT and Planck) only allowed detailed studies of the intra cluster medium for low redshift clusters ($z0.5$) high resolution and high sensitivity SZ observations are needed. With both a wide field of view (6.5 arcmin) and a high angular resolution (17.7 and 11.2 arcsec at 150 and 260 GHz), the NIKA2 camera installed at the IRAM 30-m telescope (Pico Veleta, Spain) is particularly well adapted for these observations. The NIKA2 SZ observation program will map a large sample of clusters (50) at redshifts between 0.5 and 0.9. As a pilot study for NIKA2, several clusters of galaxies have been observed with the pathfinder, NIKA, at the IRAM 30-m telescope to cover the various configurations and observation conditions expected for NIKA2.

Deformations of the hemisphere that increase scalar curvature

Consider a compact Riemannian manifold M of dimension n whose boundary \partial M is totally geodesic and is isometric to the standard sphere S^{n-1}. A natural conjecture of Min-Oo asserts that if the scalar curvature of M is at least n(n-1), then M is isometric to the hemisphere S_+^n equipped with its standard metric. This conjecture is inspired by the positive mass theorem in general relativity, and has been verified in many special cases. In this paper, we construct counterexamples to Min-Oo's conjecture in dimension n \geq 3.Comment: Revised version, to appear in Invent. Mat

Large tunable valley splitting in edge-free graphene quantum dots on boron nitride

Coherent manipulation of binary degrees of freedom is at the heart of modern quantum technologies. Graphene offers two binary degrees: the electron spin and the valley. Efficient spin control has been demonstrated in many solid state systems, while exploitation of the valley has only recently been started, yet without control on the single electron level. Here, we show that van-der Waals stacking of graphene onto hexagonal boron nitride offers a natural platform for valley control. We use a graphene quantum dot induced by the tip of a scanning tunneling microscope and demonstrate valley splitting that is tunable from -5 to +10 meV (including valley inversion) by sub-10-nm displacements of the quantum dot position. This boosts the range of controlled valley splitting by about one order of magnitude. The tunable inversion of spin and valley states should enable coherent superposition of these degrees of freedom as a first step towards graphene-based qubits