Expression of Mcm2, geminin and Ki67 in normal oral mucosa, oral epithelial dysplasias and their corresponding squamous-cell carcinomas

Proteins necessary for the normal regulation of the cell cycle include minichromosome maintenance protein 2 (Mcm2) and geminin. These are overexpressed in several premalignant and malignant tumours. The Mcm2/Ki67 ratio can be used to estimate the population of cells that are in early G1 (licensed to proliferate), and the geminin/Ki67 ratio can determine the relative length of G1. A high ratio indicates a short G1 and a high rate of cell proliferation. Mcm2 and geminin have been scarcely explored in oral epithelial dysplasia (OED) and oral squamous-cell carcinoma (OSCC). The purpose of this study was to identify the expression pattern of Mcm2, Ki67 and geminin in normal oral mucosa (NOM), OED and their subsequent OSCC, to determine if expression could help predict the prognosis of OED. Paraffin sections of 41 OED cases that progressed to carcinoma, 40 OED without malignant progression, 38 OSCC and 15 NOM were immunostained with antibodies against Mcm2, geminin and Ki67. Labelling indices (LIs) increased progressively from NOM, OED and OSCC (Mcm2, Po0.001; geminin, Po0.001 and Ki67, Po0.001). In all the OED cases (n ¼ 81) the levels of expression of Mcm2 (LI, 73.6), geminin (LI, 24.4) and Ki67 (LI, 44.5) were elevated indicating a constant cellcycle re-entry. When the OED groups were compared, Mcm2 protein expression was higher in the OED with malignant progression (P ¼ 0.04), likewise there was a significant increase in the Mcm2/Ki67 and geminin/Ki67 ratios (P ¼ 0.04 and 0.02 respectively). Mcm2 and geminin proteins seem to be novel biomarkers of growth and may be useful prognostic tools for OED

Spatial control of Cdc42 signalling by a GM130-RasGRF complex regulates polarity and tumorigenesis

The small GTPase Cdc42 is a key regulator of polarity, but little is known in mammals about its spatial regulation and the relevance of spatial Cdc42 pools for polarity. Here we report the identification of a GM130-RasGRF complex as a regulator of Cdc42 at the Golgi. Silencing GM130 results in RasGRF-dependent inhibition of the Golgi pool of Cdc42, but does not affect Cdc42 at the cell surface. Furthermore, active Cdc42 at the Golgi is important to sustain asymmetric front-rear Cdc42-GTP distribution in directionally migrating cells. Concurrent to Cdc42 inhibition, silencing GM130 also results in RasGRF-dependent Ras-ERK pathway activation. Moreover, depletion of GM130 is sufficient to induce E-cadherin downregulation, indicative of a loss in cell polarity and epithelial identity. Accordingly, GM130 expression is frequently lost in colorectal and breast cancer patients. These findings establish a previously unrecognized role for a GM130-RasGRF-Cdc42 connection in regulating polarity and tumorigenesis

Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex

Alternative splicing is prevalent in the mammalian brain. To interrogate the functional role of alternative splicing in neural development, we analyzed purified neural progenitor cells (NPCs) and neurons from developing cerebral cortices, revealing hundreds of differentially spliced exons that preferentially alter key protein domains—especially in cytoskeletal proteins—and can harbor disease-causing mutations. We show that Ptbp1 and Rbfox proteins antagonistically govern the NPC-to-neuron transition by regulating neuron-specific exons. Whereas Ptbp1 maintains apical progenitors partly through suppressing a poison exon of Flna in NPCs, Rbfox proteins promote neuronal differentiation by switching Ninein from a centrosomal splice form in NPCs to a non-centrosomal isoform in neurons. We further uncover an intronic human mutation within a PTBP1-binding site that disrupts normal skipping of the FLNA poison exon in NPCs and causes a brain-specific malformation. Our study indicates that dynamic control of alternative splicing governs cell fate in cerebral cortical development. Keywords: filamin A; Ninein; Ptbp1; Rbfox; microcephaly; periventricular nodular heterotopia; mother centrioleNational Cancer Institute (U.S.) (Grant P01-CA42063

The Cherenkov Telescope Array Large Size Telescope

The two arrays of the Very High Energy gamma-ray observatory Cherenkov Telescope Array (CTA) will include four Large Size Telescopes (LSTs) each with a 23 m diameter dish and 28 m focal distance. These telescopes will enable CTA to achieve a low-energy threshold of 20 GeV, which is critical for important studies in astrophysics, astroparticle physics and cosmology. This work presents the key specifications and performance of the current LST design in the light of the CTA scientific objectives.Comment: 4 pages, 5 figures, In Proceedings of the 33rd International Cosmic Ray Conference (ICRC2013), Rio de Janeiro (Brazil). All CTA contributions at arXiv:1307.223

Investigating the peculiar emission from the new VHE gamma-ray source H1722+119

The MAGIC (Major Atmospheric Gamma-ray Imaging Cherenkov) telescopes observed the BL Lac object H1722+119 (redshift unknown) for six consecutive nights between 2013 May 17 and 22, for a total of 12.5 h. The observations were triggered by high activity in the optical band measured by the KVA (Kungliga Vetenskapsakademien) telescope. The source was for the first time detected in the very high energy (VHE, $E > 100$ GeV) $\gamma$-ray band with a statistical significance of 5.9 $\sigma$. The integral flux above 150 GeV is estimated to be $(2.0\pm 0.5)$ per cent of the Crab Nebula flux. We used contemporaneous high energy (HE, 100 MeV $< E < 100$ GeV) $\gamma$-ray observations from Fermi-LAT (Large Area Telescope) to estimate the redshift of the source. Within the framework of the current extragalactic background light models, we estimate the redshift to be $z = 0.34 \pm 0.15$. Additionally, we used contemporaneous X-ray to radio data collected by the instruments on board the Swift satellite, the KVA, and the OVRO (Owens Valley Radio Observatory) telescope to study multifrequency characteristics of the source. We found no significant temporal variability of the flux in the HE and VHE bands. The flux in the optical and radio wavebands, on the other hand, did vary with different patterns. The spectral energy distribution (SED) of H1722+119 shows surprising behaviour in the $\sim 3\times10^{14} - 10^{18}$ Hz frequency range. It can be modelled using an inhomogeneous helical jet synchrotron self-Compton model.Comment: 12 pages, 5 figures, 2 table

Limits to dark matter annihilation cross-section from a combined analysis of MAGIC and Fermi-LAT observations of dwarf satellite galaxies

We present the first joint analysis of gamma-ray data from the MAGIC Cherenkov telescopes and the Fermi Large Area Telescope (LAT) to search for gamma-ray signals from dark matter annihilation in dwarf satellite galaxies. We combine 158 hours of Segue 1 observations with MAGIC with 6-year observations of 15 dwarf satellite galaxies by the Fermi-LAT. We obtain limits on the annihilation cross-section for dark matter particle masses between 10 GeV and 100 TeV - the widest mass range ever explored by a single gamma-ray analysis. These limits improve on previously published Fermi-LAT and MAGIC results by up to a factor of two at certain masses. Our new inclusive analysis approach is completely generic and can be used to perform a global, sensitivity-optimized dark matter search by combining data from present and future gamma-ray and neutrino detectors.Comment: 19 pages, 3 figures. V2: Few typos corrected and references added. Matches published version JCAP 02 (2016) 03

Multi-Wavelength Observations of the Blazar 1ES 1011+496 in Spring 2008

The BL Lac object 1ES 1011+496 was discovered at Very High Energy gamma-rays by MAGIC in spring 2007. Before that the source was little studied in different wavelengths. Therefore a multi-wavelength (MWL) campaign was organized in spring 2008. Along MAGIC, the MWL campaign included the Metsahovi radio observatory, Bell and KVA optical telescopes and the Swift and AGILE satellites. MAGIC observations span from March to May, 2008 for a total of 27.9 hours, of which 19.4 hours remained after quality cuts. The light curve showed no significant variability. The differential VHE spectrum could be described with a power-law function. Both results were similar to those obtained during the discovery. Swift XRT observations revealed an X-ray flare, characterized by a harder when brighter trend, as is typical for high synchrotron peak BL Lac objects (HBL). Strong optical variability was found during the campaign, but no conclusion on the connection between the optical and VHE gamma-ray bands could be drawn. The contemporaneous SED shows a synchrotron dominated source, unlike concluded in previous work based on nonsimultaneous data, and is well described by a standard one zone synchrotron self Compton model. We also performed a study on the source classification. While the optical and X-ray data taken during our campaign show typical characteristics of an HBL, we suggest, based on archival data, that 1ES 1011+496 is actually a borderline case between intermediate and high synchrotron peak frequency BL Lac objects.Comment: 13 pages, accepted for publication in MNRA

Detection of very high energy gamma-ray emission from the gravitationally-lensed blazar QSO B0218+357 with the MAGIC telescopes

Context. QSO B0218+357 is a gravitationally lensed blazar located at a redshift of 0.944. The gravitational lensing splits the emitted radiation into two components, spatially indistinguishable by gamma-ray instruments, but separated by a 10-12 day delay. In July 2014, QSO B0218+357 experienced a violent flare observed by the Fermi-LAT and followed by the MAGIC telescopes. Aims. The spectral energy distribution of QSO B0218+357 can give information on the energetics of z ~ 1 very high energy gamma- ray sources. Moreover the gamma-ray emission can also be used as a probe of the extragalactic background light at z ~ 1. Methods. MAGIC performed observations of QSO B0218+357 during the expected arrival time of the delayed component of the emission. The MAGIC and Fermi-LAT observations were accompanied by quasi-simultaneous optical data from the KVA telescope and X-ray observations by Swift-XRT. We construct a multiwavelength spectral energy distribution of QSO B0218+357 and use it to model the source. The GeV and sub-TeV data, obtained by Fermi-LAT and MAGIC, are used to set constraints on the extragalactic background light. Results. Very high energy gamma-ray emission was detected from the direction of QSO B0218+357 by the MAGIC telescopes during the expected time of arrival of the trailing component of the flare, making it the farthest very high energy gamma-ray sources detected to date. The observed emission spans the energy range from 65 to 175 GeV. The combined MAGIC and Fermi-LAT spectral energy distribution of QSO B0218+357 is consistent with current extragalactic background light models. The broad band emission can be modeled in the framework of a two zone external Compton scenario, where the GeV emission comes from an emission region in the jet, located outside the broad line region.Comment: 11 pages, 6 figures, accepted for publication in A&

Long-term multi-wavelength variability and correlation study of Markarian 421 from 2007 to 2009

We study the multi-band variability and correlations of the TeV blazar Mrk 421 on year time scales, which can bring additional insight on the processes responsible for its broadband emission. We observed Mrk 421 in the very high energy (VHE) gamma-ray range with the Cherenkov telescope MAGIC-I from March 2007 to June 2009 for a total of 96 hours of effective time after quality cuts. The VHE flux variability is quantified with several methods, including the Bayesian Block algorithm, which is applied to data from Cherenkov telescopes for the first time. The 2.3 year long MAGIC light curve is complemented with data from the Swift/BAT and RXTE/ASM satellites and the KVA, GASP-WEBT, OVRO, and Mets\"ahovi telescopes from February 2007 to July 2009, allowing for an excellent characterisation of the multi-band variability and correlations over year time scales. Mrk 421 was found in different gamma-ray emission states during the 2.3 year long observation period. Flares and different levels of variability in the gamma-ray light curve could be identified with the Bayesian Block algorithm. The same behaviour of a quiet and active emission was found in the X-ray light curves measured by Swift/BAT and the RXTE/ASM, with a direct correlation in time. The behaviour of the optical light curve of GASP-WEBT and the radio light curves by OVRO and Mets\"ahovi are different as they show no coincident features with the higher energetic light curves and a less variable emission. The fractional variability is overall increasing with energy. The comparable variability in the X-ray and VHE bands and their direct correlation during both high- and low-activity periods spanning many months show that the electron populations radiating the X-ray and gamma-ray photons are either the same, as expected in the Synchrotron-Self-Compton mechanism, or at least strongly correlated, as expected in electromagnetic cascades.Comment: Corresponding authors: Ann-Kristin Overkemping ([email protected]), Marina Manganaro ([email protected]), Diego Tescaro ([email protected]), To be published in Astronomy&Astrophysics (A&A), 12 pages, 9 figure