β-catenin negatively regulates expression of the prostaglandin transporter PGT in the normal intestinal epithelium and colorectal tumour cells: A role in the chemopreventive efficacy of aspirin

Background: Levels of the pro-tumorigenic prostaglandin PGE 2 are increased in colorectal cancer, previously attributed to increased synthesis through COX-2 upregulation and, more recently, to decreased catabolism. The functionally linked genes 15-prostaglandin dehydrogenase (15-PGDH) and the prostaglandin transporter PGT co-operate in prostaglandin degradation and are downregulated in colorectal cancer. We previously reported repression of 15-PGDH expression by the Wnt/β-catenin pathway, commonly deregulated during early colorectal neoplasia. Here we asked whether β-catenin also regulates PGT expression. Methods: The effect of β-catenin deletion in vivo was addressed by PGT immunostaining of β-catenin/lox-villin-cre-ERT2 mouse tissue. The effect of siRNA-mediated β-catenin knockdown and dnTCF4 induction in vitro was addressed by semi-quantitative and quantitative real-time RT-PCR and immunoblotting. Results: This study shows for the first time that deletion of β-catenin in murine intestinal epithelium in vivo upregulates PGT protein, especially in the crypt epithelium. Furthermore, β-catenin knockdown in vitro increases PGT expression in both colorectal adenoma-and carcinoma-derived cell lines, as does dnTCF4 induction in LS174T cells.Conclusions:These data suggest that β-catenin employs a two-pronged approach to inhibiting prostaglandin turnover during colorectal neoplasia by repressing PGT expression in addition to 15-PGDH. Furthermore, our data highlight a potential mechanism that may contribute to the non-selective NSAID aspirins chemopreventive efficacy. © 2012 Cancer Research UK All rights reserved

Liverpool telescope 2: a new robotic facility for rapid transient follow-up

The Liverpool Telescope is one of the world's premier facilities for time domain astronomy. The time domain landscape is set to radically change in the coming decade, with surveys such as LSST providing huge numbers of transient detections on a nightly basis; transient detections across the electromagnetic spectrum from other facilities such as SVOM, SKA and CTA; and the era of `multi-messenger astronomy', wherein events are detected via non-electromagnetic means, such as gravitational wave emission. We describe here our plans for Liverpool Telescope 2: a new robotic telescope designed to capitalise on this new era of time domain astronomy. LT2 will be a 4-metre class facility co-located with the LT at the Observatorio del Roque de Los Muchachos on the Canary island of La Palma. The telescope will be designed for extremely rapid response: the aim is that the telescope will take data within 30 seconds of the receipt of a trigger from another facility. The motivation for this is twofold: firstly it will make it a world-leading facility for the study of fast fading transients and explosive phenomena discovered at early times. Secondly, it will enable large-scale programmes of low-to-intermediate resolution spectral classification of transients to be performed with great efficiency. In the target-rich environment of the LSST era, minimising acquisition overheads will be key to maximising the science gains from any follow-up programme. The telescope will have a diverse instrument suite which is simultaneously mounted for automatic changes, but it is envisaged that the primary instrument will be an intermediate resolution, optical/infrared spectrograph for scientific exploitation of transients discovered with the next generation of synoptic survey facilities. In this paper we outline the core science drivers for the telescope, and the requirements for the optical and mechanical design

Supernova remnants: the X-ray perspective

Supernova remnants are beautiful astronomical objects that are also of high scientific interest, because they provide insights into supernova explosion mechanisms, and because they are the likely sources of Galactic cosmic rays. X-ray observations are an important means to study these objects.And in particular the advances made in X-ray imaging spectroscopy over the last two decades has greatly increased our knowledge about supernova remnants. It has made it possible to map the products of fresh nucleosynthesis, and resulted in the identification of regions near shock fronts that emit X-ray synchrotron radiation. In this text all the relevant aspects of X-ray emission from supernova remnants are reviewed and put into the context of supernova explosion properties and the physics and evolution of supernova remnants. The first half of this review has a more tutorial style and discusses the basics of supernova remnant physics and thermal and non-thermal X-ray emission. The second half offers a review of the recent advances.The topics addressed there are core collapse and thermonuclear supernova remnants, SN 1987A, mature supernova remnants, mixed-morphology remnants, including a discussion of the recent finding of overionization in some of them, and finally X-ray synchrotron radiation and its consequences for particle acceleration and magnetic fields.Comment: Published in Astronomy and Astrophysics Reviews. This version has 2 column-layout. 78 pages, 42 figures. This replaced version has some minor language edits and several references have been correcte

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Localization and broadband follow-up of the gravitational-wave transient GW150914

A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser Interferometer Gravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the GW data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network circulars, giving an overview of the participating facilities, the GW sky localization coverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-up campaign are being disseminated in papers by the individual teams

The X-ray counterpart to the gravitational wave event GW 170817

A long-standing paradigm in astrophysics is that collisions- or mergers- of two neutron stars (NSs) form highly relativistic and collimated outflows (jets) powering gamma-ray bursts (GRBs) of short (< 2 s) duration. However, the observational support for this model is only indirect. A hitherto outstanding prediction is that gravitational wave (GW) events from such mergers should be associated with GRBs, and that a majority of these GRBs should be off-axis, that is, they should point away from the Earth. Here we report the discovery of the X-ray counterpart associated with the GW event GW170817. While the electromagnetic counterpart at optical and infrared frequencies is dominated by the radioactive glow from freshly synthesized r-process material in the merger ejecta, known as kilonova, observations at X-ray and, later, radio frequencies exhibit the behavior of a short GRB viewed off-axis. Our detection of X-ray emission at a location coincident with the kilonova transient provides the missing observational link between short GRBs and GWs from NS mergers, and gives independent confirmation of the collimated nature of the GRB emission.Comment: 38 pages, 10 figures, Nature, in pres

Metopic synostosis

Premature closure of the metopic suture results in a growth restriction of the frontal bones, which leads to a skull malformation known as trigonocephaly. Over the course of recent decades, its incidence has been rising, currently making it the second most common type of craniosynostosis. Treatment consists of a cranioplasty, usually preformed before the age of 1 year. Metopic synostosis is linked with an increased level of neurodevelopmental delays. Theories on the etiology of these delays range from a reduced volume of the anterior cranial fossa to intrinsic malformations of the brain. This paper aims to provide an overview of this entity by giving an update on the epidemiology, etiology, evolution of treatment, follow-up, and neurodevelopment of metopic synostosis

Localization and broadband follow-up of the gravitational-wave transient GW150914

A gravitational-wave transient was identified in data recorded by the Advanced LIGO detectors on 2015 September 14. The event candidate, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the gravitational wave data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network Circulars, giving an overview of the participating facilities, the gravitational wave sky localization coverage, the timeline and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the electromagnetic data and results of the electromagnetic follow-up campaign will be disseminated in the papers of the individual teams