The lincRNA MIRAT binds to IQGAP1 and modulates the MAPK pathway in NRAS mutant melanoma.

Despite major advances in targeted melanoma therapies, drug resistance limits their efficacy. Long noncoding RNAs (lncRNAs) are transcriptome elements that do not encode proteins but are important regulatory molecules. LncRNAs have been implicated in cancer development and response to different therapeutics and are thus potential treatment targets; however, the majority of their functions and molecular interactions remain unexplored. In this study, we identify a novel cytoplasmic intergenic lincRNA (MIRAT), which is upregulated following prolonged MAPK inhibition in NRAS mutant melanoma and modulates MAPK signaling by binding to the MEK scaffold protein IQGAP1. Collectively, our results present MIRAT's direct modulatory effect on the MAPK pathway and highlight the relevance of cytoplasmic lncRNAs as potential targets in drug resistant cancer

Measuring magnetism in the Milky Way with the Square Kilometre Array

Magnetic fields in the Milky Way are present on a wide variety of sizes and strengths, influencing many processes in the Galactic ecosystem such as star formation, gas dynamics, jets, and evolution of supernova remnants or pulsar wind nebulae. Observation methods are complex and indirect; the most used of these are a grid of rotation measures of unresolved polarized extragalactic sources, and broadband polarimetry of diffuse emission. Current studies of magnetic fields in the Milky Way reveal a global spiral magnetic field with a significant turbulent component; the limited sample of magnetic field measurements in discrete objects such as supernova remnants and HII regions shows a wide variety in field configurations; a few detections of magnetic fields in Young Stellar Object jets have been published; and the magnetic field structure in the Galactic Center is still under debate. The SKA will unravel the 3D structure and configurations of magnetic fields in the Milky Way on sub-parsec to galaxy scales, including field structure in the Galactic Center. The global configuration of the Milky Way disk magnetic field, probed through pulsar RMs, will resolve controversy about reversals in the Galactic plane. Characteristics of interstellar turbulence can be determined from the grid of background RMs. We expect to learn to understand magnetic field structures in protostellar jets, supernova remnants, and other discrete sources, due to the vast increase in sample sizes possible with the SKA. This knowledge of magnetic fields in the Milky Way will not only be crucial in understanding of the evolution and interaction of Galactic structures, but will also help to define and remove Galactic foregrounds for a multitude of extragalactic and cosmological studies.Comment: 19 pages, 2 figures; to appear as part of 'Cosmic Magnetism' in Proceedings 'Advancing Astrophysics with the SKA (AASKA14)', PoS(AASKA14)09

Discovery of a Dynamical Cold Point in the Heart of the Sagittarius dSph Galaxy with Observations from the APOGEE Project

The dynamics of the core of the Sagittarius (Sgr) dwarf spheroidal (dSph) galaxy are explored using high-resolution (R~22,500), H-band, near-infrared spectra of over 1,000 giant stars in the central 3 deg^2 of the system, of which 328 are identified as Sgr members. These data, among some of the earliest observations from the SDSS-III/Apache Point Observatory Galactic Evolution Experiment (APOGEE) and the largest published sample of high resolution Sgr dSph spectra to date, reveal a distinct gradient in the velocity dispersion of Sgr from 11-14 km/s for radii >0.8 degrees from center to a dynamical cold point of 8 km/s in the Sgr center --- a trend differing from that found in previous kinematical analyses of Sgr over larger scales that suggest a more or less flat dispersion profile at these radii. Well-fitting mass models with either cored and cusped dark matter distributions can be found to match the kinematical results, although the cored profile succeeds with significantly more isotropic stellar orbits than required for a cusped profile. It is unlikely that the cold point reflects an unusual mass distribution. The dispersion gradient may arise from variations in the mixture of populations with distinct kinematics within the dSph; this explanation is suggested (e.g., by detection of a metallicity gradient across similar radii), but not confirmed, by the present data. Despite these remaining uncertainties about their interpretation, these early test data (including some from instrument commissioning) demonstrate APOGEE's usefulness for precision dynamical studies, even for fields observed at extreme airmasses.Comment: 15 pages, 3 figure

Identifying Contributions to the Stellar Halo from Accreted, Kicked-Out, and In Situ Populations

[Abridged] We present a medium-resolution spectroscopic survey of late-type giant stars at mid-Galactic latitudes of (30$^{\circ}<|b|<60^{\circ}$), designed to probe the properties of this population to distances of $\sim$9 kpc. Because M giants are generally metal-rich and we have limited contamination from thin disk stars by the latitude selection, most of the stars in the survey are expected to be members of the thick disk ($\sim$-0.6) with some contribution from the metal-rich component of the nearby halo. Here we report first results for 1799 stars. The distribution of radial velocity (RV) as a function of l for these stars shows (1) the expected thick disk population and (2) local metal-rich halo stars moving at high speeds relative to the disk, that in some cases form distinct sequences in RV-$l$ space. High-resolution echelle spectra taken for 34 of these "RV outliers" reveal the following patterns across the [Ti/Fe]-[Fe/H] plane: seventeen of the stars have abundances reminiscent of the populations present in dwarf satellites of the Milky Way; eight have abundances coincident with those of the Galactic disk and more metal-rich halo; and nine of the stars fall on the locus defined by the majority of stars in the halo. The chemical abundance trends of the RV outliers suggest that this sample consists predominantly of stars accreted from infalling dwarf galaxies. A smaller fraction of stars in the RV outlier sample may have been formed in the inner Galaxy and subsequently kicked to higher eccentricity orbits, but the sample is not large enough to distinguish conclusively between this interpretation and the alternative that these stars represent the tail of the velocity distribution of the thick disk. Our data do not rule out the possibility that a minority of the sample could have formed from gas {\it in situ} on their current orbits.Comment: 43 pages, 9 figures, 4 tables, published in the Astrophysical Journa

Adenosine and lymphocyte regulation

Adenosine is a potent extracellular messenger that is produced in high concentrations under metabolically unfavourable conditions. Tissue hypoxia, consequent to a compromised cellular energy status, is followed by the enhanced breakdown of ATP leading to the release of adenosine. Through the interaction with A2 and A3 membrane receptors, adenosine is devoted to the restoration of tissue homeostasis, acting as a retaliatory metabolite. Several aspects of the immune response have to be taken into consideration and even though in general it is very important to dampen inflammation, in some circumstances, such as the case of cancer, it is also necessary to increase the activity of immune cells against pathogens. Therefore, adenosine receptors that are defined as ‘sensors–of metabolic changes in the local tissue environment may be very important targets for modulation of immune responses and drugs devoted to regulating the adenosinergic system are promising in different clinical situations

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs

The potential of unmanned aerial systems for sea turtle research and conservation: a review and future directions

Contains fulltext : 195205.pdf (publisher's version ) (Open Access

The Design and Implementation of OpenORB 2

Established middleware platforms such as CORBA and DCOM are not flexible enough to meet the needs of emerging distributed applications. This article discusses the architecture of Open ORB 2, a middleware platform based on reflection and component technology. Middleware has emerged as an important architectural component in modern distributed systems largely because it offers a high-level, platform-independent programming model that helps mask distribution problems. Examples of key middleware platforms include DCE, CORBA, DCOM, .NET, and the Java-based series of technologies, including RMI, Jini, and EJBs (for more information on these platforms, see the Middleware Platforms sidebar). Traditionally, developers have deployed such platforms in areas such as banking and finance to overcome heterogeneity and support the integration of legacy systems. More recently, however, developers have applied middleware technologies in a wider range of areas, including safety-critical, embedded, and real-time systems. It is now becoming apparent that middleware technologies cannot respond to such diverse requirements or technical challenges because of the limitations of the black-box philosophy maintained by developers of most existing middleware platforms. In particular, existing middleware platforms offer fixed services to their users; it is typically impossible to view or alter the implementation of these services. Inevitably, the architecture of this platform then represents a compromise design that features, for example, general-purpose protocols and associated management strategies. It is not possible to specialize platforms to meet the needs of more specific target domains. Other researchers in the field have also recognized these problems.1,2 Middleware designers are aware of these problems and have responded with several initiatives. The Object Management Group, focusing on CORBA, introduced a series of platform specifications that includes real-time CORBA and Minimal CORBA. But these specifications are specific solutions for specific domains, not general solutions to this problem. Modern middleware platforms also typically offer more flexibility through mechanisms such as interceptors and configurable protocol stacks. While these are important developments, they do not offer a complete solution to the problem. We believe next generation middleware platforms should be configurable, to meet the needs of a given application domain, dynamically reconfigurable, to enable the platforms to respond to changes in their environment, and evolvable, to meet the needs of changing platform design. Recently, several reflective middleware technologies have emerged in response to such requirements (see the Related Work sidebar). Reflection is a technology that has previously been deployed successfully in the design of languages and operating systems. The key to the approach is to offer a meta-interface supporting the inspection and adaptation of the underlying virtual machine. In the context of middleware, the meta-interface would support operations to discover the internal operation and structure of the middleware platform (such as the deployed protocols and management structures) and to make changes at runtime. The design of such a meta-interface is central to studies of reflection: The interface should be sufficiently general to permit unanticipated changes to the platform but should also be restricted to prevent the integrity of the system from being destroyed. This article presents the design and implementation of Open ORB, a reflective middleware platform developed at Lancaster University. Specifically, we focus on Open ORB 2, a significant redesign that builds on our experience from the first implementation.3 Note that, for simplicity, we generally refer to Open ORB 2 as simply Open ORB in the rest of this article