Alternate routes to the cell surface underpin insulin-regulated membrane trafficking of GLUT4

Insulin-stimulated delivery of glucose transporters (GLUT4) from specialized intracellular GLUT4 storage vesicles (GSVs) to the surface of fat and muscle cells is central to whole-body glucose. This translocation and subsequent internalization of GLUT4 back into intracellular stores transits numerous small membrane-bound compartments (internal GLUT4-containing vesicles; IGVs) including GSVs, but the function of these different compartments is not clear. Cellugyrin and sortilin define distinct populations of IGV; sortilin-positive IGVs represent GSVs, but the function of cellugyrin-containing IGVs is unknown. Here we demonstrate a role for cellugyrin in intracellular sequestration of GLUT4 in HeLa cells and have used a proximity ligation assay to follow changes in pairwise associations between cellugyrin, sortilin, GLUT4 and membrane trafficking machinery following insulin-stimulation of 3T3-L1 adipoctyes. Our data suggest that insulin stimulates traffic from cellugyrin- to sortilin- membranes, and that cellugyrin-IGVs provide an insulin-sensitive reservoir to replenish GSVs following insulin-stimulated exocytosis of GLUT4. Furthermore, our data support the existence of a pathway from cellugyrin-membranes to the surface of 3T3-L1 adipocytes that bypasses GSVs under basal conditions, and that insulin diverts traffic away from this into GSVs

DEKAS - An evolutionary case-based reasoning system to support protection scheme design

This paper describes a decision support system being developed in conjunction with two UK utility companies to aid the design of electrical power transmission protection systems. A brief overview of the application domain is provided, followed by a description of the work carried out to date concerning the development and deployment of the Design Engineering Knowledge Application System (DEKAS). The paper then discusses the provision of intelligent decision support to the design engineer through the application of case-based reasoning (CBR). The key benefits from this will be outlined in conjunction with a relevant case study

Targeting long non-coding RNAs (lncRNAs) with oligonucleotides in cancer therapy

This document is the Accepted Manuscript version of a published work that appeared in final form in Translational Cancer Research. To access the final edited and published work see http://dx.doi.org/10.21037/tcr.2016.10.63No abstrac

The hormone response element mimic sequence of GAS5 lncRNA is sufficient to induce apoptosis in breast cancer cells.

Growth arrest-specific 5 (GAS5) lncRNA promotes apoptosis, and its expression is down-regulated in breast cancer. GAS5 lncRNA is a decoy of glucocorticoid/related receptors; a stem-loop sequence constitutes the GAS5 hormone response element mimic (HREM), which is essential for the regulation of breast cancer cell apoptosis. This preclinical study aimed to determine if the GAS5 HREM sequence alone promotes the apoptosis of breast cancer cells. Nucleofection of hormone-sensitive and -insensitive breast cancer cell lines with a GAS5 HREM DNA oligonucleotide increased both basal and ultraviolet-C-induced apoptosis, and decreased culture viability and clonogenic growth, similar to GAS5 lncRNA. The HREM oligonucleotide demonstrated similar sequence specificity to the native HREM for its functional activity and had no effect on endogenous GAS5 lncRNA levels. Certain chemically modified HREM oligonucleotides, notably DNA and RNA phosphorothioates, retained pro-apoptotic. activity. Crucially the HREM oligonucleotide could overcome apoptosis resistance secondary to deficient endogenous GAS5 lncRNA levels. Thus, the GAS5 lncRNA HREM sequence alone is sufficient to induce apoptosis in breast cancer cells, including triple-negative breast cancer cells. These findings further suggest that emerging knowledge of structure/function relationships in the field of lncRNA biology can be exploited for the development of entirely novel, oligonucleotide mimic-based, cancer therapies.Breast Cancer No

Let Your Library Shine: Creating a Student Newsletter to Raise the Profile of an Academic Library

Developed to raise the profile of the library among ETSU\u27s student community, which is comprised of nearly 15,000 undergraduate and graduate students, The Sherrod Library Student Newsletter is released twice per semester and highlights library events, resources, and services that students may not otherwise know about. It is our library\u27s hope that creating such a newsletter will increase student attendance at library events as well as increase the use of featured library resources and services. Join us as we discuss the steps and logistics of planning, creating, funding, and releasing a student newsletter

Galaxy-Galaxy Lensing in the Hubble Deep Field: The Halo Tully-Fisher Relation at Intermediate Redshift

A tangential distortion of background source galaxies around foreground lens galaxies in the Hubble Deep Field is detected at the 99.3% confidence level. An important element of our analysis is the use of photometric redshifts to determine distances of lens and source galaxies and rest-frame B-band luminosities of the lens galaxies. The lens galaxy halos obey a Tully-Fisher relation between halo circular velocity and luminosity; the typical lens galaxy, at a redshift z = 0.6, has a circular velocity of 210 +/-40 km/s at M_B = -18.5, if q_0 = 0.5. Control tests, in which lens and source positions and source ellipticities are randomized, confirm the significance level of the detection quoted above. Furthermore, a marginal signal is also detected from an independent, fainter sample of source galaxies without photometric redshifts. Potential systematic effects, such as contamination by aligned satellite galaxies, the distortion of source shapes by the light of the foreground galaxies, PSF anisotropies, and contributions from mass distributed on the scale of galaxy groups are shown to be negligible. A comparison of our result with the local Tully-Fisher relation indicates that intermediate-redshift galaxies are fainter than local spirals by 1.0 +/- 0.6 B mag at a fixed circular velocity. This is consistent with some spectroscopic studies of the rotation curves of intermediate-redshift galaxies. This result suggests that the strong increase in the global luminosity density with redshift is dominated by evolution in the galaxy number density.Comment: Revised version with minor changes. 13 pages, 7 figures, LaTeX2e, uses emulateapj and multicol styles (included). Accepted by Ap

A definitive merger-AGN connection at z~0 with CFIS: mergers have an excess of AGN and AGN hosts are more frequently disturbed

The question of whether galaxy mergers are linked to the triggering of active galactic nuclei (AGN) continues to be a topic of considerable debate. The issue can be broken down into two distinct questions: 1) Can galaxy mergers trigger AGN? 2) Are galaxy mergers the dominant AGN triggering mechanism? A complete picture of the AGN-merger connection requires that both of these questions are addressed with the same dataset. In previous work, we have shown that galaxy mergers selected from the Sloan Digital Sky Survey (SDSS) show an excess of both optically-selected, and mid-IR colour-selected AGN, demonstrating that the answer to the first of the above questions is affirmative. Here, we use the same optical and mid-IR AGN selection to address the second question, by quantifying the frequency of morphological disturbances in low surface brightness r-band images from the Canada France Imaging Survey (CFIS). Only ~30 per cent of optical AGN host galaxies are morphologically disturbed, indicating that recent interactions are not the dominant trigger. However, almost 60 per cent of mid-IR AGN hosts show signs of visual disturbance, indicating that interactions play a more significant role in nuclear feeding. Both mid-IR and optically selected AGN have interacting fractions that are a factor of two greater than a mass and redshift matched non-AGN control sample, an excess that increases with both AGN luminosity and host galaxy stellar mass.Comment: Accepted for publication in MNRA

de Sitter Vacua in Type IIB String Theory: Classical Solutions and Quantum Corrections

We revisit the classical theory of ten-dimensional two-derivative gravity coupled to fluxes, scalar fields, D-branes, anti D-branes and Orientifold-planes. We show that such set-ups do not give rise to a four-dimensional positive curvature spacetime with the isometries of de Sitter spacetime. We further argue that a de Sitter solution in type IIB theory may still be achieved if the higher-order curvature corrections are carefully controlled. Our analysis relies on the derivation of the de Sitter condition from an explicit background solution by going beyond the supergravity limit of type IIB theory. As such this also tells us how the background supersymmetry should be broken and under what conditions D-term uplifting can be realized with non self-dual fluxes

GAS5 lncRNA Modulates the Action of mTOR Inhibitors in Prostate Cancer Cells

Background There is a need to develop new therapies for castrate-resistant prostate cancer (CRPC) and growth arrest-specific 5 (GAS5) long non-coding RNA (lncRNA), which riborepresses androgen receptor action, may offer novel opportunities in this regard. GAS5 lncRNA expression declines as prostate cancer cells acquire castrate-resistance, and decreased GAS5 expression attenuates the responses of prostate cancer cells to apoptotic stimuli. Enhancing GAS5 lncRNA expression may therefore offer a strategy to improve the effectiveness of chemotherapeutic agents. GAS5 is a member of the 5' terminal oligopyrimidine gene family, and we have therefore examined if mTOR inhibition can enhance cellular GAS5 levels in prostate cancer cells. In addition, we have determined if GAS5 lncRNA itself is required for mTOR inhibitor action in prostate cancer cells, as recently demonstrated in lymphoid cells. Method The effects of mTOR inhibitors on GAS5 lncRNA expression and cell proliferation were determined in a range of prostate cancer cell lines. Transfection of cells with GAS5 siRNA and plasmid constructs was performed to determine the involvement of GAS5 lncRNA in mTOR inhibitor action. Results Treatment with rapamycin and rapalogues increased cellular GAS5 levels and inhibited culture growth in both androgen-dependent (LNCaP) and androgen-sensitive (22Rv1) cell lines, but not in androgen-independent (PC-3 and DU145) cells. GAS5 silencing in both LNCaP and 22Rv1 cells decreased their sensitivity to growth inhibition by mTOR inhibitors. Moreover, transfection of GAS5 lncRNA sensitized PC-3 and DU145 cells to mTOR inhibitors, resulting in inhibition of culture growth. Conclusion mTOR inhibition enhances GAS5 transcript levels in some, but not all, prostate cancer cell lines. This may in part be related to endogenous levels of GAS5 expression, which tend to be lower in prostate cancer cells representative of advanced disease, particularly since current findings demonstrate a role for GAS5 lncRNA in mTOR inhibitor action in prostate cancer cells

Galaxies at the extremes: Ultra-diffuse galaxies in the Virgo Cluster

We report the discovery of three large (R29 >~ 1 arcminute) extremely low surface brightness (mu_(V,0) ~ 27.0) galaxies identified using our deep, wide-field imaging of the Virgo Cluster from the Burrell Schmidt telescope. Complementary data from the Next Generation Virgo Cluster Survey do not resolve red giant branch stars in these objects down to i=24, yielding a lower distance limit of 2.5 Mpc. At the Virgo distance, these objects have half-light radii 3-10 kpc and luminosities L_V=2-9x10^7 Lsun. These galaxies are comparable in size but lower in surface brightness than the large ultradiffuse LSB galaxies recently identified in the Coma cluster, and are located well within Virgo's virial radius; two are projected directly on the cluster core. One object appears to be a nucleated LSB in the process of being tidally stripped to form a new Virgo ultracompact dwarf galaxy. The others show no sign of tidal disruption, despite the fact that such objects should be most vulnerable to tidal destruction in the cluster environment. The relative proximity of Virgo makes these objects amenable to detailed studies of their structural properties and stellar populations. They thus provide an important new window onto the connection between cluster environment and galaxy evolution at the extremes.Comment: 7 pages, 4 figures, to appear in ApJ Letters. Updated with minor revisions to match accepted versio