The drug efflux pump Pgp1 in pro-inflammatory lymphocytes is a target for novel treatment strategies in COPD

Extent: 8 p.BACKGROUND: Pro-inflammatory/cytotoxic T cells (IFNγ, TNFα, granzyme B+) are increased in the peripheral circulation in COPD. NKT-like and NK cells are effector lymphocytes that we have also shown to be major sources of pro-inflammatory cytokines and granzymes. P-glycoprotein 1 (Pgp1) is a transmembrane efflux pump well characterised in drug resistant cancer cells. We hypothesized that Pgp1 would be increased in peripheral blood T, NKT-like and NK cells in patients with COPD, and that this would be accompanied by increased expression of IFNγ, TNFα and granzyme B. We further hypothesized that treatment with cyclosporine A, a Pgp1 inhibitor, would render cells more sensitive to treatment with corticosteroids. METHODS: Pgp1, granzyme B, IFNγ and TNFα expression were measured in peripheral blood T, NK and NKT-like cells from COPD patients and control subjects (± cyclosporine A and prednisolone) following in vitro stimulation and results correlated with uptake of efflux dye Calcein-AM using flow cytometry. RESULTS: There was increased Pgp1 expression by peripheral blood T, NKT-like and NK cells co-expressing IFNγ, TNFα and granzyme B in COPD patients compared with controls (e.g. %IFNγ/Pgp1 T, NKT-like, NK for COPD (Control): 25(6), 54(27), 39(23)). There was an inverse correlation between Pgp1 expression and Calcein-AM uptake. Treatment with 2.5 ng/ml cylosporin A and10-6 M prednisolone resulted in synergistic inhibition of pro-inflammatory cytokines in Pgp1 + cells (p < 0.05 for all). CONCLUSIONS: Treatment strategies that target Pgp1 in T, NKT-like and NK cells may reduce systemic inflammatory mediators in COPD and improve patient morbidity.Greg Hodge, Mark Holmes, Hubertus Jersmann, Paul N. Reynolds and Sandra Hodg

Landscapes and Fragilities

The concept of fragility provides a possibility to rank different supercooled liquids on the basis of the temperature dependence of dynamic and/or thermodynamic quantities. We recall here the definitions of kinetic and thermodynamic fragility proposed in the last years and discuss their interrelations. At the same time we analyze some recently introduced models for the statistical properties of the potential energy landscape. Building on the Adam-Gibbs relation, which connects structural relaxation times to configurational entropy, we analyze the relation between statistical properties of the landscape and fragility. We call attention to the fact that the knowledge of number, energy depth and shape of the basins of the potential energy landscape may not be sufficient for predicting fragility. Finally, we discuss two different possibilities for generating strong behavior.Comment: 17 pages, 10 figures; accepted version, minor correction

Monitoring the Low-Energy Gamma-Ray Sky Using Earth Occultation with GLAST GBM

Long term all-sky monitoring of the 20 keV – 2 MeV gamma-ray sky using the Earth occultation technique was demonstrated by the BATSE instrument on the Compton Gamma Ray Observatory. The principles and techniques used for the development of an end-to-end earth occultation data analysis system for BATSE can be extended to the GLAST Burst Monitor (GBM), resulting in multiband light curves and time-resolved spectra in the energy range 8 keV to above 1 MeV for known gamma-ray sources and transient outbursts, as well as the discovery of new sources of gamma-ray emission. In this paper we describe the application of the technique to the GBM. We also present the expected sensitivity for the GBM

Changes in mass balance of South Cascade Glacier, North Cascades, 1959 to 1994

EXTRACT (SEE PDF FOR FULL ABSTRACT): Annual, winter, and summer mass balance measurements at South Cascade Glacier in the North Cascade Mountains of Washington State constitute a continuous time series 36 years long, from 1959 to 1994. ... The long-term trends at South Cascade Glacier are decreased winter accumulation and increased summer ablation, neither of which is conducive to glacier growth, so the trend in the Pacific Northwest is clearly away from an ice-age type of climate at the current time. The data also demonstrate that a glaciologically significant long-term change in snow precipitation can occur rapidly, in as short an interval as 1 year, much more rapidly than changes in temperature

The Stellar Populations of NGC 3109: Another Dwarf Irregular Galaxy with a Population II Stellar Halo

We have obtained V and I-band photometry for about 17500 stars in the field of the dwarf irregular galaxy NGC3109, located in the outskirts of the Local Group. The photometry allows us to study the stellar populations present inside and outside the disk of this galaxy. From the VI color-magnitude diagram we infer metallicities and ages for the stellar populations in the main body and in the halo of NGC3109. The stars in the disk of this galaxy have a wide variety of ages, including very young stars with approximately 10^7 yr. Our main result is to establish the presence of a halo consisting of population II stars, extending out to about 4.5 arcmin (or 1.8 kpc) above and below the plane of this galaxy. For these old stars we derive an age of > 10 Gyr and a metallicity of [Fe/H] = -1.8 +/- 0.2. We construct a deep luminosity function, obtaining an accurate distance modulus (m-M)_0 = 25.62 +/- 0.1 for this galaxy based on the I-magnitude of the red giant branch (RGB) tip and adopting E(V-I) = 0.05.Comment: Accepted for publication in the Astronomical Journal 23 pages, latex, 12 Figures (Fig 1 not available in electronic format

Update and clinical utility of the LenSx femtosecond laser in cataract surgery

� 2016 Roberts et al. The introduction of femtosecond lasers to cataract surgery has been the major disruptive technology introduced into ophthalmic surgery in the last decade. Femtosecond laser cataract surgery (FLACS) integrates high-resolution anterior segment imaging with a femtosecond laser allowing key steps of cataract surgery to be performed with computer-guided laser accuracy, precision, and reproducibility. Since the introduction of FLACS, there have been significant advances in laser software and hardware as well as surgeon experience, with over 250 articles published in the peer-reviewed literature. This review examines the published evidence relating to the LenSx platform and discusses surgical techniques, indications, safety, and clinical results

Earth Occultation Imaging of the Low Energy Gamma-Ray Sky with GBM

The Earth Occultation Technique (EOT) has been applied to Fermi's Gamma-ray Burst Monitor (GBM) to perform all-sky monitoring for a predetermined catalog of hard X-ray/soft gamma-ray sources. In order to search for sources not in the catalog, thus completing the catalog and reducing a source of systematic error in EOT, an imaging method has been developed -- Imaging with a Differential filter using the Earth Occultation Method (IDEOM). IDEOM is a tomographic imaging method that takes advantage of the orbital precession of the Fermi satellite. Using IDEOM, all-sky reconstructions have been generated for ~sim 4 years of GBM data in the 12-50 keV, 50-100 keV and 100-300 keV energy bands in search of sources otherwise unmodeled by the GBM occultation analysis. IDEOM analysis resulted in the detection of 57 sources in the 12-50 keV energy band, 23 sources in the 50-100 keV energy band, and 7 sources in the 100-300 keV energy band. Seventeen sources were not present in the original GBM-EOT catalog and have now been added. We also present the first joined averaged spectra for four persistent sources detected by GBM using EOT and by the Large Area Telescope (LAT) on Fermi: NGC 1275, 3C 273, Cen A, and the Crab

The Glass Transition Temperature of Water: A Simulation Study

We report a computer simulation study of the glass transition for water. To mimic the difference between standard and hyperquenched glass, we generate glassy configurations with different cooling rates and calculate the $T$ dependence of the specific heat on heating. The absence of crystallization phenomena allows us, for properly annealed samples, to detect in the specific heat the simultaneous presence of a weak pre-peak (``shadow transition''), and an intense glass transition peak at higher temperature. We discuss the implications for the currently debated value of the glass transition temperature of water. We also compare our simulation results with the Tool-Narayanaswamy-Moynihan phenomenological model.Comment: submitted to Phys. Re

An HST/WFPC2 Survey of Bright Young Clusters in M31 III. Structural Parameters

Surface brightness profiles for 23 M31 star clusters were measured using images from the Wide Field Planetary Camera 2 on the Hubble Space Telescope, and fit to two types of models to determine the clusters' structural properties. The clusters are primarily young (~10^8 yr) and massive (~10^4.5 solar masses), with median half-light radius 7 pc and dissolution times of a few Gyr. The properties of the M31 clusters are comparable to those of clusters of similar age in the Magellanic Clouds. Simulated star clusters are used to derive a conversion from statistical measures of cluster size to half-light radius so that the extragalactic clusters can be compared to young massive clusters in the Milky Way. All three sets of star clusters fall approximately on the same age-size relation. The young M31 clusters are expected to dissolve within a few Gyr and will not survive to become old, globular clusters. However, they do appear to follow the same fundamental plane relations as old clusters; if confirmed with velocity dispersion measurements, this would be a strong indication that the star cluster fundamental plane reflects universal cluster formation conditions.Comment: AJ in press; 37 pages, 12 figure

The Absence of Extra-Tidal Structure in the Sculptor Dwarf Spheroidal Galaxy

The results of a wide-field survey of the Sculptor dwarf spheroidal galaxy are presented. Our aims were to obtain an accurate map of the outer structure of Sculptor, and to determine the level of interaction between this system and the Galaxy. Photometry was obtained in two colours down to the magnitude limits of V=20 and I=19, covering a 3.1 times 3.1 square deg area centred on Sculptor. The resulting colour-magnitude data were used as a mask to select candidate horizontal branch and red giant branch stars for this system. Previous work has shown that the red horizontal branch (HB) stars are more concentrated than the blue HB stars. We have determined the radial distributions of these two populations and show that the overall Sculptor density profile is well described by a two component model based on a combination of these radial distributions. Additionally, spectra of the Ca ii triplet region were obtained for over 700 candidate red giant stars over the 10 square deg region using the 2dF instrument on the Anglo-Australian Telescope. These spectra were used to remove foreground Galactic stars based on radial velocity and Ca ii triplet strength. The final list of Sculptor members contained 148 stars, seven of which are located beyond the nominal tidal radius. Both the photometric and spectroscopic datasets indicate no significant extra-tidal structure. These results support at most a mild level of interaction between this system and the Galaxy, and we have measured an upper mass limit for extra-tidal material to be 2.3 +/- 0.6% of the Sculptor luminous mass. This lack of tidal interaction indicates that previous velocity dispersion measurements (and hence the amount of dark matter detected) in this system are not strongly influenced by the Galactic tidal field.Comment: 53 pages, 23 figures. Accepted for publication in the Astronomical Journal. Some figures are reduced in size, and a full version is available at: ftp://ftp.mso.anu.edu.au/pub/coleman/sculptor.pd