A Deep Proper-Motion Survey in Kapteyn Selected Areas: I. Survey Description and First Results for Stars in the Tidal Tail of Sagittarius and in the Monoceros Ring

We describe a high-precision, deep (to V ~ 19-21) absolute proper-motion survey that samples ~50 lines of sight in the Kapteyn Selected Areas along declination zones -15, 0 and 15 degrees. In many fields the astrometric baseline reaches nearly a century. We demonstrate that these data provide typical per star precisions between ~ 1 and 3 mas/yr to the above magnitude limits, with the absolute reference frame established by numerous extragalactic sources in each survey field. Combined with existing and ongoing photometric and radial velocity surveys in these fields, these astrometric data will enable, among other things, accurate, detailed dynamical modeling of satellite interactions with our Galaxy. In this contribution we describe the astrometric part of our survey and show preliminary results along the trailing tail of the Sagittarius dwarf galaxy, and in the Monoceros ring region.Comment: Accepter for publication in the Astronomical Journa

Absolute Proper Motion of the Fornax Dwarf Spheroidal Galaxy from Photographic and HST WFPC2 Data

We have measured the absolute proper motion of the Fornax dwarf spheroidal galaxy from a combination of photographic plate material and HST WFPC2 data that provide a time baseline of up to 50 years. The extragalactic reference frame consists of 8 QSO images and 48 galaxies. The absolute proper motion is mu_alpha cos(delta) = 0.59 +-0.16 mas/yr and mu_delta = -0.15 +- 0.16 mas/yr. The corresponding orbit of Fornax is polar, with an eccentricity of 0.27, and a radial period of 4.5 Gyr. Fornax's current location is near pericenter. The direction of the motion of Fornax supports the notion that Fornax belongs to the Fornax-LeoI-LeoII-Sculptor-Sextans stream as hypothesized by Lynden-Bell (1976, 1982) and Majewski (1994). According to our orbit determination, Fornax crossed the Magellanic plane \~190 Myr ago, a time that coincides with the termination of the star-formation process in Fornax. We propose that ram-pressure stripping due to the passage of Fornax through a gaseous medium denser than the typical intragalactic medium left behind from the LMC may have caused the end of star formation in Fornax. The excess, anomalous clouds within the South Galactic pole region of the Magellanic Stream whose origin has long been debated in the literature as constituents of either the Magellanic Stream or of the extragalactic Sculptor group, are found to lie along the orbit of Fornax. We speculate that these clouds are stripped material from Fornax as the dwarf crossed the Magellanic Clouds' orbit.Comment: Accepted for publication in Astronomical Journal. The version with high resolution figures can be found at ftp://pegasus.astro.yale.edu/pub/dana/paper

Orbits of Globular Clusters in the Outer Galaxy: NGC 7006

We present a proper motion study of the distant globular cluster NGC 7006 based on the measurement of 25 photographic plates spanning a 40-year interval. The absolute proper motion determined with respect to extragalactic objects is (-0.96, -1.14) +- (0.35, 0.40) mas/yr. The total space velocity of NGC 7006 in a Galactocentric rest frame is 279 km/s, placing the cluster on one of the most energetic orbits (Ra =102 kpc) known to date for clusters within 40-kpc from the Galactic center. We compare the orbits of four clusters that have apocentric radii larger than 80 kpc (NGC 5466, NGC 6934, NGC 7006 and Pal 13) with those of Galactic satellites with well-measured proper motions. These clusters have orbits that are highly eccentric and of various inclinations with respect to the Galactic plane. In contrast, the orbits of the Galactic satellites are of low to moderate eccentricity and highly inclined. Based on orbit types, chemical abundances and cluster parameters, we discuss the properties of the hypothetical host systems of the remote globular clusters in the Searle-Zinn paradigm. It is apparent that clusters such as NGC 5466, NGC 6934 and NGC 7006 formed in systems that more likely resemble the Fornax dSph, rather than the Sagittarius dSph. We also discuss plausible causes for the difference found so far between the orbit type of outer halo clusters and that of Galactic satellites and for the tentative, yet suggestive phase-space scatter found among outer halo clusters.Comment: 27 pages, 5 figures, to be published in the Astronomical Journa

Absolute Proper Motions to B~22.5: V. Detection of Sagittarius Dwarf Spheroidal Debris in the Direction of the Galactic Anticenter

We have detected a population of predominantly blue (B-V <= 1.1) stars in the direction l = 167 deg., b = -35 deg. (Kapteyn Selected Area 71) that cannot be accounted for by standard starcount models. Down to V ~ 20, the colors and magnitudes of these stars are similar to those of the southern overdensity detected by the Sloan Digital Sky Survey, and identified as stripped material from the Sagittarius dwarf spheroidal galaxy. We present absolute proper motions for the stars in SA 71, and we find that the excess blue stars represent a distinct, kinematically cooler component than the Galactic field, and in reasonable agreement with predictions of Sgr disruption models. The density of the excess SA 71 stars at V ~ 18.8 and B-V <=1.1 is within a factor of two of the density of the SDSS-south Sgr stripped material, and of that predicted by the Helmi and White disruption model. Three additional anticenter fields (SA 29, 45 and 118) show very good agreement with standard starcount models.Comment: 13 pages, 3 figures, submitted to ApJL, accepted for Ap

Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease

Chronic obstructive lung disease is characterized by persistent abnormalities in epithelial and immune cell function that are driven, at least in part, by infection. Analysis of parainfluenza virus infection in mice revealed an unexpected role for innate immune cells in IL-13–dependent chronic lung disease, but the upstream driver for the immune axis in this model and in humans with similar disease was undefined. We demonstrate here that lung levels of IL-33 are selectively increased in postviral mice with chronic obstructive lung disease and in humans with very severe chronic obstructive pulmonary disease (COPD). In the mouse model, IL-33/IL-33 receptor signaling was required for Il13 and mucin gene expression, and Il33 gene expression was localized to a virus-induced subset of airway serous cells and a constitutive subset of alveolar type 2 cells that are both linked conventionally to progenitor function. In humans with COPD, IL33 gene expression was also associated with IL13 and mucin gene expression, and IL33 induction was traceable to a subset of airway basal cells with increased capacities for pluripotency and ATP-regulated release of IL-33. Together, these findings provide a paradigm for the role of the innate immune system in chronic disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production

Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model

BACKGROUND: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel(®)) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. METHODS: Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. RESULTS: Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). CONCLUSION: These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV

Targeting the PAI-1 Mechanism with a Small Peptide Increases the Efficacy of Alteplase in a Rabbit Model of Chronic Empyema

The incidence of empyema is increasing and associated with a mortality rate of 20% in patients older than 65 years. Since 30% of patients with advanced empyema have contraindications to surgical treatment, novel, low-dose, pharmacological treatments are needed. A Streptococcus pneumoniae-induced rabbit model of chronic empyema recapitulates the progression, loculation, fibrotic repair, and pleural thickening of human disease. Treatment with single chain (sc) urokinase (scuPA) or tissue type (sctPA) plasminogen activators in doses 1.0–4.0 mg/kg were only partially effective in this model. Docking Site Peptide (DSP; 8.0 mg/kg), which decreased the dose of sctPA for successful fibrinolytic therapy in acute empyema model did not improve efficacy in combination with 2.0 mg/kg scuPA or sctPA. However, a two-fold increase in either sctPA or DSP (4.0 and 8.0 mg/kg or 2.0 and 16.0 mg/kg sctPA and DSP, respectively) resulted in 100% effective outcome. Thus, DSP-based Plasminogen Activator Inhibitor 1-Targeted Fibrinolytic Therapy (PAI-1-TFT) of chronic infectious pleural injury in rabbits increases the efficacy of alteplase rendering ineffective doses of sctPA effective. PAI-1-TFT represents a novel, well-tolerated treatment of empyema that is amenable to clinical introduction. The chronic empyema model recapitulates increased resistance of advanced human empyema to fibrinolytic therapy, thus allowing for studies of muti-injection treatments

Yersinia pestis Evolution on a Small Timescale: Comparison of Whole Genome Sequences from North America

Yersinia pestis, the etiologic agent of plague, was responsible for several devastating epidemics throughout history and is currently of global importance to current public heath and biodefense efforts. Y. pestis is widespread in the Western United States. Because Y. pestis was first introduced to this region just over 100 years ago, there has been little time for genetic diversity to accumulate. Recent studies based upon single nucleotide polymorphisms have begun to quantify the genetic diversity of Y. pestis in North America.To examine the evolution of Y. pestis in North America, a gapped genome sequence of CA88-4125 was generated. Sequence comparison with another North American Y. pestis strain, CO92, identified seven regions of difference (six inversions, one rearrangement), differing IS element copy numbers, and several SNPs.The relatively large number of inverted/rearranged segments suggests that North American Y. pestis strains may be undergoing inversion fixation at high rates over a short time span, contributing to higher-than-expected diversity in this region. These findings will hopefully encourage the scientific community to sequence additional Y. pestis strains from North America and abroad, leading to a greater understanding of the evolutionary history of this pathogen

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts