Spectroscopy and Time Variability of Absorption Lines in the Direction of the Vela Supernova Remnant

We present high resolution (R~75,000), high signal-to-noise (S/N~100) Ca II $\lambda$3933.663 and Na I $\lambda\lambda$5889.951, 5895.924 spectra of 68 stars in the direction of the Vela supernova remnant. The spectra comprise the most complete high resolution, high S/N, optical survey of early type stars in this region of the sky. A subset of the sight lines has been observed at multiple epochs, 1993/1994 and 1996. Of the thirteen stars observed twice, seven have spectra revealing changes in the equivalent width and/or velocity structure of lines, most of which arise from remnant gas. Such time variability has been reported previously for the sight lines towards HD 72089 and HD 72997 by Danks & Sembach (1995) and for HD 72127 by Hobbs et al. (1991). We have confirmed the ongoing time variability of these spectra and present new evidence of variability in the spectra of HD 73658, HD 74455, HD 75309 and HD 75821. We have tabulated Na I and Ca II absorption line information for the sight lines in our sample to serve as a benchmark for further investigations of the dynamics and evolution of the Vela SNR.Comment: 8 pages of text, 4 tables, 16 pages of figures Accepted and to be published in ApJ

Galactic Structure Toward the Carina Tangent

This investigation presents a photometric study of the Galactic structure toward the Carina arm tangent. The field is located between 280 deg and 286 deg galactic longitude and -4 deg to 4 deg galactic latitude. All currently available uvbybeta data is used to obtain homogeneous color excesses and distances for more than 260 stars of spectral types O to G. We present revised distances and average extinction for the open clusters and cluster candidates NGC 3293, NGC 3114, Loden 46 and Loden 112. The cluster candidate Loden 112 appears to be a very compact group at a true distance modulus of 11.06 +\- 0.11 (s.e.) (1629 +84,-80 pc), significantly closer than previous estimates. We found other OB stars at that same distance and, based on their proper motions, suggest a new OB association at coordinates 282 deg < l < 285 deg, -2 deg < b < 2 deg. Utilizing BV photometry and spectral classification of the known O-type stars in the very young open cluster Wd 2 we provide a new distance estimate of 14.13 +\-0.16 (s.e.) (6698 +512,-475 pc), in excellent agreement with recent distance determinations to the giant molecular structures in this direction. We also discuss a possible connection between the HII region RCW 45 and the highly-reddened B+ star CPD -55 3036 and provide a revised distance for the luminous blue variable HR Car.Comment: accepted to PAS

Orally active antischistosomal early leads identified from the open access malaria box.

BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 µM) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 µM against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

FUSE Measurements of Far Ultraviolet Extinction. I. Galactic Sight Lines

We present extinction curves that include data down to far ultraviolet wavelengths (FUV; 1050 - 1200 A) for nine Galactic sight lines. The FUV extinction was measured using data from the Far Ultraviolet Spectroscopic Explorer. The sight lines were chosen for their unusual extinction properties in the infrared through the ultraviolet; that they probe a wide range of dust environments is evidenced by the large spread in their measured ratios of total-to-selective extinction, R_V = 2.43 - 3.81. We find that extrapolation of the Fitzpatrick & Massa relationship from the ultraviolet appears to be a good predictor of the FUV extinction behavior. We find that predictions of the FUV extinction based upon the Cardelli, Clayton & Mathis (CCM) dependence on R_V give mixed results. For the seven extinction curves well represented by CCM in the infrared through ultraviolet, the FUV extinction is well predicted in three sight lines, over-predicted in two sight lines, and under-predicted in 2 sight lines. A Maximum Entropy Method analysis using a simple three component grain model shows that seven of the nine sight lines in the study require a larger fraction of grain materials to be in dust when FUV extinction is included in the models. Most of the added grain material is in the form of small (radii < 200 A) grains.Comment: Accepted for publication in the Astrophysical Journal. 31 pages with 7 figure

VarGoats project: a dataset of 1159 whole-genome sequences to dissect Capra hircus global diversity

Background: Since their domestication 10,500&nbsp;years ago, goat populations with distinctive genetic backgrounds have adapted to a broad variety of environments and breeding conditions. The VarGoats project is an international 1000-genome resequencing program designed to understand the consequences of domestication and breeding on the genetic diversity of domestic goats and to elucidate how speciation and hybridization have modeled the genomes of a set of species representative of the genus Capra. Findings: A dataset comprising 652 sequenced goats and 507 public goat sequences, including 35 animals representing eight wild species, has been collected worldwide. We identified 74,274,427 single nucleotide polymorphisms (SNPs) and 13,607,850 insertion-deletions (InDels) by aligning these sequences to the latest version of the goat reference genome (ARS1). A Neighbor-joining tree based on Reynolds genetic distances showed that goats from Africa, Asia and Europe tend to group into independent clusters. Because goat breeds from Oceania and Caribbean (Creole) all derive from imported animals, they are distributed along the tree according to their ancestral geographic origin. Conclusions: We report on an unprecedented international effort to characterize the genome-wide diversity of domestic goats. This large range of sequenced individuals represents a unique opportunity to ascertain how the demographic and selection processes associated with post-domestication history have shaped the diversity of this species. Data generated for the project will also be extremely useful to identify deleterious mutations and polymorphisms with causal effects on complex traits, and thus will contribute to new knowledge that could be used in genomic prediction and genome-wide association studies

Atomic super-resolution tomography

We consider the problem of reconstructing a nanocrystal at atomic resolution from electron microscopy images taken at a few tilt angles. A popular reconstruction approach called discrete tomography confines the atom locations to a coarse spatial grid, which is inspired by the physical a priori knowledge that atoms in a crystalline solid tend to form regular lattices. Although this constraint has proven to be powerful for solving this very under-determined inverse problem in many cases, its key limitation is that, in practice, defects may occur that cause atoms to deviate from regular lattice positions. Here we propose a grid-free discrete tomography algorithm that allows for continuous deviations of the atom locations similar to super-resolution approaches for microscopy. The new formulation allows us to define atomic interaction potentials explicitly, which results in a both meaningful and powerful incorporation of the available physical a priori knowledge about the crystal's properties. In computational experiments, we compare the proposed grid-free method to established grid-based approaches and show that our approach can indeed recover the atom positions more accurately for common lattice defects

LEAP2 Impairs the Capability of the Growth Hormone Secretagogue Receptor to Regulate the Dopamine 2 Receptor Signaling

The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (CaV2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood. Here, we investigated the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on CaV2.2 function. Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2 currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSR antagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSR from modulating the effects of D2R signaling on CaV2.2 currents, and that the GHSRbinding N-terminal region LEAP2 underlies these effects. Using purified labeled receptors assembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET) assessments, we found that the N-terminal region of LEAP2 stabilizes an inactive conformation of GHSR that is dissociated from Gq protein and, consequently, reverses the effect of GHSR on D2R-dependent Gi activation. Thus, our results provide critical molecular insights into the mechanism mediating LEAP2 modulation of GHSR.Instituto Multidisciplinario de Biología Celula

Kaposi's Sarcoma-Associated Herpesvirus K7 Induces Viral G Protein-Coupled Receptor Degradation and Reduces Its Tumorigenicity

The Kaposi's sarcoma-associated herpesvirus (KSHV) genome encodes a G protein-coupled receptor (vGPCR). vGPCR is a ligand-independent, constitutively active signaling molecule that promotes cell growth and proliferation; however, it is not clear how vGPCR is negatively regulated. We report here that the KSHV K7 small membrane protein interacts with vGPCR and induces its degradation, thereby dampening vGPCR signaling. K7 interaction with vGPCR is readily detected in transiently transfected human cells. Mutational analyses reveal that the K7 transmembrane domain is necessary and sufficient for this interaction. Biochemical and confocal microscopy studies indicate that K7 retains vGPCR in the endoplasmic reticulum (ER) and induces vGPCR proteasomeal degradation. Indeed, the knockdown of K7 by shRNA-mediated silencing increases vGPCR protein expression in BCBL-1 cells that are induced for KSHV lytic replication. Interestingly, K7 expression significantly reduces vGPCR tumorigenicity in nude mice. These findings define a viral factor that negatively regulates vGPCR protein expression and reveal a post-translational event that modulates GPCR-dependent transformation and tumorigenicity