The astrometric Gaia-FUN-SSO observation campaign of 99 942 Apophis

Astrometric observations performed by the Gaia Follow-Up Network for Solar System Objects (Gaia-FUN-SSO) play a key role in ensuring that moving objects first detected by ESA's Gaia mission remain recoverable after their discovery. An observation campaign on the potentially hazardous asteroid (99 942) Apophis was conducted during the asteroid's latest period of visibility, from 12/21/2012 to 5/2/2013, to test the coordination and evaluate the overall performance of the Gaia-FUN-SSO . The 2732 high quality astrometric observations acquired during the Gaia-FUN-SSO campaign were reduced with the Platform for Reduction of Astronomical Images Automatically (PRAIA), using the USNO CCD Astrograph Catalogue 4 (UCAC4) as a reference. The astrometric reduction process and the precision of the newly obtained measurements are discussed. We compare the residuals of astrometric observations that we obtained using this reduction process to data sets that were individually reduced by observers and accepted by the Minor Planet Center. We obtained 2103 previously unpublished astrometric positions and provide these to the scientific community. Using these data we show that our reduction of this astrometric campaign with a reliable stellar catalog substantially improves the quality of the astrometric results. We present evidence that the new data will help to reduce the orbit uncertainty of Apophis during its close approach in 2029. We show that uncertainties due to geolocations of observing stations, as well as rounding of astrometric data can introduce an unnecessary degradation in the quality of the resulting astrometric positions. Finally, we discuss the impact of our campaign reduction on the recovery process of newly discovered asteroids.Comment: Accepted for publication in A&

Gaia Universe Model Snapshot : A statistical analysis of the expected contents of the Gaia catalogue

Context. This study has been developed in the framework of the computational simulations executed for the preparation of the ESA Gaia astrometric mission. Aims. We focus on describing the objects and characteristics that Gaia will potentially observe without taking into consideration instrumental effects (detection efficiency, observing errors). Methods. The theoretical Universe Model prepared for the Gaia simulation has been statistically analyzed at a given time. Ingredients of the model are described, giving most attention to the stellar content, the double and multiple stars, and variability. Results. In this simulation the errors have not been included yet. Hence we estimate the number of objects and their theoretical photometric, astrometric and spectroscopic characteristics in the case that they are perfectly detected. We show that Gaia will be able to potentially observe 1.1 billion of stars (single or part of multiple star systems) of which about 2% are variable stars, 3% have one or two exoplanets. At the extragalactic level, observations will be potentially composed by several millions of galaxies, half million to 1 million of quasars and about 50,000 supernovas that will occur during the 5 years of mission. The simulated catalogue will be made publicly available by the DPAC on the Gaia portal of the ESA web site http://www.rssd.esa.int/gaia/.Comment: 21 pages, 21 figures, accepted for publication in Astronomy and Astrophysics, typos corrected in author name

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC

Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells

Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF). Neuropilin-1 is expressed in pancreatic cancer, but not in nonmalignant pancreatic tissue. We hypothesised that NRP-1 expression by pancreatic cancer cells contributes to the malignant phenotype. To determine the role of NRP-1 in pancreatic cancer, NRP-1 was stably transfected into the human pancreatic cancer cell line FG. Signal transduction was assessed by Western blot analysis. Susceptibility to anoikis (detachment induced apoptosis) was evaluated by colony formation after growth in suspension. Chemosensitivity to gemcitabine or 5-fluorouracil (5-FU) was assessed by MTT assay in pancreatic cancer cells following NRP-1 overexpression or siRNA-induced downregulation of NRP-1. Differential expression of apoptosis-related genes was determined by gene array and further evaluated by Western blot analysis. Neuropilin-1 overexpression increased constitutive mitogen activated protein kinase (MAPK) signalling, possibly via an autocrine loop. Neuropilin-1 overexpression in FG cells enhanced anoikis resistance and increased survival of cells by >30% after exposure to clinically relevant levels of gemcitabine and 5-FU. In contrast, downregulation of NRP-1 expression in Panc-1 cells markedly increased chemosensitivity, inducing >50% more cell death at clinically relevant concentrations of gemcitabine. Neuropilin-1 overexpression also increased expression of the antiapoptotic regulator, MCL-1. Neuropilin-1 overexpression in pancreatic cancer cell lines is associated with (a) increased constitutive MAPK signalling, (b) inhibition of anoikis, and (c) chemoresistance. Targeting NRP-1 in pancreatic cancer cells may downregulate survival signalling pathways and increase sensitivity to chemotherapy

Negative Supercoiling Creates Single-Stranded Patches of DNA That Are Substrates for AID–Mediated Mutagenesis

Antibody diversification necessitates targeted mutation of regions within the immunoglobulin locus by activation-induced cytidine deaminase (AID). While AID is known to act on single-stranded DNA (ssDNA), the source, structure, and distribution of these substrates in vivo remain unclear. Using the technique of in situ bisulfite treatment, we characterized these substrates—which we found to be unique to actively transcribed genes—as short ssDNA regions, that are equally distributed on both DNA strands. We found that the frequencies of these ssDNA patches act as accurate predictors of AID activity at reporter genes in hypermutating and class switching B cells as well as in Escherichia coli. Importantly, these ssDNA patches rely on transcription, and we report that transcription-induced negative supercoiling enhances both ssDNA tract formation and AID mutagenesis. In addition, RNaseH1 expression does not impact the formation of these ssDNA tracts indicating that these structures are distinct from R-loops. These data emphasize the notion that these transcription-generated ssDNA tracts are one of many in vivo substrates for AID

Low Concentrations of Methamphetamine Can Protect Dopaminergic Cells against a Larger Oxidative Stress Injury: Mechanistic Study

Mild stress can protect against a larger insult, a phenomenon termed preconditioning or tolerance. To determine if a low intensity stressor could also protect cells against intense oxidative stress in a model of dopamine deficiency associated with Parkinson disease, we used methamphetamine to provide a mild, preconditioning stress, 6-hydroxydopamine (6-OHDA) as a source of potentially toxic oxidative stress, and MN9D cells as a model of dopamine neurons. We observed that prior exposure to subtoxic concentrations of methamphetamine protected these cells against 6-OHDA toxicity, whereas higher concentrations of methamphetamine exacerbated it. The protection by methamphetamine was accompanied by decreased uptake of both [3H] dopamine and 6-OHDA into the cells, which may have accounted for some of the apparent protection. However, a number of other effects of methamphetamine exposure suggest that the drug also affected basic cellular survival mechanisms. First, although methamphetamine preconditioning decreased basal pERK1/2 and pAkt levels, it enhanced the 6-OHDA-induced increase in these phosphokinases. Second, the apparent increase in pERK1/2 activity was accompanied by increased pMEK1/2 levels and decreased activity of protein phosphatase 2. Third, methamphetamine upregulated the pro-survival protein Bcl-2. Our results suggest that exposure to low concentrations of methamphetamine cause a number of changes in dopamine cells, some of which result in a decrease in their vulnerability to subsequent oxidative stress. These observations may provide insights into the development of new therapies for prevention or treatment of PD

Integration of P2Y receptor-activated signal transduction pathways in G protein-dependent signalling networks

The role of nucleotides in intracellular energy provision and nucleic acid synthesis has been known for a long time. In the past decade, evidence has been presented that, in addition to these functions, nucleotides are also autocrine and paracrine messenger molecules that initiate and regulate a large number of biological processes. The actions of extracellular nucleotides are mediated by ionotropic P2X and metabotropic P2Y receptors, while hydrolysis by ecto-enzymes modulates the initial signal. An increasing number of studies have been performed to obtain information on the signal transduction pathways activated by nucleotide receptors. The development of specific and stable purinergic receptor agonists and antagonists with therapeutical potential largely contributed to the identification of receptors responsible for nucleotide-activated pathways. This article reviews the signal transduction pathways activated by P2Y receptors, the involved second messenger systems, GTPases and protein kinases, as well as recent findings concerning P2Y receptor signalling in C6 glioma cells. Besides vertical signal transduction, lateral cross-talks with pathways activated by other G protein-coupled receptors and growth factor receptors are discussed

The astrometric Gaia-FUN-SSO observation campaign of 99942 Apophis

© 2015 ESO. Aims. Astrometric observations performed by the Gaia Follow-Up Network for Solar System Objects (Gaia-FUN-SSO) play a key role in ensuring that moving objects first detected by ESA's Gaia mission remain recoverable after their discovery. An observation campaign on the potentially hazardous asteroid (99 942) Apophis was conducted during the asteroid's latest period of visibility, from 12/21/2012 to 5/2/2013, to test the coordination and evaluate the overall performance of the Gaia-FUN-SSO. Methods. The 2732 high quality astrometric observations acquired during the Gaia-FUN-SSO campaign were reduced with the Platform for Reduction of Astronomical Images Automatically (PRAIA), using the USNO CCD Astrograph Catalogue 4 (UCAC4) as a reference. The astrometric reduction process and the precision of the newly obtained measurements are discussed. We compare the residuals of astrometric observations that we obtained using this reduction process to data sets that were individually reduced by observers and accepted by the Minor Planet Center. Results. We obtained 2103 previously unpublished astrometric positions and provide these to the scientific community. Using these data we show that our reduction of this astrometric campaign with a reliable stellar catalog substantially improves the quality of the astrometric results. We present evidence that the new data will help to reduce the orbit uncertainty of Apophis during its close approach in 2029. We show that uncertainties due to geolocations of observing stations, as well as rounding of astrometric data can introduce an unnecessary degradation in the quality of the resulting astrometric positions. Finally, we discuss the impact of our campaign reduction on the recovery process of newly discovered asteroids