Spitzer Survey of the Large Magellanic Cloud, Surveying the Agents of a Galaxy's Evolution (SAGE) I: Overview and Initial Results

We are performing a uniform and unbiased, ~7x7 degrees imaging survey of the Large Magellanic Cloud (LMC), using the IRAC and MIPS instruments on board the Spitzer Space Telescope in order to survey the agents of a galaxy's evolution (SAGE), the interstellar medium (ISM) and stars in the LMC. The detection of diffuse ISM with column densities >1.2x10^21 H cm^-2 permits detailed studies of dust processes in the ISM. SAGE's point source sensitivity enables a complete census of newly formed stars with masses >3 solar masses that will determine the current star formation rate in the LMC. SAGE's detection of evolved stars with mass loss rates >1x10^-8 solar masses per year will quantify the rate at which evolved stars inject mass into the ISM of the LMC. The observing strategy includes two epochs in 2005, separated by three months, that both mitigate instrumental artifacts and constrain source variability. The SAGE data are non-proprietary. The data processing includes IRAC and MIPS pipelines and a database for mining the point source catalogs, which will be released to the community in support of Spitzer proposal cycles 4 and 5. We present initial results on the epoch 1 data with a special focus on the N79 and N83 region. The SAGE epoch 1 point source catalog has ~4 million sources. The point source counts are highest for the IRAC 3.6 microns band and decrease dramatically towards longer wavelengths consistent with the fact that stars dominate the point source catalogs and that the dusty objects, e.g. young stellar objects and dusty evolved stars that detected at the longer wavelengths, are rare in comparison. We outline a strategy for identifying foreground MW stars, that may comprise as much as 18% of the source list, and background galaxies, that may comprise ~12% of the source list.Comment: Accepted by the Astronomical Journa

Spitzer survey of the Large Magellanic Cloud, surveying the agents of a galaxy's evolution (SAGE). IV. Dust properties in the interstellar medium

The goal of this paper is to present the results of a preliminary analysis of the extended infrared (IR) emission by dust in the interstellar medium (ISM) of the Large Magellanic Cloud (LMC). We combine Spitzer Surveying the Agents of Galaxy Evolution (SAGE) and Infrared Astronomical Satellite (IRAS) data and correlate the infrared emission with gas tracers of H I, CO, and Hα. We present a global analysis of the infrared emission as well as detailed modeling of the spectral energy distribution (SED) of a few selected regions. Extended emission by dust associated with the neutral, molecular, and diffuse ionized phases of the ISM is detected at all IR bands from 3.6 μm to 160 μm. The relative abundance of the various dust species appears quite similar to that in the Milky Way (MW) in all the regions we have modeled. We construct maps of the temperature of large dust grains. The temperature map shows variations in the range 12.1-34.7 K, with a systematic gradient from the inner to outer regions, tracing the general distribution of massive stars and individual H II regions as well as showing warmer dust in the stellar bar. This map is used to derive the far-infrared (FIR) optical depth of large dust grains. We find two main departures in the LMC with respect to expectations based on the MW: (1) excess mid-infrared (MIR) emission near 70 μm, referred to as the 70 μm excess, and (2) departures from linear correlation between the FIR optical depth and the gas column density, which we refer to as FIR excess emission. The 70 μm excess increases gradually from the MW to the LMC to the Small Magellanic Cloud (SMC), suggesting evolution with decreasing metallicity. The excess is associated with the neutral and diffuse ionized gas, with the strongest excess region located in a loop structure next to 30 Dor. We show that the 70 μm excess can be explained by a modification of the size distribution of very small grains with respect to that in the MW, and a corresponding mass increase of ≃13% of the total dust mass in selected regions. The most likely explanation is that the 70 μm excess is due to the production of large very small grains (VSG) through erosion of larger grains in the diffuse medium. This FIR excess could be due to intrinsic variations of the dust/gas ratio, which would then vary from 4.6 to 2.3 times lower than the MW values across the LMC, but X_(CO) values derived from the IR emission would then be about three times lower than those derived from the Virial analysis of the CO data. We also investigate the possibility that the FIR excess is associated with an additional gas component undetected in the available gas tracers. Assuming a constant dust abundance in all ISM phases, the additional gas component would have twice the known H I mass. We show that it is plausible that the FIR excess is due to cold atomic gas that is optically thick in the 21 cm line, while the contribution by a pure H_2 phase with no CO emission remains a possible explanation

Probiotic modulation of symbiotic gut microbial–host metabolic interactions in a humanized microbiome mouse model

The transgenomic metabolic effects of exposure to either Lactobacillus paracasei or Lactobacillus rhamnosus probiotics have been measured and mapped in humanized extended genome mice (germ-free mice colonized with human baby flora). Statistical analysis of the compartmental fluctuations in diverse metabolic compartments, including biofluids, tissue and cecal short-chain fatty acids (SCFAs) in relation to microbial population modulation generated a novel top-down systems biology view of the host response to probiotic intervention. Probiotic exposure exerted microbiome modification and resulted in altered hepatic lipid metabolism coupled with lowered plasma lipoprotein levels and apparent stimulated glycolysis. Probiotic treatments also altered a diverse range of pathways outcomes, including amino-acid metabolism, methylamines and SCFAs. The novel application of hierarchical-principal component analysis allowed visualization of multicompartmental transgenomic metabolic interactions that could also be resolved at the compartment and pathway level. These integrated system investigations demonstrate the potential of metabolic profiling as a top-down systems biology driver for investigating the mechanistic basis of probiotic action and the therapeutic surveillance of the gut microbial activity related to dietary supplementation of probiotics

Protocadherin-18 Is a Novel Differentiation Marker and an Inhibitory Signaling Receptor for CD8+ Effector Memory T Cells

CD8+ tumor infiltrating T cells (TIL) lack effector-phase functions due to defective proximal TCR-mediated signaling previously shown to result from inactivation of p56lck kinase. We identify a novel interacting partner for p56lck in nonlytic TIL, Protocadherin-18 (‘pcdh18’), and show that pcdh18 is transcribed upon in vitro or in vivo activation of all CD8+ central memory T cells (CD44+CD62LhiCD127+) coincident with conversion into effector memory cells (CD44+CD62LloCD127+). Expression of pcdh18 in primary CD8+ effector cells induces the phenotype of nonlytic TIL: defective proximal TCR signaling, cytokine secretion, and cytolysis, and enhanced AICD. pcdh18 contains a motif (centered at Y842) shared with src kinases (QGQYQP) that is required for the inhibitory phenotype. Thus, pcdh18 is a novel activation marker of CD8+ memory T cells that can function as an inhibitory signaling receptor and restrict the effector phase

De novo CD5+ diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort: CD5 positivity affects DLBCL outcome

De novo CD5+ diffuse large B-cell lymphomas (DLBCL) are a distinct subgroup of DLBCL with poor prognosis. However the role of rituximab-containing therapy and salvage stem cell transplantation in this patients’ population remain to be defined. We retrospectively reviewed clinical features and outcomes of 102 patients with de novo CD5+ DLBCL treated with rituximab-containing therapy at 9 different institutions. By Hans’ criteria, 64 patients had activated B-cell (ABC) subtype, 24 germinal center B-cell (GCB) subtype, and 14 were not evaluated. No patients had a myc translocation. Eighty-three patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), 7 with rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, prednisone (R-EPOCH) and 6 with R-CHOP with methotrexate, 3 g/m2. The overall response rate to frontline therapy was 85%. The 3-year progression free survival (PFS) and overall survival (OS) for all patients were 40% and 65%, respectively. The 3-year PFS for ABC- and GCB-subtypes was 34% and 45%, respectively. The 3-year OS for ABC- and GCB-subtypes was 62% and 67%, respectively. The median time to second treatment failure was 3 months and 1 month for ABC- and GCB-subtypes, respectively. Twenty of 28 (71%) transplanted patients with autologous, allogeneic, or both, relapsed. This study confirms the poor prognosis of de novo CD5+ DLBCL in a large multi-center cohort despite initial rituximab-containing chemotherapy and suggests that stem cell transplantation fails to salvage the majority of these patients. Approaches to prevent recurrence and/or novel therapies for relapsed disease are needed for this subgroup of DLBCL patients

Deletion of the Mitochondrial Superoxide Dismutase sod-2 Extends Lifespan in Caenorhabditis elegans

The oxidative stress theory of aging postulates that aging results from the accumulation of molecular damage caused by reactive oxygen species (ROS) generated during normal metabolism. Superoxide dismutases (SODs) counteract this process by detoxifying superoxide. It has previously been shown that elimination of either cytoplasmic or mitochondrial SOD in yeast, flies, and mice results in decreased lifespan. In this experiment, we examine the effect of eliminating each of the five individual sod genes present in Caenorhabditis elegans. In contrast to what is observed in other model organisms, none of the sod deletion mutants shows decreased lifespan compared to wild-type worms, despite a clear increase in sensitivity to paraquat- and juglone-induced oxidative stress. In fact, even mutants lacking combinations of two or three sod genes survive at least as long as wild-type worms. Examination of gene expression in these mutants reveals mild compensatory up-regulation of other sod genes. Interestingly, we find that sod-2 mutants are long-lived despite a significant increase in oxidatively damaged proteins. Testing the effect of sod-2 deletion on known pathways of lifespan extension reveals a clear interaction with genes that affect mitochondrial function: sod-2 deletion markedly increases lifespan in clk-1 worms while clearly decreasing the lifespan of isp-1 worms. Combined with the mitochondrial localization of SOD-2 and the fact that sod-2 mutant worms exhibit phenotypes that are characteristic of long-lived mitochondrial mutants—including slow development, low brood size, and slow defecation—this suggests that deletion of sod-2 extends lifespan through a similar mechanism. This conclusion is supported by our demonstration of decreased oxygen consumption in sod-2 mutant worms. Overall, we show that increased oxidative stress caused by deletion of sod genes does not result in decreased lifespan in C. elegans and that deletion of sod-2 extends worm lifespan by altering mitochondrial function

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three genomic nomenclature systems to all sequence data from the World Health Organization European Region available until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation, compare the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe