Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic Cancer

SummaryCancer-associated inflammation is thought to be a barrier to immune surveillance, particularly in pancreatic ductal adenocarcinoma (PDA). Gr-1+ CD11b+ cells are a key feature of cancer inflammation in PDA, but remain poorly understood. Using a genetically engineered mouse model of PDA, we show that tumor-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) is necessary and sufficient to drive the development of Gr-1+ CD11b+ cells that suppressed antigen-specific T cells. In vivo, abrogation of tumor-derived GM-CSF inhibited the recruitment of Gr-1+ CD11b+ cells to the tumor microenvironment and blocked tumor development—a finding that was dependent on CD8+ T cells. In humans, PDA tumor cells prominently expressed GM-CSF in vivo. Thus, tumor-derived GM-CSF is an important regulator of inflammation and immune suppression within the tumor microenvironment

Cosmic-Ray Positrons: Are There Primary Sources?

Cosmic rays at the Earth include a secondary component originating in collisions of primary particles with the diffuse interstellar gas. The secondary cosmic rays are relatively rare but carry important information on the Galactic propagation of the primary particles. The secondary component includes a small fraction of antimatter particles, positrons and antiprotons. In addition, positrons and antiprotons may also come from unusual sources and possibly provide insight into new physics. For instance, the annihilation of heavy supersymmetric dark matter particles within the Galactic halo could lead to positrons or antiprotons with distinctive energy signatures. With the High-Energy Antimatter Telescope (HEAT) balloon-borne instrument, we have measured the abundances of positrons and electrons at energies between 1 and 50 GeV. The data suggest that indeed a small additional antimatter component may be present that cannot be explained by a purely secondary production mechanism. Here we describe the signature of the effect and discuss its possible origin.Comment: 15 pages, Latex, epsfig and aasms4 macros required, to appear in Astroparticle Physics (1999

Cell-intrinsic lysosomal lipolysis is essential for macrophage alternative activation

Alternative (M2) macrophage activation driven through interleukin 4 receptor α (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of fatty acids to support this metabolic program has not been clear. We show that the uptake of triacylglycerol substrates via CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation (OXPHOS), enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth, and blocked protective responses against this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation

Orbital Refinement and Stellar Properties for the HD 9446, HD 43691, and HD 179079 Planetary Systems

The Transit Ephemeris Refinement and Monitoring Survey is a project that aims to detect transits of intermediate-long period planets by refining orbital parameters of the known radial velocity planets using additional data from ground-based telescopes, calculating a revised transit ephemeris for the planet, then monitoring the planet host star during the predicted transit window. Here we present the results from three systems that had high probabilities of transiting planets: HD 9446 b and c, HD 43691 b, and HD 179079 b. We provide new radial velocity (RV) measurements that are then used to improve the orbital solution for the known planets. We search the RV data for indications of additional planets in orbit and find that HD 9446 shows a strong linear trend of 4.8σ. Using the newly refined planet orbital solutions, which include a new best-fit solution for the orbital period of HD 9446 c, and an improved transit ephemerides, we found no evidence of transiting planets in the photometry for each system. Transits of HD 9446 b can be ruled out completely and transits HD 9446 c and HD 43691 b can be ruled out for impact parameters up to b = 0.5778 and b = 0.898, respectively, due to gaps in the photometry. A transit of HD 179079 b cannot be ruled out, however, due to the relatively small size of this planet compared to the large star and thus low signal to noise. We determine properties of the three host stars through spectroscopic analysis and find through photometric analysis that HD 9446 exhibits periodic variability

Photometric transit search for planets around cool stars from the western Italian Alps: A pilot study

[ABRIDGED] In this study, we set out to a) demonstrate the sensitivity to <4 R_E transiting planets with periods of a few days around our program stars, and b) improve our knowledge of some astrophysical properties(e.g., activity, rotation) of our targets by combining spectroscopic information and our differential photometric measurements. We achieve a typical nightly RMS photometric precision of ~5 mmag, with little or no dependence on the instrumentation used or on the details of the adopted methods for differential photometry. The presence of correlated (red) noise in our data degrades the precision by a factor ~1.3 with respect to a pure white noise regime. Based on a detailed stellar variability analysis, a) we detected no transit-like events; b) we determined photometric rotation periods of ~0.47 days and ~0.22 days for LHS 3445 and GJ 1167A, respectively; c) these values agree with the large projected rotational velocities (~25 km/s and ~33 km/s, respectively) inferred for both stars based on the analysis of archival spectra; d) the estimated inclinations of the stellar rotation axes for LHS 3445 and GJ 1167A are consistent with those derived using a simple spot model; e) short-term, low-amplitude flaring events were recorded for LHS 3445 and LHS 2686. Finally, based on simulations of transit signals of given period and amplitude injected in the actual (nightly reduced) photometric data for our sample, we derive a relationship between transit detection probability and phase coverage. We find that, using the BLS search algorithm, even when phase coverage approaches 100%, there is a limit to the detection probability of ~90%. Around program stars with phase coverage >50% we would have had >80% chances of detecting planets with P0.5%, corresponding to minimum detectable radii in the range 1.0-2.2 R_E. [ABRIDGED]Comment: 23 pages, 17 figures, 7 tables. Accepted for publication in MNRA

Compensatory T Cell Responses in IRG-Deficient Mice Prevent Sustained Chlamydia trachomatis Infections

The obligate intracellular pathogen Chlamydia trachomatis is the most common cause of bacterial sexually transmitted diseases in the United States. In women C. trachomatis can establish persistent genital infections that lead to pelvic inflammatory disease and sterility. In contrast to natural infections in humans, experimentally induced infections with C. trachomatis in mice are rapidly cleared. The cytokine interferon-γ (IFNγ) plays a critical role in the clearance of C. trachomatis infections in mice. Because IFNγ induces an antimicrobial defense system in mice but not in humans that is composed of a large family of Immunity Related GTPases (IRGs), we questioned whether mice deficient in IRG immunity would develop persistent infections with C. trachomatis as observed in human patients. We found that IRG-deficient Irgm1/m3(-/-) mice transiently develop high bacterial burden post intrauterine infection, but subsequently clear the infection more efficiently than wildtype mice. We show that the delayed but highly effective clearance of intrauterine C. trachomatis infections in Irgm1/m3(-/-) mice is dependent on an exacerbated CD4+ T cell response. These findings indicate that the absence of the predominant murine innate effector mechanism restricting C. trachomatis growth inside epithelial cells results in a compensatory adaptive immune response, which is at least in part driven by CD4+ T cells and prevents the establishment of a persistent infection in mice

Reverberation mapping of optical emission lines in five active galaxies

For a video summarizing the main results, see https://www.youtube.com/watch?v=KaC-jPsIY0QWe present the first results from an optical reverberation mapping campaign executed in 2014 targeting the active galactic nuclei (AGNs) MCG+08-11-011, NGC 2617, NGC 4051, 3C 382, and Mrk 374. Our targets have diverse and interesting observational properties, including a "changing look" AGN and a broad-line radio galaxy. Based on continuum-Hβ lags, we measure black hole masses for all five targets. We also obtain Hγ and He ii λ4686 lags for all objects except 3C 382. The He ii λ4686 lags indicate radial stratification of the BLR, and the masses derived from different emission lines are in general agreement. The relative responsivities of these lines are also in qualitative agreement with photoionization models. These spectra have extremely high signal-to-noise ratios (100–300 per pixel) and there are excellent prospects for obtaining velocity-resolved reverberation signatures.Publisher PDFPeer reviewe

Historical Research Approaches to the Analysis of Internationalisation

Historical research methods and approaches can improve understanding of the most appropriate techniques to confront data and test theories in internationalisation research. A critical analysis of all “texts” (sources), time series analyses, comparative methods across time periods and space, counterfactual analysis and the examination of outliers are shown to have the potential to improve research practices. Examples and applications are shown in these key areas of research with special reference to internationalisation processes. Examination of these methods allows us to see internationalisation processes as a sequenced set of decisions in time and space, path dependent to some extent but subject to managerial discretion. Internationalisation process research can benefit from the use of historical research methods in analysis of sources, production of time-lines, using comparative evidence across time and space and in the examination of feasible alternative choices