Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production.

Microglial priming and enhanced reactivity to secondary insults cause substantial neuronal damage and are hallmarks of brain aging, traumatic brain injury and neurodegenerative diseases. It is, thus, of particular interest to identify mechanisms involved in microglial priming. Here, we demonstrate that priming of microglia with interferon-γ (IFN γ) substantially enhanced production of reactive oxygen species (ROS) following stimulation of microglia with ATP. Priming of microglial ROS production was substantially reduced by inhibition of p38 MAPK activity with SB203580, by increases in intracellular glutathione levels with N-Acetyl-L-cysteine, by blockade of NADPH oxidase subunit NOX2 activity with gp91ds-tat or by inhibition of nitric oxide production with L-NAME. Together, our data indicate that priming of microglial ROS production involves reduction of intracellular glutathione levels, upregulation of NADPH oxidase subunit NOX2 and increases in nitric oxide production, and suggest that these simultaneously occurring processes result in enhanced production of neurotoxic peroxynitrite. Furthermore, IFNγ-induced priming of microglial ROS production was reduced upon blockade of Kir2.1 inward rectifier K+ channels with ML133. Inhibitory effects of ML133 on microglial priming were mediated via regulation of intracellular glutathione levels and nitric oxide production. These data suggest that microglial Kir2.1 channels may represent novel therapeutic targets to inhibit excessive ROS production by primed microglia in brain pathology

A Spitzer survey of Deep Drilling Fields to be targeted by the Vera C. Rubin Observatory Legacy Survey of Space and Time

The Vera C. Rubin Observatory Legacy Survey of Space and Time (LSST) will observe several Deep Drilling Fields (DDFs) to a greater depth and with a more rapid cadence than the main survey. In this paper, we describe the ‘DeepDrill’ survey, which used the Spitzer Space Telescope Infrared Array Camera (IRAC) to observe three of the four currently defined DDFs in two bands, centred on 3.6 and 4.5 μm. These observations expand the area that was covered by an earlier set of observations in these three fields by the Spitzer Extragalactic Representative Volume Survey (SERVS). The combined DeepDrill and SERVS data cover the footprints of the LSST DDFs in the Extended Chandra Deep Field–South (ECDFS) field, the ELAIS-S1 field (ES1), and the XMM-Large-Scale Structure Survey field (XMM-LSS). The observations reach an approximate 5σ point-source depth of 2 μJy (corresponding to an AB magnitude of 23.1; sufficient to detect a 10$^{11} \, \mathrm{M}_{\odot}$ galaxy out to z ≈ 5) in each of the two bands over a total area of $\approx 29\,$ deg2. The dual-band catalogues contain a total of 2.35 million sources. In this paper, we describe the observations and data products from the survey, and an overview of the properties of galaxies in the survey. We compare the source counts to predictions from the Shark semi-analytic model of galaxy formation. We also identify a population of sources with extremely red ([3.6]−[4.5] >1.2) colours which we show mostly consists of highly obscured active galactic nuclei

Co-expression of CD147 (EMMPRIN), CD44v3-10, MDR1 and monocarboxylate transporters is associated with prostate cancer drug resistance and progression

Background: The aim of this study is to seek an association between markers of metastatic potential, drug resistance-related protein and monocarboxylate transporters in prostate cancer (CaP). Methods: We evaluated the expression of invasive markers (CD147, CD44v3-10), drug-resistance protein (MDR1) and monocarboxylate transporters (MCT1 and MCT4) in CaP metastatic cell lines and CaP tissue microarrays (n=140) by immunostaining. The co-expression of CD147 and CD44v3-10 with that of MDR1, MCT1 and MCT4 in CaP cell lines was evaluated using confocal microscopy. The relationship between the expression of CD147 and CD44v3-10 and the sensitivity (IC50) to docetaxel in CaP cell lines was assessed using MTT assay. The relationship between expression of CD44v3-10, MDR1 and MCT4 and various clinicopathological CaP progression parameters was examined. Results: CD147 and CD44v3-10 were co-expressed with MDR1, MCT1 and MCT4 in primary and metastatic CaP cells. Both CD147 and CD44v3-10 expression levels were inversely related to docetaxel sensitivity (IC50) in metastatic CaP cell lines. Overexpression of CD44v3-10, MDR1 and MCT4 was found in most primary CaP tissues, and was significantly associated with CaP progression. Conclusions: Our results suggest that the overexpression of CD147, CD44v3-10, MDR1 and MCT4 is associated with CaP progression. Expression of both CD147 and CD44v3-10 is correlated with drug resistance during CaP metastasis and could be a useful potential therapeutic target in advanced disease

Stimulation of bovine monocyte-derived macrophages with lipopolysaccharide, interferon-ɣ, Interleukin-4 or Interleukin-13 does not induce detectable changes in nitric oxide or arginase activity

Background: Bacterial lipopolysaccharide and interferon-γ stimulation of rodent macrophages in vitro induces up-regulation of inducible nitric oxide synthase, whereas interleukin-4 stimulation results in increased activity of arginase-1. Thus different stimulants result in differing macrophage phenotypes, appropriate for responses to a range of pathogens. The current study was conducted in order to determine whether bovine macrophages derived from monocytes and spleen respond similarly. Results: Lipopolysaccharide and interferon-γ did not induce detectable increases in nitric oxide production by bovine monocyte-derived or splenic macrophages in vitro. Similarly, interleukin-4 and interleukin-13 did not affect arginase activity. However, changes in transcription of genes coding for these products were detected. Conclusion: Differences between macrophage activation patterns exist between cattle and other species and these differences may occur during the post-transcription phase

Localization and broadband follow-up of the gravitational-wave transient GW150914

A gravitational-wave transient was identified in data recorded by the Advanced LIGO detectors on 2015 September 14. The event candidate, initially designated G184098 and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimates of the time, significance, and sky location of the event were shared with 63 teams of observers covering radio, optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter we describe the low-latency analysis of the gravitational wave data and present the sky localization of the first observed compact binary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-ray Coordinates Network Circulars, giving an overview of the participating facilities, the gravitational wave sky localization coverage, the timeline and depth of the observations. As this event turned out to be a binary black hole merger, there is little expectation of a detectable electromagnetic signature. Nevertheless, this first broadband campaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broad capabilities of the transient astronomy community and the observing strategies that have been developed to pursue neutron star binary merger events. Detailed investigations of the electromagnetic data and results of the electromagnetic follow-up campaign will be disseminated in the papers of the individual teams

Predicting episodic memory performance using different biomarkers: results from Argentina-Alzheimer’s Disease Neuroimaging Initiative

María Julieta Russo,1 Gabriela Cohen,1 Patricio Chrem Mendez,1 Jorge Campos,1 Federico E Nahas,1 Ezequiel I Surace,1 Silvia Vazquez,1 Deborah Gustafson,2,3 Salvador Guinjoan,1 Ricardo F Allegri,1 Gustavo Sevlever1 On behalf of the Argentina-Alzheimer’s Disease Neuroim­aging Initiative group 1Center of Aging and Memory of Neurological Research Institute (FLENI), Buenos Aires, Argentina; 2Department of Neurology, State University of New York-Downstate Medical Center, Brooklyn, NY, USA; 3Neuropsychiatric Epidemiology Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SwedenPurpose: Argentina-Alzheimer’s Disease Neuroimaging Initiative (Arg-ADNI) is the first ADNI study to be performed in Latin America at a medical center with the appropriate infrastructure. Our objective was to describe baseline characteristics and to examine whether biomarkers related to Alzheimer’s disease (AD) physiopathology were associated with worse memory performance.Patients and methods: Fifteen controls and 28 mild cognitive impairment and 13 AD dementia subjects were included. For Arg-ADNI, all biomarker parameters and neuropsychological tests of ADNI-II were adopted. Results of positron emission tomography (PET) with fluorodeoxyglucose and 11C-Pittsburgh compound-B (PIB-PET) were available from all participants. Cerebrospinal fluid biomarker results were available from 39 subjects.Results: A total of 56 participants were included and underwent baseline evaluation. The three groups were similar with respect to years of education and sex, and they differed in age (F=5.10, P=0.01). Mean scores for the baseline measurements of the neuropsychological evaluation differed significantly among the three groups at P<0.001, showing a continuum in their neuropsychological performance. No significant correlations were found between the principal measures (long-delay recall, C-Pittsburgh compound-B scan, left hippocampal volume, and APOEε4) and either age, sex, or education (P>0.1). Baseline amyloid deposition and left hippocampal volume separated the three diagnostic groups and correlated with the memory performance (P<0.001).Conclusion: Cross-sectional analysis of baseline data revealed links between cognition, structural changes, and biomarkers. Follow-up of a larger and more representative cohort, particularly analyzing cerebrospinal fluid and brain biomarkers, will allow better characterization of AD in our country.Keywords: aging, Alzheimer’s disease, amyloid imaging, biomarkers, mild cognitive impairmen

Cognitive reserve and Aβ1-42 in mild cognitive impairment (Argentina-Alzheimer’s Disease Neuroimaging Initiative)

Paula Harris,1,2 Marcos Fernandez Suarez,1 Ezequiel I Surace,1,2 Patricio Chrem Méndez,1 María Eugenia Martín,1 María Florencia Clarens,1 Fernanda Tapajóz,1,2 Maria Julieta Russo,1 Jorge Campos,1 Salvador M Guinjoan,1,2 Gustavo Sevlever,1 Ricardo F Allegri1,2 1Instituto de Investigaciones Neurológicas, 2Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina Background: The purpose of this study was to investigate the relationship between cognitive reserve and concentration of Aβ1-42 in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment, those with Alzheimer’s disease, and in control subjects. Methods: Thirty-three participants from the Argentina-Alzheimer’s Disease Neuroimaging Initiative database completed a cognitive battery, the Cognitive Reserve Questionnaire (CRQ), and an Argentinian accentuation reading test (TAP-BA) as a measure of premorbid intelligence, and underwent lumbar puncture for CSF biomarker quantification. Results: The CRQ significantly correlated with TAP-BA, education, and Aβ1-42. When considering Aβ1-42 levels, significant differences were found in CRQ scores; higher levels of CSF Aβ1-42 were associated with higher CRQ scores. Conclusion: Reduced Aβ1-42 in CSF is considered as evidence of amyloid deposition in the brain. Previous results suggest that individuals with higher education, higher occupational attainment, and participation in leisure activities (cognitive reserve) have a reduced risk of developing Alzheimer’s disease. Our results support the notion that enhanced neural activity has a protective role in mild cognitive impairment, as evidenced by higher CSF Aβ1-42 levels in individuals with more cognitive reserve. Keywords: amyloid, biomarkers, cerebrospinal fluid, Alzheimer’s disease&nbsp