Brain Neuronal CB2 Cannabinoid Receptors in Drug Abuse and Depression: From Mice to Human Subjects

BACKGROUND: Addiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs) in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R) but not (H316Y) polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naïve mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity

Evolutionary Heritage Influences Amazon Tree Ecology

Lineages tend to retain ecological characteristics of their ancestors through time. However, for some traits, selection during evolutionary history may have also played a role in determining trait values. To address the relative importance of these processes requires large-scale quantification of traits and evolutionary relationships among species. The Amazonian tree flora comprises a high diversity of angiosperm lineages and species with widely differing life-history characteristics, providing an excellent system to investigate the combined influences of evolutionary heritage and selection in determining trait variation. We used trait data related to the major axes of life-history variation among tropical trees (e.g. growth and mortality rates) from 577 inventory plots in closed-canopy forest, mapped onto a phylogenetic hypothesis spanning more than 300 genera including all major angiosperm clades to test for evolutionary constraints on traits. We found significant phylogenetic signal (PS) for all traits, consistent with evolutionarily related genera having more similar characteristics than expected by chance. Although there is also evidence for repeated evolution of pioneer and shade tolerant life-history strategies within independent lineages, the existence of significant PS allows clearer predictions of the links between evolutionary diversity, ecosystem function and the response of tropical forests to global change

Gaia Data Release 2: The astrometric solution

Gaia Data Release 2 (Gaia DR2) contains results for 1693 million sources in the magnitude range 3 to 21 based on observations collected by the European Space Agency Gaia satellite during the first 22 months of its operational phase. We describe the input data, models, and processing used for the astrometric content of Gaia DR2, and the validation of these results performed within the astrometry task. Some 320 billion centroid positions from the pre-processed astrometric CCD observations were used to estimate the five astrometric parameters (positions, parallaxes, and proper motions) for 1332 million sources, and approximate positions at the reference epoch J2015.5 for an additional 361 million mostly faint sources. Special validation solutions were used to characterise the random and systematic errors in parallax and proper motion. For the sources with five-parameter astrometric solutions, the median uncertainty in parallax and position at the reference epoch J2015.5 is about 0.04 mas for bright (G<14 mag) sources, 0.1 mas at G=17 mag, and 0.7 mas at G=20 mag. In the proper motion components the corresponding uncertainties are 0.05, 0.2, and 1.2 mas/yr, respectively. The optical reference frame defined by Gaia DR2 is aligned with ICRS and is non-rotating with respect to the quasars to within 0.15 mas/yr. From the quasars and validation solutions we estimate that systematics in the parallaxes depending on position, magnitude, and colour are generally below 0.1 mas, but the parallaxes are on the whole too small by about 0.03 mas. Significant spatial correlations of up to 0.04 mas in parallax and 0.07 mas/yr in proper motion are seen on small (<1 deg) and intermediate (20 deg) angular scales. Important statistics and information for the users of the Gaia DR2 astrometry are given in the appendices.Includes STFC

Gaia Focused Product Release: A catalogue of sources around quasars to search for strongly lensed quasars

Context. Strongly lensed quasars are fundamental sources for cosmology. The Gaia space mission covers the entire sky with the unprecedented resolution of $0.18$" in the optical, making it an ideal instrument to search for gravitational lenses down to the limiting magnitude of 21. Nevertheless, the previous Gaia Data Releases are known to be incomplete for small angular separations such as those expected for most lenses. Aims. We present the Data Processing and Analysis Consortium GravLens pipeline, which was built to analyse all Gaia detections around quasars and to cluster them into sources, thus producing a catalogue of secondary sources around each quasar. We analysed the resulting catalogue to produce scores that indicate source configurations that are compatible with strongly lensed quasars. Methods. GravLens uses the DBSCAN unsupervised clustering algorithm to detect sources around quasars. The resulting catalogue of multiplets is then analysed with several methods to identify potential gravitational lenses. We developed and applied an outlier scoring method, a comparison between the average BP and RP spectra of the components, and we also used an extremely randomised tree algorithm. These methods produce scores to identify the most probable configurations and to establish a list of lens candidates. Results. We analysed the environment of 3 760 032 quasars. A total of 4 760 920 sources, including the quasars, were found within 6" of the quasar positions. This list is given in the Gaia archive. In 87\% of cases, the quasar remains a single source, and in 501 385 cases neighbouring sources were detected. We propose a list of 381 lensed candidates, of which we identified 49 as the most promising. Beyond these candidates, the associate tables in this Focused Product Release allow the entire community to explore the unique Gaia data for strong lensing studies further.Comment: 35 pages, 60 figures, accepted for publication by Astronomy and Astrophysic

ANTARES search for point-sources of neutrinos using astrophysical catalogs: a likelihood stacking analysis

A search for astrophysical point-like neutrino sources using the data collected by the ANTARES detector between January 29, 2007 and December 31, 2017 is presented. A likelihood stacking method is used to assess the significance of an excess of muon neutrinos inducing track-like events in correlation with the location of a list of possible sources. Different sets of objects are tested in the analysis: a) a sub-sample of the \textit{Fermi} 3LAC catalog of blazars, b) a jet-obscured AGN population, c) a sample of soft gamma-ray selected radio galaxies, d) a star-forming galaxy catalog , and e) a public sample of 56 very-high-energy track events from the IceCube experiment. None of the tested sources shows a significant association with the sample of neutrinos detected by ANTARES. The smallest p-value is obtained for the radio galaxies catalog with an equal weights hypothesis, with a pre-trial p-value equivalent to a $2.8 \, \sigma$ excess, equivalent to $1.6 \, \sigma$ post-trial. In addition, the results of a dedicated analysis for the blazar MG3 J225517+2409 are also reported: this source is found to be the most significant within the \textit{Fermi} 3LAC sample, with 5 ANTARES events located at less than one degree from the source. This blazar showed evidence of flaring activity in \textit{Fermi} data, in space-time coincidence with a high-energy track detected by IceCube. An \emph{a posteriori} significance of $2.0\, \sigma$ for the combination of ANTARES and IceCube data is reported

Measurement of the atmospheric νe and νμ energy spectra with the ANTARES neutrino telescope

The authors acknowledge the financial support of the funding agencies: Centre National de la Recherche Scientifique (CNRS), Commissariat a l'Energie Atomique et aux Energies Alternatives(CEA), Commission Europeenne (FEDER fund and Marie Curie Program), Institut Universitaire de France (IUF), Labex UnivEarthS(ANR-10-LABX-0023 and ANR-18-IDEX-0001), Region Ile-de-France (DIM-ACAV), Region Alsace (contrat CPER), Region Provence-AlpesCote d'Azur, Departement du Var and Ville de La Seyne-sur-Mer, France; Bundesministerium fur Bildung und Forschung (BMBF), Germany; Instituto Nazionale di Fisica Nucleare(INFN), Italy; Nederlandse Organisatie voor Wetenschappelijk Onderzoek(NWO), the Netherlands; Council of the President of the Russian Federation for young scientists and leading scientific schools supporting grants, Russia; Executive Unit for Financing Higher Education, Research, Development and Innovation (UEFISCDI), Romania; Ministerio de Ciencia e Innovacion (MCI) and Agencia Estatal de Investigacion: Programa Estatal de Generacion de Conocimiento (refs. PGC2018096663-B-C41, -A-C42, -B-C43, -B-C44) (MCI/FEDER), Severo Ochoa Centre of Excellence and MultiDark Consolider, Junta de Andalucia (ref. SOMM17/6104/UGR and A-FQM-053-UGR18), Generalitat Valenciana: Grisolia (ref. GRISOLIA/2018/119) and GenT (ref. CIDEGENT/2018/034) programs, Spain; Ministry of Higher Education, Scientific Research and Professional Training, Morocco. We also acknowledge the technical support of Ifremer, AIM and Foselev Marine for the sea operation and the CC-IN2P3 for the computing facilities. The authors acknowledge the financial support of the funding agencies: Centre National de la Recherche Scientifique (CNRS), Commissariat a l'Energie Atomique et aux Energies Alternatives(CEA), Commission Europeenne (FEDER fund and Marie Curie Program), Institut Universitaire de France (IUF), Labex UnivEarthS(ANR-10-LABX-0023 and ANR-18-IDEX-0001), Region Ile-de-France (DIM-ACAV), Region Alsace (contrat CPER), Region Provence-AlpesCote d'Azur, Departement du Var and Ville de La Seyne-sur-Mer, France; Bundesministerium fur Bildung und Forschung (BMBF), Germany; Instituto Nazionale di Fisica Nucleare(INFN), Italy; Nederlandse Organisatie voor Wetenschappelijk Onderzoek(NWO), the Netherlands; Council of the President of the Russian Federation for young scientists and leading scientific schools supporting grants, Russia; Executive Unit for Financing Higher Education, Research, Development and Innovation (UEFISCDI), Romania; Ministerio de Ciencia e Innovacion (MCI) and Agencia Estatal de Investigacion: Programa Estatal de Generacion de Conocimiento (refs. PGC2018096663-B-C41, -A-C42, -B-C43, -B-C44) (MCI/FEDER), Severo Ochoa Centre of Excellence and MultiDark Consolider, Junta de Andalucia (ref. SOMM17/6104/UGR and A-FQM-053-UGR18), Generalitat Valenciana: Grisolia (ref. GRISOLIA/2018/119) and GenT (ref. CIDEGENT/2018/034) programs, Spain; Ministry of Higher Education, Scientific Research and Professional Training, Morocco. We also acknowledge the technical support of Ifremer, AIM and Foselev Marine for the sea operation and the CC-IN2P3 for the computing facilities.This letter presents a combined measurement of the energy spectra of atmospheric nu(e) and nu(mu) in the energy range between similar to 100 GeV and similar to 50 TeV with the ANTARES neutrino telescope. The analysis uses 3012 days of detector livetime in the period 2007-2017, and selects 1016 neutrinos interacting in (or close to) the instrumented volume of the detector, yielding shower-like events (mainly from nu(e) + (nu) over bar (e) charged current plus all neutrino neutral current interactions) and starting track events (mainly from nu(mu) + (nu) over bar (mu) charged current interactions). The contamination by atmospheric muons in the final sample is suppressed at the level of a few per mill by different steps in the selection analysis, including a Boosted Decision Tree classifier. The distribution of reconstructed events is unfolded in terms of electron and muon neutrino fluxes. The derived energy spectra are compared with previous measurements that, above 100 GeV, are limited to experiments in polar ice and, for nu(mu), to Super-Kamiokande.Centre National de la Recherche Scientifique (CNRS)French Atomic Energy CommissionCommission Europeenne (FEDER fund)Institut Universitaire de France (IUF)Labex UnivEarthS ANR-10-LABX-0023 ANR-18-IDEX-0001Region Ile-de-FranceRegion Grand-EstRegion Provence-Alpes-Cote d'AzurRegion Provence-Alpes-Cote d'AzurFederal Ministry of Education & Research (BMBF)Instituto Nazionale di Fisica Nucleare(INFN), ItalyNetherlands Organization for Scientific Research (NWO)Netherlands GovernmentCouncil of the President of the Russian Federation for young scientists and leading scientific schools supporting grants, RussiaConsiliul National al Cercetarii Stiintifice (CNCS)Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (UEFISCDI)Spanish Government PGC2018096663-B-C41 PGC2018096663-A-C42 PGC2018096663-B-C43 PGC2018096663-B-C44Severo Ochoa Centre of Excellence and MultiDark ConsoliderJunta de Andalucia SOMM17/6104/UGR A-FQM-053-UGR18Generalitat Valenciana: Grisolia program, Spain GRISOLIA/2018/119Generalitat Valenciana: GenT program, Spain CIDEGENT/2018/034Ministry of Higher Education, Scientific Research and Professional Training, MoroccoAgencia Estatal de Investigacion PGC2018096663-B-C41 PGC2018096663-A-C42 PGC2018096663-B-C43 PGC2018096663-B-C44Commission Europeenne (Marie Curie Program

Molecular characterization of occult hepatitis B virus infection in patients with end-stage liver disease in Colombia.

ABSTARCT: Hepatitis B virus (HBV) occult infection (OBI) is a risk factor to be taken into account in transfusion, hemodialysis and organ transplantation. The aim of this study was to identify and characterize at the molecular level OBI cases in patients with end-stage liver disease. METHODS: Sixty-six liver samples were obtained from patients with diagnosis of end-stage liver disease submitted to liver transplantation in Medellin (North West, Colombia). Samples obtained from patients who were negative for the surface antigen of HBV (n = 50) were tested for viral DNA detection by nested PCR for ORFs S, C, and X and confirmed by Southern-Blot. OBI cases were analyzed by sequencing the viral genome to determine the genotype and mutations; additionally, viral genome integration events were examined by the Alu-PCR technique. RESULTS: In five cases out of 50 patients (10%) the criteria for OBI was confirmed. HBV genotype F (subgenotypes F1 and F3), genotype A and genotype D were characterized in liver samples. Three integration events in chromosomes 5q14.1, 16p13 and 20q12 affecting Receptor-type tyrosine-protein phosphatase T, Ras Protein Specific Guanine Nucleotide Releasing Factor 2, and the zinc finger 263 genes were identified in two OBI cases. Sequence analysis of the viral genome of the 5 OBI cases showed several punctual missense and nonsense mutations affecting ORFs S, P, Core and X. CONCLUSIONS: This is the first characterization of OBI in patients with end-stage liver disease in Colombia. The OBI cases were identified in patients with HCV infection or cryptogenic cirrhosis. The integration events (5q14.1, 16p13 and 20q12) described in this study have not been previously reported. Further studies are required to validate the role of mutations and integration events in OBI pathogenesis

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals

Pulsations in main sequence OBAF-type stars

CONTEXT: The third Gaia data release provides photometric time series covering 34 months for about 10 million stars. For many of those stars, a characterisation in Fourier space and their variability classification are also provided. This paper focuses on intermediate- to high-mass (IHM) main sequence pulsators (M ≥  1.3 M⊙) of spectral types O, B, A, or F, known as β Cep, slowly pulsating B (SPB), δ Sct, and γ Dor stars. These stars are often multi-periodic and display low amplitudes, making them challenging targets to analyse with sparse time series. AIMS: We investigate the extent to which the sparse Gaia DR3 data can be used to detect OBAF-type pulsators and discriminate them from other types of variables. We aim to probe the empirical instability strips and compare them with theoretical predictions. The most populated variability class is that of the δ Sct variables. For these stars, we aim to confirm their empirical period-luminosity (PL) relation, and verify the relation between their oscillation amplitude and rotation. METHODS: All datasets used in this analysis are part of the Gaia DR3 data release. The photometric time series were used to perform a Fourier analysis, while the global astrophysical parameters necessary for the empirical instability strips were taken from the Gaia DR3 gspphot tables, and the v sin i data were taken from the Gaia DR3 esphs tables. The δ Sct PL relation was derived using the same photometric parallax method as the one recently used to establish the PL relation for classical Cepheids using Gaia data. RESULTS: We show that for nearby OBAF-type pulsators, the Gaia DR3 data are precise and accurate enough to pinpoint them in the Hertzsprung-Russell (HR) diagram. We find empirical instability strips covering broader regions than theoretically predicted. In particular, our study reveals the presence of fast rotating gravity-mode pulsators outside the strips, as well as the co-existence of rotationally modulated variables inside the strips as reported before in the literature. We derive an extensive period–luminosity relation for δ Sct stars and provide evidence that the relation features different regimes depending on the oscillation period. We demonstrate how stellar rotation attenuates the amplitude of the dominant oscillation mode of δ Sct stars. CONCLUSIONS: The Gaia DR3 time-series photometry already allows for the detection of the dominant (non-)radial oscillation mode in about 100 000 intermediate- and high-mass dwarfs across the entire sky. This detection capability will increase as the time series becomes longer, allowing the additional delivery of frequencies and amplitudes of secondary pulsation modes

A Search for Photons with Energies above 2 × 1017eV Using Hybrid Data from the Low-Energy Extensions of the Pierre Auger Observatory

Ultra-high-energy photons with energies exceeding 1017 eV offer a wealth of connections to different aspects of cosmic-ray astrophysics as well as to gamma-ray and neutrino astronomy. The recent observations of photons with energies in the 1015 eV range further motivate searches for even higher-energy photons. In this paper, we present a search for photons with energies exceeding 2 × 1017 eV using about 5.5 yr of hybrid data from the low-energy extensions of the Pierre Auger Observatory. The upper limits on the integral photon flux derived here are the most stringent ones to date in the energy region between 1017 and 1018 eV