A Multiple Classifier System Identifies Novel Cannabinoid CB2 Receptor Ligands

open access articleDrugs have become an essential part of our lives due to their ability to improve people’s health and quality of life. However, for many diseases, approved drugs are not yet available or existing drugs have undesirable side effects, making the pharmaceutical industry strive to discover new drugs and active compounds. The development of drugs is an expensive process, which typically starts with the detection of candidate molecules (screening) for an identified protein target. To this end, the use of high-performance screening techniques has become a critical issue in order to palliate the high costs. Therefore, the popularity of computer-based screening (often called virtual screening or in-silico screening) has rapidly increased during the last decade. A wide variety of Machine Learning (ML) techniques has been used in conjunction with chemical structure and physicochemical properties for screening purposes including (i) simple classifiers, (ii) ensemble methods, and more recently (iii) Multiple Classifier Systems (MCS). In this work, we apply an MCS for virtual screening (D2-MCS) using circular fingerprints. We applied our technique to a dataset of cannabinoid CB2 ligands obtained from the ChEMBL database. The HTS collection of Enamine (1.834.362 compounds), was virtually screened to identify 48.432 potential active molecules using D2-MCS. This list was subsequently clustered based on circular fingerprints and from each cluster, the most active compound was maintained. From these, the top 60 were kept, and 21 novel compounds were purchased. Experimental validation confirmed six highly active hits (>50% displacement at 10 μM and subsequent Ki determination) and an additional five medium active hits (>25% displacement at 10 μM). D2-MCS hence provided a hit rate of 29% for highly active compounds and an overall hit rate of 52%

The 9<i>H</i>-fluoren vinyl ether derivative SAM461 inhibits bacterial luciferase activity and protects <i>Artemia franciscana</i> from luminescent vibriosis

Vibrio campbellii is a major pathogen in aquaculture. It is a causative agent of the so-called “luminescent vibriosis,” a life-threatening condition caused by bioluminescent Vibrio spp. that often involves mass mortality of farmed shrimps. The emergence of multidrug resistant Vibrio strains raises a concern and poses a challenge for the treatment of this infection in the coming years. Inhibition of bacterial cell-to-cell communication or quorum sensing (QS) has been proposed as an alternative to antibiotic therapies. Aiming to identify novel QS disruptors, the 9H-fluroen-9yl vinyl ether derivative SAM461 was found to thwart V. campbellii bioluminescence, a QS-regulated phenotype. Phenotypic and gene expression analyses revealed, however, that the mode of action of SAM461 was unrelated to QS inhibition. Further evaluation with purified Vibrio fischeri and NanoLuc luciferases revealed enzymatic inhibition at micromolar concentrations. In silico analysis by molecular docking suggested binding of SAM461 in the active site cavities of both luciferase enzymes. Subsequent in vivo testing of SAM461 with gnotobiotic Artemia franciscana nauplii demonstrated naupliar protection against V. campbellii infection at low micromolar concentrations. Taken together, these findings suggest that suppression of luciferase activity could constitute a novel paradigm in the development of alternative anti-infective chemotherapies against luminescent vibriosis, and pave the ground for the chemical synthesis and biological characterization of derivatives with promising antimicrobial prospects

Mental health and substance use screening in HIV primary care before and during the early COVID-19 pandemic

Background: Mental health and substance use disorders disproportionately affect people with HIV (PWH), and may have been exacerbated during COVID-19. The Promoting Access to Care Engagement (PACE) trial was designed to assess the effectiveness of electronic screening for mental health and substance use in HIV primary care and enrolled PWH from October 2018 to July 2020. Our objective here was to compare screening rates and results for PWH before (October 2018 – February 2020) and early in the COVID-19 pandemic (March-July 2020). Methods: Adult (≥ 18 years) PWH from 3 large HIV primary care clinics in a US-based integrated healthcare system were offered electronic screening online or via in-clinic tablet computer every 6 months. Screening completion and results (for depression, suicidal ideation, anxiety, and substance use) were analyzed using logistic regression with generalized estimating equations to estimate prevalence ratios (PR) before and after the start of the regional COVID-19 shelter-in-place orders on March 17, 2020. Models adjusted for demographics (age, sex, race/ethnicity), HIV risk factors (men who have sex with men, injection drug use, heterosexual, other), medical center, and modality of screening completion (online or tablet). We conducted qualitative interviews with providers participating in the intervention to evaluate how the pandemic impacted patient care. Results: Of 8,954 eligible visits, 3,904 completed screenings (420 during COVID, 3,484 pre-COVID), with lower overall completion rates during COVID (38% vs. 44%). Patients completing screening during COVID were more likely to be White (63% vs. 55%), male (94% vs. 90%), and MSM (80% vs., 75%). Adjusted PRs comparing COVID and pre-COVID (reference) were 0.70 (95% CI), 0.92 (95% CI), and 0.54 (95% CI) for tobacco use, any substance use, and suicidal ideation, respectively. No significant differences were found by era for depression, anxiety, alcohol, or cannabis use. These results were in contrast to provider-reported impressions of increases in substance use and mental health symptoms. Conclusion: Findings suggest PWH had modest declines in screening rates early in the COVID-19 pandemic which may have been affected by the shift to telemedicine. There was no evidence that mental health problems and substance use increased for PWH in primary care. Trial registration: NCT03217058 (First registration date: 7/13/2017); https://clinicaltrials.gov/ct2/show/NCT03217058

Performance of prototypes for the ALICE electromagnetic calorimeter

The performance of prototypes for the ALICE electromagnetic sampling calorimeter has been studied in test beam measurements at FNAL and CERN. A $4\times4$ array of final design modules showed an energy resolution of about 11% /$\sqrt{E(\mathrm{GeV})}$ $\oplus$ 1.7 % with a uniformity of the response to electrons of 1% and a good linearity in the energy range from 10 to 100 GeV. The electromagnetic shower position resolution was found to be described by 1.5 mm $\oplus$ 5.3 mm /$\sqrt{E \mathrm{(GeV)}}$. For an electron identification efficiency of 90% a hadron rejection factor of $>600$ was obtained.Comment: 10 pages, 10 figure

Strange particle production in proton-proton collisions at s=0.9\sqrt{s}=0.9 TeV with ALICE at the LHC

The production of mesons containing strange quarks (K$^0_s$, $\phi$) and both singly and doubly strange baryons ($\Lambda$, Anti-$\Lambda$, and $\Xi$+Anti-$\Xi$) are measured at central rapidity in pp collisions at $\sqrt{s}$ = 0.9 TeV with the ALICE experiment at the LHC. The results are obtained from the analysis of about 250 k minimum bias events recorded in 2009. Measurements of yields (dN/dy) and transverse momentum spectra at central rapidities for inelastic pp collisions are presented. For mesons, we report yields () of 0.184 $\pm$ 0.002 stat. $\pm$ 0.006 syst. for K$^0_s$ and 0.021 $\pm$ 0.004 stat. $\pm$ 0.003 syst. for $\phi$. For baryons, we find = 0.048 $\pm$ 0.001 stat. $\pm$ 0.004 syst. for $\Lambda$, 0.047 $\pm$ 0.002 stat. $\pm$ 0.005 syst. for Anti-$\Lambda$ and 0.0101 $\pm$ 0.0020 stat. $\pm$ 0.0009 syst. for $\Xi$+Anti-$\Xi$. The results are also compared with predictions for identified particle spectra from QCD-inspired models and provide a baseline for comparisons with both future pp measurements at higher energies and heavy-ion collisions.Comment: 33 pages, 21 captioned figures, 10 tables, authors from page 28, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/387

Heavy quarkonium: progress, puzzles, and opportunities

A golden age for heavy quarkonium physics dawned a decade ago, initiated by the confluence of exciting advances in quantum chromodynamics (QCD) and an explosion of related experimental activity. The early years of this period were chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in 2004, which presented a comprehensive review of the status of the field at that time and provided specific recommendations for further progress. However, the broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles could only be partially anticipated. Since the release of the YR, the BESII program concluded only to give birth to BESIII; the $B$-factories and CLEO-c flourished; quarkonium production and polarization measurements at HERA and the Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the deconfinement regime. All these experiments leave legacies of quality, precision, and unsolved mysteries for quarkonium physics, and therefore beg for continuing investigations. The plethora of newly-found quarkonium-like states unleashed a flood of theoretical investigations into new forms of matter such as quark-gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the spectroscopy, decays, production, and in-medium behavior of c\bar{c}, b\bar{b}, and b\bar{c} bound states have been shown to validate some theoretical approaches to QCD and highlight lack of quantitative success for others. The intriguing details of quarkonium suppression in heavy-ion collisions that have emerged from RHIC have elevated the importance of separating hot- and cold-nuclear-matter effects in quark-gluon plasma studies. This review systematically addresses all these matters and concludes by prioritizing directions for ongoing and future efforts.Comment: 182 pages, 112 figures. Editors: N. Brambilla, S. Eidelman, B. K. Heltsley, R. Vogt. Section Coordinators: G. T. Bodwin, E. Eichten, A. D. Frawley, A. B. Meyer, R. E. Mitchell, V. Papadimitriou, P. Petreczky, A. A. Petrov, P. Robbe, A. Vair

Two-pion Bose-Einstein correlations in central Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 2.76 TeV

The first measurement of two-pion Bose-Einstein correlations in central Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV at the Large Hadron Collider is presented. We observe a growing trend with energy now not only for the longitudinal and the outward but also for the sideward pion source radius. The pion homogeneity volume and the decoupling time are significantly larger than those measured at RHIC.Comment: 17 pages, 5 captioned figures, 1 table, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/388

Suppression of charged particle production at large transverse momentum in central Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}} = 2.76 TeV

Inclusive transverse momentum spectra of primary charged particles in Pb-Pb collisions at $\sqrt{s_{_{\rm NN}}}$ = 2.76 TeV have been measured by the ALICE Collaboration at the LHC. The data are presented for central and peripheral collisions, corresponding to 0-5% and 70-80% of the hadronic Pb-Pb cross section. The measured charged particle spectra in $|\eta|<0.8$ and $0.3 < p_T < 20$ GeV/$c$ are compared to the expectation in pp collisions at the same $\sqrt{s_{\rm NN}}$, scaled by the number of underlying nucleon-nucleon collisions. The comparison is expressed in terms of the nuclear modification factor $R_{\rm AA}$. The result indicates only weak medium effects ($R_{\rm AA} \approx$ 0.7) in peripheral collisions. In central collisions, $R_{\rm AA}$ reaches a minimum of about 0.14 at $p_{\rm T}=6$-7GeV/$c$ and increases significantly at larger $p_{\rm T}$. The measured suppression of high-$p_{\rm T}$ particles is stronger than that observed at lower collision energies, indicating that a very dense medium is formed in central Pb-Pb collisions at the LHC.Comment: 15 pages, 5 captioned figures, 3 tables, authors from page 10, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/98

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter