The influence of anti-asthma drugs on the transcriptional regulation of chemokine receptor 3 (CCR3)

Introduction: Chemokine receptor 3 (CCR3), the major chemokine receptor expressed on eosinophils, binds promiscuously to several ligands, mainly the eotaxin family of chemokines which are up-regulated in inflammatory response. CCR3 expression in airway epithelial cells, has been reported to be upregulated in asthma, and has been proposed to play an important role in airway inflammation by amplifying the expression of chemokine transcripts. The promoter region of CCR3 gene has recently been characterized in the literature and contains promoter elements which include a TATA box and motifs for transcription factors such as NF-κB, AP-1 and GATA-1. Aim: The aim of this study was to investigate the effects of transcription modifier anti-asthma drugs on the transcriptional regulation of the CCR3 promoter. Methodology: pGL3E luciferase-based reporter deletion constructs were generated for the 1.6kb CCR3 promoter region, using standard cloning approaches in DH5α E.Coli cells. Each promoter construct was transfected to A549 cells in microwell plate format and stimulated with dexamethasone, cortisol, and theophylline, in a dose dependent manner. Results: A CCR3 promoter tri-phasic response (i.e. activation at low concentration 10-8M, repression at medium concentration 10-7M, and activation at high concentration 10- 6 M) to dexamethasone was observed, indicating a complex transcriptional regulatory mechanism. Unlike dexamethasone, cortisol did not activate CCR3 promoter activity at any of the concentrations investigated, but rather showed significant transcriptional repression at concentrations of 10-6M and 10-7M. Theophylline showed significant transcriptional repression at all three concentrations investigated (10-4M, 10-5M and 10-6M). Conclusions: Dexamethasone-induced transcriptional regulation of the CCR3 promoter in A549 cells appears to occur in a complex dose-dependent manner, potentially involving additional mechanisms besides the established NF-κB and AP-1 transcriptional pathways. Changes in CCR3 promoter activity in response to cortisol were different from those observed for dexamethasone, and can be explained by doserelated increases in transcriptional repression. Our results have also shown that theophylline significantly represses CCR3 promoter activity in the absence of glucocorticoids, suggesting that this may be another mechanism by which theophylline exerts its pharmacological effects.peer-reviewe

The Structure and Function of Research Ethics Committees in Africa: A Case Study

Kass and colleagues explore the strengths and weaknesses of research ethics committees in Africa

Investigation into the genetic and functional relevance of the association of rS12477314 with pulmonary function

Introduction: Recent Genome-Wide Association Study (GWAS) metaanalyses have identified a number of significant association signals for pulmonary function, one of which maps to a locus (rs12477314) in an intergenic region on 2q37.3 flanked by two oppositely transcribed genes - HDAC4 and Twist2, and a lincRNA (FLJ43879). Aim: The aim of this study is to investigate the genetic and functional relevance of the association of single nucleotide polymorphism (SNP) rs12477314 with pulmonary function.peer-reviewe

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Search for Eccentric Black Hole Coalescences during the Third Observing Run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass $M>70$ $M_\odot$) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities $0 < e \leq 0.3$ at $0.33$ Gpc$^{-3}$ yr$^{-1}$ at 90\% confidence level.Comment: 24 pages, 5 figure

Open data from the third observing run of LIGO, Virgo, KAGRA and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in April of 2019 and lasting six months, O3b starting in November of 2019 and lasting five months, and O3GK starting in April of 2020 and lasting 2 weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main dataset, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages.Comment: 27 pages, 3 figure

Open data from the third observing run of LIGO, Virgo, KAGRA, and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in 2019 April and lasting six months, O3b starting in 2019 November and lasting five months, and O3GK starting in 2020 April and lasting two weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main data set, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages