Pharmacological validation of targets regulating CD14 during macrophage differentiation

The signalling receptor for LPS, CD14, is a key marker of, and facilitator for, pro-inflammatory macrophage function. Pro-inflammatory macrophage differentiation remains a process facilitating a broad array of disease pathologies, and has recently emerged as a potential target against cytokine storm in COVID19. Here, we perform a whole-genome CRISPR screen to identify essential nodes regulating CD14 expression in myeloid cells, using the differentiation of THP-1 cells as a starting point. This strategy uncovers many known pathways required for CD14 expression and regulating macrophage differentiation while additionally providing a list of novel targets either promoting or limiting this process. To speed translation of these results, we have then taken the approach of independently validating hits from the screen using well-curated small molecules. In this manner, we identify pharmacologically tractable hits that can either increase CD14 expression on non-differentiated monocytes or prevent CD14 upregulation during macrophage differentiation. An inhibitor for one of these targets, MAP2K3, translates through to studies on primary human monocytes, where it prevents upregulation of CD14 following M-CSF induced differentiation, and pro-inflammatory cytokine production in response to LPS. Therefore, this screening cascade has rapidly identified pharmacologically tractable nodes regulating a critical disease-relevant process

Schmidt-hammer exposure ages from periglacial patterned ground (sorted circles) in Jotunheimen, Norway, and their interpretative problems

© 2016 Swedish Society for Anthropology and Geography Periglacial patterned ground (sorted circles and polygons) along an altitudinal profile at Juvflya in central Jotunheimen, southern Norway, is investigated using Schmidt-hammer exposure-age dating (SHD). The patterned ground surfaces exhibit R-value distributions with platycurtic modes, broad plateaus, narrow tails, and a negative skew. Sample sites located between 1500 and 1925 m a.s.l. indicate a distinct altitudinal gradient of increasing mean R-values towards higher altitudes interpreted as a chronological function. An established regional SHD calibration curve for Jotunheimen yielded mean boulder exposure ages in the range 6910 ± 510 to 8240 ± 495 years ago. These SHD ages are indicative of the timing of patterned ground formation, representing minimum ages for active boulder upfreezing and maximum ages for the stabilization of boulders in the encircling gutters. Despite uncertainties associated with the calibration curve and the age distribution of the boulders, the early-Holocene age of the patterned ground surfaces, the apparent cessation of major activity during the Holocene Thermal Maximum (HTM) and continuing lack of late-Holocene activity clarify existing understanding of the process dynamics and palaeoclimatic significance of large-scale sorted patterned ground as an indicator of a permafrost environment. The interpretation of SHD ages from patterned ground surfaces remains challenging, however, owing to their diachronous nature, the potential for a complex history of formation, and the influence of local, non-climatic factors

Estimation and Mapping of Wet and Dry Mercury Deposition Across Northeastern North America

Whereas many ecosystem characteristics and processes influence mercury accumulation in higher trophic-level organisms, the mercury flux from the atmosphere to a lake and its watershed is a likely factor in potential risk to biota. Atmospheric deposition clearly affects mercury accumulation in soils and lake sediments. Thus, knowledge of spatial patterns in atmospheric deposition may provide information for assessing the relative risk for ecosystems to exhibit excessive biotic mercury contamination. Atmospheric mercury concentrations in aerosol, vapor, and liquid phases from four observation networks were used to estimate regional surface concentration fields. Statistical models were developed to relate sparsely measured mercury vapor and aerosol concentrations to the more commonly measured mercury concentration in precipitation. High spatial resolution deposition velocities for different phases (precipitation, cloud droplets, aerosols, and reactive gaseous mercury (RGM)) were computed using inferential models. An empirical model was developed to estimate gaseous elemental mercury (GEM) deposition. Spatial patterns of estimated total mercury deposition were complex. Generally, deposition was higher in the southwest and lower in the northeast. Elevation, land cover, and proximity to urban areas modified the general pattern. The estimated net GEM and RGM fluxes were each greater than or equal to wet deposition in many areas. Mercury assimilation by plant foliage may provide a substantial input of methyl-mercury (MeHg) to ecosystems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44443/1/10646_2004_Article_6259.pd

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

ABCB1 (MDR1) rs1045642 is associated with increased overall survival in plasma cell myeloma

Multi-drug resistance (MDR) may compromise the successful management of haematological malignancies, impairing the effectiveness of chemotherapy. The P-glycoprotein (P-gp) drug efflux pump, encoded by the gene ABCB1 (MDR1), is the most widely studied component in MDR. A single nucleotide polymorphism (SNP) has been identified within ABCB1, rs1045642 (C3435T), which may alter P-gp substrate specificity and have an impact on the effectiveness of treatment, and hence overall survival (OS). We estimated the frequency of this SNP in the Northern Irish population and investigated its impact on the OS of patients with plasma cell myeloma (PCM). There was no significant difference in the frequency of rs1045642 between the PCM cohort and an age- and gender-matched control population. Findings within the PCM cohort suggest that rs1045642 genotype influences OS (p=210-2). If confirmed in larger studies, these results suggest that genotyping rs1045642 may be a useful predictor of outcome in PCM and could indicate modified treatment modalities in certain individuals

Confirmation of 1RXS J165443.5–191620 as an intermediate polar and its orbital and spin periods

Aims: We investigate the physical nature of the X-ray emitting source 1RXS J165443.5-191620 through optical photometry and time-resolved spectroscopy. Methods: Optical photometry is obtained from a variety of telescopes all over the world spanning about 27 days. Additionally, time-resolved spectroscopy is obtained from the MDM observatory. Results: The optical photometry clearly displays modulations consistent with those observed in magnetic cataclysmic variables: a low-frequency signal interpreted as the orbital period, a high-frequency signal interpreted as the white dwarf spin period, and an orbital sideband modulation. Our findings and interpretations are further confirmed through optical, time-resolved, spectroscopy that displays H-alpha radial velocity shifts modulated on the binary orbital period. Conclusion: We confirm the true nature of 1RXS J165443.5-191620 as an intermediate polar with a spin period of 546 seconds and an orbital period of 3.7 hours. In particular, 1RXS J165443.5-191620 is part of a growing subset of intermediate polars, all displaying hard X-ray emission above 15keV, white dwarf spin periods below 30 minutes, and spin-to-orbital ratios below 0.1.Comment: 7 pages, 9 figures, 6 tables, accepted for publication in A&