The HOPE mass spectrometer of the Radiation Belt Storm Probes (RBSP) mission (renamed the Van Allen Probes) is designed to measure the
in situ
plasma ion and electron fluxes over 4
π
sr at each RBSP ...spacecraft within the terrestrial radiation belts. The scientific goal is to understand the underlying physical processes that govern the radiation belt structure and dynamics. Spectral measurements for both ions and electrons are acquired over 1 eV to 50 keV in 36 log-spaced steps at an energy resolution Δ
E
FWHM
/
E
≈15 %. The dominant ion species (H
+
, He
+
, and O
+
) of the magnetosphere are identified using foil-based time-of-flight (TOF) mass spectrometry with channel electron multiplier (CEM) detectors. Angular measurements are derived using five polar pixels coplanar with the spacecraft spin axis, and up to 16 azimuthal bins are acquired for each polar pixel over time as the spacecraft spins. Ion and electron measurements are acquired on alternate spacecraft spins. HOPE incorporates several new methods to minimize and monitor the background induced by penetrating particles in the harsh environment of the radiation belts. The absolute efficiencies of detection are continuously monitored, enabling precise, quantitative measurements of electron and ion fluxes and ion species abundances throughout the mission. We describe the engineering approaches for plasma measurements in the radiation belts and present summaries of HOPE measurement strategy and performance.
Evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME).
Multicenter, ...randomized clinical trial.
A total of 854 study eyes of 691 participants with visual acuity (approximate Snellen equivalent) of 20/32 to 20/320 and DME involving the fovea.
Eyes were randomized to sham injection + prompt laser (n=293), 0.5 mg ranibizumab + prompt laser (n=187), 0.5 mg ranibizumab + deferred (> or =24 weeks) laser (n=188), or 4 mg triamcinolone + prompt laser (n=186). Retreatment followed an algorithm facilitated by a web-based, real-time data-entry system.
Best-corrected visual acuity and safety at 1 year.
The 1-year mean change (+/-standard deviation) in the visual acuity letter score from baseline was significantly greater in the ranibizumab + prompt laser group (+9+/-11, P<0.001) and ranibizumab + deferred laser group (+9+/-12, P<0.001) but not in the triamcinolone + prompt laser group (+4+/-13, P=0.31) compared with the sham + prompt laser group (+3+/-13). Reduction in mean central subfield thickness in the triamcinolone + prompt laser group was similar to both ranibizumab groups and greater than in the sham + prompt laser group. In the subset of pseudophakic eyes at baseline (n=273), visual acuity improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. No systemic events attributable to study treatment were apparent. Three eyes (0.8%) had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Two-year visual acuity outcomes were similar to 1-year outcomes.
Intravitreal ranibizumab with prompt or deferred laser is more effective through at least 1 year compared with prompt laser alone for the treatment of DME involving the central macula. Ranibizumab as applied in this study, although uncommonly associated with endophthalmitis, should be considered for patients with DME and characteristics similar to those in this clinical trial. In pseudophakic eyes, intravitreal triamcinolone + prompt laser seems more effective than laser alone but frequently increases the risk of intraocular pressure elevation.
ABSTRACT
We report the results of optical follow-up observations of 29 gravitational-wave (GW) triggers during the first half of the LIGO–Virgo Collaboration (LVC) O3 run with the Gravitational-wave ...Optical Transient Observer (GOTO) in its prototype 4-telescope configuration (GOTO-4). While no viable electromagnetic (EM) counterpart candidate was identified, we estimate our 3D (volumetric) coverage using test light curves of on- and off-axis gamma-ray bursts and kilonovae. In cases where the source region was observable immediately, GOTO-4 was able to respond to a GW alert in less than a minute. The average time of first observation was 8.79 h after receiving an alert (9.90 h after trigger). A mean of 732.3 square degrees were tiled per event, representing on average 45.3 per cent of the LVC probability map, or 70.3 per cent of the observable probability. This coverage will further improve as the facility scales up alongside the localization performance of the evolving GW detector network. Even in its 4-telescope prototype configuration, GOTO is capable of detecting AT2017gfo-like kilonovae beyond 200 Mpc in favourable observing conditions. We cannot currently place meaningful EM limits on the population of distant ($\hat{D}_L = 1.3$ Gpc) binary black hole mergers because our test models are too faint to recover at this distance. However, as GOTO is upgraded towards its full 32-telescope, 2 node (La Palma & Australia) configuration, it is expected to be sufficiently sensitive to cover the predicted O4 binary neutron star merger volume, and will be able to respond to both northern and southern triggers.
Although regulatory T cells (Treg) are highly enriched in human tumours compared with peripheral blood, expression of the immune-checkpoint receptors, immunosuppressive molecules and function of Treg ...in these two sites remains undefined.
Tumour-infiltrating lymphocytes and peripheral blood lymphocytes were isolated from a cohort of head and neck squamous cell carcinoma (HNSCC) patients. The immunosuppressive phenotypes and function of intratumoral Treg were compared with those of peripheral blood Treg.
The frequency of immune-checkpoint receptor-positive cells was higher on intratumoral FOXP3(+)CD25(hi) Treg compared with circulating Treg (CTLA-4, P=0.002; TIM-3, P=0.002 and PD-1, P=0.002). Immunosuppressive effector molecules, LAP and ectonucleotidase CD39 were also upregulated on intratumoral FOXP3(+) Treg (P=0.002 and P=0.004, respectively). CTLA-4 and CD39 were co-expressed on the majority of intratumoral FOXP3(+)CD4(+) Treg, suggesting that these molecules have a key role in regulatory functions of these cells in situ. Notably, intratumoral Treg exhibited more potently immunosuppressive activity than circulating Treg.
These results indicate that intratumoral Treg are more immunosuppressive than circulating Treg and CTLA-4 and CD39 expressed can be potential target molecules to inhibit suppressive activities of intratumoral Treg in situ.
Previous analyses from a randomised trial in women aged 24-45 years have shown the quadrivalent human papillomavirus (qHPV) vaccine to be efficacious in the prevention of infection, cervical ...intraepithelial neoplasia (CIN), and external genital lesions (EGLs) related to HPV 6/11/16/18. In this report, we present end-of-study efficacy, safety, and immunogenicity data with a median follow-up time of 4.0 years.
We enrolled 3819 24-45-year-old women with no history of cervical disease or genital warts in the past 5 years. Women received quadrivalent vaccine or placebo at day 1, and at months 2 and 6. Ascertainment of CIN/EGL was accomplished through Pap testing, genital inspection, and cervicovaginal sampling (every 6 months). The main analysis was conducted in a per-protocol efficacy population (that received three doses, was naive to the relevant HPV types at day 1, and remained free of infection through month 7). Efficacy was also estimated in other naive and non-naive populations.
Vaccine efficacy against the combined incidence of persistent infection, CIN/EGL related to HPV6/11/16/18 in the per-protocol population was 88.7% (95% CI: 78.1, 94.8). Efficacy for women who were seropositive and DNA negative for the relevant vaccine HPV type at the time of enrolment who received at least 1 dose was 66.9% (95% CI: 4.3, 90.6). At month 48, 91.5, 92.0, 97.4, and 47.9% of vaccinated women were seropositive to HPV 6/11/16/18, respectively. No serious vaccine-related adverse experiences were reported.
The qHPV vaccine demonstrated high efficacy, immunogenicity, and acceptable safety in women aged 24-45 years, regardless of previous exposure to HPV vaccine type.
Here, we describe the Compact Array Broad-band Backend (CABB) and present first results obtained with the upgraded Australia Telescope Compact Array (ATCA). The 16-fold increase in observing ...bandwidth, from 2 × 128 to 2 × 2048 MHz, high-bit sampling and the addition of 16 zoom windows (each divided into further 2048 channels) provide major improvements for all ATCA observations. The benefits of the new system are: (1) hugely increased radio continuum and polarization sensitivity as well as image fidelity; (2) substantially improved capability to search for and map emission and absorption lines over large velocity ranges; (3) simultaneous multi-line and continuum observations; (4) increased sensitivity, survey speed and dynamic range due to high-bit sampling and (5) high-velocity resolution, while maintaining full polarization output. The new CABB system encourages all observers to make use of both spectral line and continuum data to achieve their full potential.
Given the dramatic increase of the ATCA capabilities in all bands (ranging from 1.1 to 105 GHz) CABB enables scientific projects that were not feasible before the upgrade, such as simultaneous observations of multiple spectral lines, on-the-fly mapping, fast follow-up of radio transients (e.g. the radio afterglow of new supernovae) and maser observation at high-velocity resolution and full polarization. The first science results presented here include wide-band spectra, high dynamic-range images and polarization measurements, highlighting the increased capability and discovery potential of the ATCA.
Technical variation in metagenomic analysis must be minimized to confidently assess the contributions of microbiota to human health. Here we tested 21 representative DNA extraction protocols on the ...same fecal samples and quantified differences in observed microbial community composition. We compared them with differences due to library preparation and sample storage, which we contrasted with observed biological variation within the same specimen or within an individual over time. We found that DNA extraction had the largest effect on the outcome of metagenomic analysis. To rank DNA extraction protocols, we considered resulting DNA quantity and quality, and we ascertained biases in estimates of community diversity and the ratio between Gram-positive and Gram-negative bacteria. We recommend a standardized DNA extraction method for human fecal samples, for which transferability across labs was established and which was further benchmarked using a mock community of known composition. Its adoption will improve comparability of human gut microbiome studies and facilitate meta-analyses.
ABSTRACT
The Gravitational-wave Optical Transient Observer (GOTO) is an array of wide-field optical telescopes, designed to exploit new discoveries from the next generation of gravitational wave ...detectors (LIGO, Virgo, and KAGRA), study rapidly evolving transients, and exploit multimessenger opportunities arising from neutrino and very high energy gamma-ray triggers. In addition to a rapid response mode, the array will also perform a sensitive, all-sky transient survey with few day cadence. The facility features a novel, modular design with multiple 40-cm wide-field reflectors on a single mount. In 2017 June, the GOTO collaboration deployed the initial project prototype, with 4 telescope units, at the Roque de los Muchachos Observatory (ORM), La Palma, Canary Islands. Here, we describe the deployment, commissioning, and performance of the prototype hardware, and discuss the impact of these findings on the final GOTO design. We also offer an initial assessment of the science prospects for the full GOTO facility that employs 32 telescope units across two sites.
The effectiveness of MAPK pathway inhibitors (MAPKi) used to treat patients with BRAF-mutant melanoma is limited by a range of resistance mechanisms, including soluble TNF (solTNF)-mediated NF-kB ...signaling. solTNF preferentially signals through type-1 TNF receptor (TNFR1), however, it can also bind to TNFR2, a receptor that is primarily expressed on leukocytes. Here, we investigate the TNFR2 expression pattern on human BRAF
melanomas and its role in solTNF-driven resistance reprogramming to MAPKi.
Flow cytometry was used to test TNFR1, TNFR2 and CD271 expression on, as well as NF-kB phosphorylation in human BRAF-mutant melanoma. The ability of melanoma cell lines to acquire MAPKi resistance in response to recombinant or macrophage-derived TNF was evaluated using the MTT cytotoxicity assay. Gene editing was implemented to knock out or knock in TNF receptors in melanoma cell lines. Knockout and knock-in cell line variants were employed to assess the intrinsic roles of these receptors in TNF-induced resistance to MAPKi. Multicolor immunofluorescence microscopy was utilized to test TNFR2 expression by melanoma in patients receiving MAPKi therapy.
TNFR1 and TNFR2 are co-expressed at various levels on 4/7 BRAF
melanoma cell lines evaluated in this study. In vitro treatments with solTNF induce MAPKi resistance solely in TNFR2-expressing BRAF
melanoma cell lines. TNFR1 and TNFR2 knockout and knock-in studies indicate that solTNF-mediated MAPKi resistance in BRAF
melanomas is predicated on TNFR1 and TNFR2 co-expression, where TNFR1 is the central mediator of NF-kB signaling, while TNFR2 plays an auxiliary role. solTNF-mediated effects are transient and can be abrogated with biologics. Evaluation of patient specimens indicates that TNFR2 is expressed on 50% of primary BRAF
melanoma cells and that MAPKi therapy may lead to the enrichment of TNFR2-expressing tumor cells.
Our data suggest that TNFR2 is essential to solTNF-induced MAPKi resistance and a possible biomarker to identify melanoma patients that can benefit from solTNF-targeting therapies.
Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years.
Women ...aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848.
For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred.
Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years.
GlaxoSmithKline Biologicals (Belgium).
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