The Monitor project: JW 380 - a 0.26-, 0.15-M⊙, pre-main-sequence eclipsing binary in the Orion nebula cluster

We report the discovery of a low-mass (0.26 ± 0.02, 0.15 ± 0.01 M⊙) pre-main-sequence (PMS) eclipsing binary (EB) with a 5.3 d orbital period. JW 380 was detected as part of a high-cadence time-resolved photometric survey (the Monitor project) using the 2.5-m Isaac Newton Telescope and Wide Field Camera for a survey of a single field in the Orion nebula cluster (ONC) region in V and i bands. The star is assigned a 99 per cent membership probability from proper motion measurements, and radial velocity observations indicate a systemic velocity within 1σ of that of the ONC. Modelling of the combined light and radial velocity curves of the system gave stellar radii of for the primary and the secondary, with a significant third light contribution which is also visible as a third peak in the cross-correlation functions used to derive radial velocities. The masses and radii appear to be consistent with stellar models for 2-3 Myr age from several authors, within the present observational errors. These observations probe an important region of mass-radius parameter space, where there are currently only a handful of known PMS EB systems with precise measurements available in the literatur

Co-ordinated expression of amino acid metabolism in response to N and S deficiency during wheat grain filling

Increasing demands for productivity together with environmental concerns about fertilizer use dictate that the future sustainability of agricultural systems will depend on improving fertilizer use efficiency. Characterization of the biological processes responsible for efficient fertilizer use will provide tools for crop improvement under reduced inputs. Transcriptomic and metabolomic approaches were used to study the impact of nitrogen (N) and sulphur (S) deficiency on N and S remobilization from senescing canopy tissues during grain filling in winter wheat (Triticum aestivum). Canopy tissue N was remobilized effectively to the grain after anthesis. S was less readily remobilized. Nuclear magnetic resonance (NMR) metabolite profiling revealed significant effects of suboptimal N or S supply in leaves but not in developing grain. Analysis of amino acid pools in the grain and leaves revealed a strategy whereby amino acid biosynthesis switches to the production of glutamine during grain filling. Glutamine accumulated in the first 7 d of grain development, prior to conversion to other amino acids and protein in the subsequent 21 d. Transcriptome analysis indicated that a down-regulation of the terminal steps in many amino acid biosynthetic pathways occurs to control pools of amino acids during leaf senescence. Grain N and S contents increased in parallel after anthesis and were not significantly affected by S deficiency, despite a suboptimal N:S ratio at final harvest. N deficiency resulted in much slower accumulation of grain N and S and lower final concentrations, indicating that vegetative tissue N has a greater control of the timing and extent of nutrient remobilization than S

The Monitor project: JW 380 -- a 0.26, 0.15 Msol pre main sequence eclipsing binary in the Orion Nebula Cluster

We report the discovery of a low-mass (0.26 +/- 0.02, 0.15 +/- 0.01 Msol) pre-main-sequence eclipsing binary with a 5.3 day orbital period. JW 380 was detected as part of a high-cadence time-resolved photometric survey (the Monitor project) using the 2.5m Isaac Newton Telescope and Wide Field Camera for a survey of a single field in the Orion Nebula Cluster (ONC) region in V and i bands. The star is assigned a 99 per cent membership probability from proper motion measurements, and radial velocity observations indicate a systemic velocity within 1 sigma of that of the ONC. Modelling of the combined light and radial velocity curves of the system gave stellar radii of 1.19 +0.04 -0.18 Rsol and 0.90 +0.17 -0.03 Rsol for the primary and secondary, with a significant third light contribution which is also visible as a third peak in the cross-correlation functions used to derive radial velocities. The masses and radii appear to be consistent with stellar models for 2-3 Myr age from several authors, within the present observational errors. These observations probe an important region of mass-radius parameter space, where there are currently only a handful of known pre-main-sequence eclipsing binary systems with precise measurements available in the literature.Comment: 11 pages, 9 figures, accepted for publication in MNRA

Bicistronic Lentiviruses Containing a Viral 2A Cleavage Sequence Reliably Co-Express Two Proteins and Restore Vision to an Animal Model of LCA1

The disease processes underlying inherited retinal disease are complex and are not completely understood. Many of the corrective gene therapies designed to treat diseases linked to mutations in genes specifically expressed in photoreceptor cells restore function to these cells but fail to stop progression of the disease. There is growing consensus that effective treatments for these diseases will require delivery of multiple therapeutic proteins that will be selected to treat specific aspects of the disease process. The purpose of this study was to design a lentiviral transgene that reliably expresses all of the proteins it encodes and does so in a consistent manner among infected cells. We show, using both in vitro and in vivo analyses, that bicistronic lentiviral transgenes encoding two fluorescent proteins fused to a viral 2A-like cleavage peptide meet these expression criteria. To determine if this transgene design is suitable for therapeutic applications, we replaced one of the fluorescent protein genes with the gene encoding guanylate cyclase -1 (GC1) and delivered lentivirus carrying this transgene to the retinas of the GUCY1*B avian model of Leber congenital amaurosis – 1 (LCA1). GUCY1*B chickens carry a null mutation in the GC1 gene that disrupts photoreceptor function and causes blindness at hatching, a phenotype that closely matches that observed in humans with LCA1. We found that treatment of these animals with the 2A lentivector encoding GC1 restored vision to these animals as evidenced by the presence of optokinetic reflexes. We conclude that 2A-like peptides, with proper optimization, can be successfully incorporated into therapeutic vectors designed to deliver multiple proteins to neural retinal. These results highlight the potential of this vector design to serve as a platform for the development of combination therapies designed to enhance or prolong the benefits of corrective gene therapies

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570