Abstract
With the conclusion of the third observing run for Advanced LIGO/Virgo (O3), we present a detailed analysis of both triggered and serendipitous observations of 17 gravitational-wave (GW) ...events (7 triggered and 10 purely serendipitous) from the Searches After Gravitational-waves Using ARizona Observatories (SAGUARO) program. We searched a total of 4935 deg
2
down to a median 5
σ
transient detection depth of 21.1 AB mag using the Mt. Lemmon 1.5 m telescope, the discovery engine for SAGUARO. In addition to triggered events within 24 hr, our transient search encompassed a time interval following GW events of <120 hr, providing observations on ∼1/2 of the events accessible to the Mt. Lemmon 1.5 m telescope. We covered 2.1%–86% of the LVC total probability (
P
total
) for individual events, with a median
P
total
≈ 8% within <120 hr. Following improvements to our pipeline and the addition of serendipitous observations, we find a total of seven new optical candidates across five GW events, which we are unable to rule out after searching for additional information and comparing to kilonova models. Using both publicly available and our own late-time data, we investigated a total of 252 optical candidates for these 17 events, finding that only 65% were followed up in some capacity by the community. Of the total 252 candidates, we are able to rule out an additional 12 previously reported counterpart candidates. In light of these results, we discuss lessons learned from the SAGUARO GW counterpart search. We discuss how community coordination of observations and candidate follow-up, as well as the role of archival data, are crucial to improving the efficiency of follow-up efforts and preventing unnecessary duplication of effort with limited electromagnetic resources.
We present Searches After Gravitational-waves Using ARizona Observatories (SAGUARO), a comprehensive effort dedicated to the discovery and characterization of optical counterparts to ...gravitational-wave (GW) events. SAGUARO utilizes ground-based facilities ranging from 1.5 to 10 m in diameter, located primarily in the Northern Hemisphere. We provide an overview of SAGUARO's telescopic resources, its pipeline for transient detection, and its database for candidate visualization. We describe SAGUARO's discovery component, which utilizes the 5 deg2 field of view optical imager on the Mt. Lemmon 1.5 m telescope, reaching limits of 21.3 AB mag while rapidly tiling large areas. We also describe the follow-up component of SAGUARO, used for rapid vetting and monitoring of optical candidates. With the onset of Advanced LIGO/Virgo's third observing run, we present results from the first three SAGUARO searches following the GW events S190408an, S190425z and S190426c, which serve as a valuable proof-of-concept of SAGUARO. We triggered and searched 15, 60, and 60 deg2 respectively, 17.6, 1.4, and 41.8 hr after the initial GW alerts. We covered 7.8%, 3.0%, and 5.1% of the total probability within the GW event localizations, reaching 3 limits of 19.8, 21.3, and 20.8 AB mag, respectively. Although no viable counterparts associated with these events were found, we recovered six known transients and ruled out five potential candidates. We also present Large Binocular Telescope spectroscopy of PS19eq/SN2019ebq, a promising kilonova candidate that was later determined to be a supernova. With the ability to tile large areas and conduct detailed follow-up, SAGUARO represents a significant addition to GW counterpart searches.
As of December, 1
, 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, resulted in more than 1 472 917 deaths worldwide and death toll is still increasing exponentially. Many COVID-19 ...infected people are asymptomatic or experience moderate symptoms and recover without medical intervention. However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality. Because current therapeutic options for COVID-19 patients are limited specifically for this elderly population at risk, Biophytis is developing BIO101 (20-hydroxyecdysone, a Mas receptor activator) as a new treatment option for managing patients with SARS-CoV-2 infection at the severe stage. The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2. Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS). The clinical picture of COVID-19 includes acute respiratory distress syndrome (ARDS), cardiomyopathy, multiorgan dysfunction and shock, all of which might result from an imbalance of the RAS. We propose that RAS balance could be restored in COVID-19 patients through MasR activation downstream of ACE2 activity, with 20-hydroxyecdysone (BIO101) a non-peptidic Mas receptor (MasR) activator. Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties. BIO101, a 97% pharmaceutical grade 20-hydroxyecdysone could then offer a new therapeutic option by improving the respiratory function and ultimately promoting survival in COVID-19 patients that develop severe forms of this devastating disease. Therefore, the objective of this COVA study is to evaluate the safety and efficacy of BIO101, whose active principle is 20-hydroxyecdysone, in COVID-19 patients with severe pneumonia.
Randomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts. Part 1: Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target population Part 2: Re-assessment of the sample size needed for the confirmatory part 2 and confirmation of the effect of BIO101 observed in part 1 in the target population. The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation. And adaptive - to allow accumulation of early data and adapt sample size in part 2 in order to inform the final design of the confirmatory part of the trial.
Inclusion criteria 1. Age: 45 and above 2. A confirmed diagnosis of COVID-19 infection, within the last 14 days, prior to randomization, as determined by PCR or other approved commercial or public health assay, in a specimen as specified by the test used. 3. Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 days 4. With evidence of pneumonia based on all of the following: a. Clinical findings on a physical examination b. Respiratory symptoms developed within the past 7 days 5. With evidence of respiratory decompensation that started not more than 4 days before start of study medication and present at screening, meeting one of the following criteria, as assessed by healthcare staff: a. Tachypnea: ≥25 breaths per minute b. Arterial oxygen saturation ≤92% c. A special note should be made if there is suspicion of COVID-19-related myocarditis or pericarditis, as the presence of these is a stratification criterion 6. Without a significant deterioration in liver function tests: a. ALT and AST ≤ 5x upper limit of normal (ULN) b. Gamma-glutamyl transferase (GGT) ≤ 5x ULN c. Total bilirubin ≤ 5×ULN 7. Willing to participate and able to sign an informed consent form (ICF). Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participant 8. Female participants should be: at least 5 years post-menopausal (i.e., persistent amenorrhea 5 years in the absence of an alternative medical cause) or surgically sterile; OR a. Have a negative urine pregnancy test at screening b. Be willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose. 9. Male participants who are sexually active with a female partner must agree to the use of an effective method of birth control throughout the study and until 3 months after the last administration of the investigational product. (Note: medically acceptable methods of contraception that may be used by the participant and/or partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, etonogestrel implant, each supplemented with a condom, as well as sterilization and vasectomy). 10. Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention. 11. Male participants must agree not to donate sperm for the purpose of reproduction throughout the study and until 3 months after the last administration of the investigational product. 12. For France only: Being affiliated with a European Social Security. Exclusion criteria 1. Not needing or not willing to remain in a healthcare facility during the study 2. Moribund condition (death likely in days) or not expected to survive for >7 days - due to other and non-COVID-19 related conditions 3. Participant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO), or high-flow Oxygen (delivery of oxygen at a flow of ≥16 L/min.). 4. Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water). 5. Disallowed concomitant medication: Consumption of any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides; Cyanotis vaga or Cyanotis arachnoidea is not allowed (e.g. performance enhancing agents). 6. Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101. 7. Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula). 8. In France only: a. Non-affiliation to compulsory French social security scheme (beneficiary or right-holder). b. Being under tutelage or legal guardianship. Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil. Maximum patients' participation in the study will last 28 days. Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days.
Two treatment arms will be tested in this study: interventional arm 350 mg b.i.d. of BIO101 (AP 20-hydroxyecdysone) and placebo comparator arm 350 mg b.i.d of placebo. Administration of daily dose is the same throughout the whole treatment period. Participants will receive the study medication while hospitalized for up to 28 days or until a clinical endpoint is reached (i.e., 'negative' or 'positive' event). Participants who are officially discharged from hospital care will no longer receive study medication.
Primary study endpoint: The proportion of participants with 'negative' events up to 28 days. 'Negative' events are defined as respiratory deterioration and all-cause mortality. For the purpose of this study, respiratory deterioration will be defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage). Requiring extracorporeal membrane oxygenation (ECMO). Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min. Only if the primary endpoint is significant at the primary final analysis the following Key secondary endpoints will be tested in that order: Proportion of participants with events of respiratory failure at Day 28 Proportion of participants with 'positive' events at Day 28. Proportion of participants with events of all-cause mortality at Day 28 A 'positive' event is defined as the official discharge from hospital care by the department due to improvement in participant condition. Secondary and exploratory endpoints: In addition, a variety of functional measures and biomarkers (including the SpO2 / FiO2 ratio, viral load and markers related to inflammation, muscles, tissue and the RAS / MAS pathways) will also be collected.
Randomization is performed using an IBM clinical development IWRS system during the baseline visit. Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio. In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above). In Part 2, randomization will be stratified by centre, gender, RAS pathway modulator use (yes/no), co-morbidities (none vs. 1 and above), receiving Continuous Positive Airway Pressure/Bi-level Positive Airway Pressure (CPAP/BiPAP) at study entry (Yes/No) and suspicion of COVID-19 related myocarditis or pericarditis (present or not).
Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process. An independent data-monitoring committee (DMC) will conduct 2 interim analyses. A first one based on the data from part 1 and a second from the data from parts 1 and 2. The first will inform about BIO101 safety, to allow the start of recruitment into part 2 followed by an analysis of the efficacy data, to obtain an indication of activity. The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power. Numbers to be randomised (sample size) Number of partici
Context
. Massive stars play important roles throughout the universe; however, their formation remains poorly understood. Observations of jets and outflows in high-mass star-forming regions, as well ...as surveys of young stellar object (YSO) content, can help test theoretical models of massive star formation.
Aims
. We aim at characterizing the massive star-forming region AFGL 5180 in the near-infrared (NIR), identifying outflows and relating these to sub-mm/mm sources, as well as surveying the overall YSO surface number density to compare to massive star formation models.
Methods
. Broad- and narrow-band imaging of AFGL 5180 was made in the NIR with the Large Binocular Telescope, in both seeing-limited (~0.5″) and high angular resolution (~0.09″) Adaptive Optics (AO) modes, as well as with the
Hubble
Space Telescope. Archival continuum data from the Atacama Millimeter/Submillimeter Array (ALMA) was also utilized.
Results
. At least 40 jet knots were identified via NIR emission from H
2
and FeII tracing shocked gas. Bright jet knots outflowing from the central most massive protostar, S4 (estimated mass ~11
M
⊙
, via SED fitting), are detected towards the east of the source and are resolved in fine detail with the AO imaging. Additional knots are distributed throughout the field, likely indicating the presence of multiple driving sources. Sub-millimeter sources detected by ALMA are shown to be grouped in two main complexes, AFGL 5180 M and a small cluster ~15″ (0.15 pc in projection) to the south, AFGL 5180 S. From our NIR continuum images we identify YSO candidates down to masses of ~0.1
M
⊙
. Combined with the sub-mm sources, this yields a surface number density of such YSOs of
N
*
~ 10
3
pc
−2
within a projected radius of about 0.1 pc. Such a value is similar to those predicted by models of both core accretion from a turbulent clump environment and competitive accretion. The radial profile of
N
*
is relatively flat on scales out to 0.2 pc, with only modest enhancement around the massive protostar inside 0.05 pc, which provides additional constraints on these massive star formation models.
Conclusions
. This study demonstrates the utility of high-resolution NIR imaging, in particular with AO, for detecting outflow activity and YSOs in distant regions. The presented images reveal the complex morphology of outflow-shocked gas within the large-scale bipolar flow of a massive protostar, as well as clear evidence for several other outflow driving sources in the region. Finally, this work presents a novel approach to compare the observed YSO surface number density from our study against different models of massive star formation.
We report the orbital distribution of the trans-Neptunian comets discovered during the first discovery year of the Canada-France Ecliptic Plane Survey (CFEPS). CFEPS is a Kuiper Belt object survey ...based on observations acquired by the Very Wide component of the Canada-France-Hawaii Telescope Legacy Survey (LS-VW). The first year's detections consist of 73 Kuiper Belt objects, 55 of which have now been tracked for three years or more, providing precise orbits. Although this sample size is small compared to the world-wide inventory, because we have an absolutely calibrated and extremely well-characterized survey (with known pointing history) we are able to de-bias our observed population and make unbiased statements about the intrinsic orbital distribution of the Kuiper Belt. By applying the (publically available) CFEPS Survey Simulator to models of the true orbital distribution and comparing the resulting simulated detections to the actual detections made by the survey, we are able to rule out several hypothesized Kuiper Belt object orbit distributions. We find that the main classical belt's so-called 'cold' component is confined in semimajor axis (a) and eccentricity (e) compared to the more extended 'hot' component; the cold component is confined to lower e and does not stretch all the way out to the 2:1 resonance but rather depletes quickly beyond a = 45 AU. For the cold main classical belt population we find a robust population estimate of N(Hg < 10) = 50 ± 5 X 103 and find that the hot component of the main classical belt represents ~60% of the total population. The inner classical belt (sunward of the 3:2 mean-motion resonance) has a population of roughly 2000 trans-Neptunian objects with absolute magnitudes Hg < 10, and may not share the inclination distribution of the main classical belt. We also find that the plutino population lacks a cold low-inclination component, and so, the population is somewhat larger than recent estimates; our analysis shows a plutino population of N(Hg < 10)~ 25+25 -12 X 103compared to our estimate of the size of main classical Kuiper Belt population of N(Hg < 10) ~ (126+50 -46) X 103.
Electroweak measurements performed with data taken at the electron–positron collider LEP at CERN from 1995 to 2000 are reported. The combined data set considered in this report corresponds to a total ...luminosity of about 3 fb−1 collected by the four LEP experiments ALEPH, DELPHI, L3 and OPAL, at centre-of-mass energies ranging from 130 GeV to 209 GeV.
Combining the published results of the four LEP experiments, the measurements include total and differential cross-sections in photon-pair, fermion-pair and four-fermion production, the latter resulting from both double-resonant WW and ZZ production as well as singly resonant production. Total and differential cross-sections are measured precisely, providing a stringent test of the Standard Model at centre-of-mass energies never explored before in electron–positron collisions. Final-state interaction effects in four-fermion production, such as those arising from colour reconnection and Bose–Einstein correlations between the two W decay systems arising in WW production, are searched for and upper limits on the strength of possible effects are obtained. The data are used to determine fundamental properties of the W boson and the electroweak theory. Among others, the mass and width of the W boson, mW and ΓW, the branching fraction of W decays to hadrons, B(W→had), and the trilinear gauge-boson self-couplings g1Z, κγ and λγ are determined to be: mW=80.376±0.033GeVΓW=2.195±0.083GeVB(W→had)=67.41±0.27%g1Z=0.984−0.020+0.018κγ=0.982±0.042λγ=−0.022±0.019.
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•The bioavailability of 20E is low (ca. 1%).•Plasma 20E concentrations can reach adequate levels to cause physiological effects.•Significant metabolism of 20E begins when it reaches ...the large intestine.•An entero-hepatic cycle helps to maintain plasma ecdysteroid levels.•20E and its metabolites are excreted mainly in the faeces within 24 h.
Phytoecdysteroids are molecules derived from sterol metabolism and found in many plants. They display a wide array of pharmacological effects on mammals (e.g. anabolic, anti-diabetic). Although these effects have been long established, the molecular targets involved remain to be identified. Like endogenous steroid hormones and bile acids, which are biochemically related, ingested or injected phytoecdysteroids undergo a set of reactions in mammals leading to the formation of numerous metabolites, only some of which have been so far identified, and it is presently unknown whether they represent active metabolites or inactivation products. In the large intestine, ecdysteroids undergo efficient 14-dehydroxylation. Other changes (reductions, epimerization, side-chain cleavage) are also observed, but whether these occur in the liver and/or large intestine is not known. The purpose of this study was to investigate the pharmacokinetics of 20-hydroxyecdysone (20E), the most common phytoecdysteroid, when administered to mice and rats, using, when required, tritium-labelled molecules to permit metabolic tracking. Bioavailability, the distribution of radioactivity and the kinetics of formation of metabolites were followed for 24−48 hours after ingestion and qualitative and quantitative analyses of circulating and excreted compounds were performed. In mice, the digestive tract always contains the majority of the ingested 20E. Within 30 min after ingestion, 20E reaches the large intestine, where microorganisms firstly remove the 14-hydroxyl group and reduce the 6-one. Then a very complex set of metabolites (not all of which have yet been identified) appears, which correspond to poststerone derivatives formed in the liver. We have observed that these compounds (like bile acids) undergo an entero-hepatic cycle, involving glucuronide conjugation in the liver and subsequent deconjugation in the intestine. Despite the very short half-life of ecdysteroids in mammals, this entero-hepatic cycle helps to maintain their plasma levels at values which, albeit low (≤0.2 μM), would be sufficient to evoke several pharmacological effects. Similar 20E metabolites were observed in mice and rats; they include in particular 14-deoxy-20E, poststerone and 14-deoxypoststerone and their diverse reduction products; the major products of this metabolism have been unambiguously identified. The major sites of metabolism of exogenous ecdysteroids in mammals are the large intestine and the liver. The entero-hepatic cycle contributes to the metabolism and to maintaining a low, but pharmacologically significant, concentration of ecdysteroids in the blood for ca. 24 h after ingestion. These data, together with parallel in vitro experiments provide a basis for the identification of 20E metabolite(s) possibly involved in the physiological effects associated with ecdysteroids in mammals.
•SARS-CoV-2 infection induces an imbalance in the renin–angiotensin system.•We present current clinical strategies that attempt to rebalance the RAS in COVID-19 patients.•There is interest in ...stimulating the protective arm of the RAS in COVID-19 patients.•20-Hydroxyecdysone, a Mas receptor (MasR) activator, has potential for the treatment of COVID-19.
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has reached pandemic proportions with negative impacts on global health, the world economy and human society. The clinical picture of COVID-19, and the fact that Angiotensin converting enzyme 2 (ACE2) is a receptor of SARS-CoV-2, suggests that SARS-CoV-2 infection induces an imbalance in the renin–angiotensin system (RAS). We review clinical strategies that are attempting to rebalance the RAS in COVID-19 patients by using ACE inhibitors, angiotensin receptor blockers, or agonists of angiotensin-II receptor type 2 or Mas receptor (MasR). We also propose that the new MasR activator BIO101, a pharmaceutical grade formulation of 20-hydroxyecdysone that has anti-inflammatory, anti-fibrotic and cardioprotective properties, could restore RAS balance and improve the health of COVID-19 patients who have severe pneumonia.
By rebalancing the renin–angiotensin system (RAS), BIO101 (20-hydroxyecdysone) could improve cardio-respiratory functions, limit the requirement for mechanical ventilation and reduce mortality in severely ill COVID-19 patients who are infected by SARS-CoV-2.
ABSTRACT Absorption lines from exoplanet atmospheres observed in transmission allow us to study atmospheric characteristics such as winds. We present a new high-resolution transit time-series of HD ...189733b, acquired with the PEPSI instrument at the LBT and analyse the transmission spectrum around the Na d lines. We model the spectral signature of the RM-CLV-effect using synthetic PHOENIX spectra based on spherical LTE atmospheric models. We find an Na d absorption signature between the second and third contact but not during the ingress and egress phases, which casts doubt on the planetary origin of the signal. Presupposing a planetary origin of the signal, the results suggest a weak day-to-nightside streaming wind in the order of 0.7 km s−1 and a moderate super-rotational streaming wind in the order of 3–4 km s−1, challenging claims of prevailing strong winds on HD 189733b.
-retinylidene-
-retinylethanolamine (A2E) has been associated with age-related macular degeneration (AMD) physiopathology by inducing cell death, angiogenesis and inflammation in retinal pigmented ...epithelial (RPE) cells. It was previously thought that the A2E effects were solely mediated via the retinoic acid receptor (RAR)-α activation. However, this conclusion was based on experiments using the RAR "specific" antagonist RO-41-5253, which was found to also be a ligand and partial agonist of the peroxisome proliferator-activated receptor (PPAR)-γ. Moreover, we previously reported that inhibiting PPAR and retinoid X receptor (RXR) transactivation with norbixin also modulated inflammation and angiogenesis in RPE cells challenged in the presence of A2E. Here, using several RAR inhibitors, we deciphered the respective roles of RAR, PPAR and RXR transactivations in an in vitro model of AMD. We showed that BMS 195614 (a selective RAR-α antagonist) displayed photoprotective properties against toxic blue light exposure in the presence of A2E. BMS 195614 also significantly reduced the AP-1 transactivation and mRNA expression of the inflammatory interleukin (IL)-6 and vascular endothelial growth factor (VEGF) induced by A2E in RPE cells in vitro, suggesting a major role of RAR in these processes. Surprisingly, however, we showed that (1) Norbixin increased the RAR transactivation and (2) AGN 193109 (a high affinity pan-RAR antagonist) and BMS 493 (a pan-RAR inverse agonist), which are photoprotective against toxic blue light exposure in the presence of A2E, also inhibited PPARs transactivation and RXR transactivation, respectively. Therefore, in our in vitro model of AMD, several commercialized RAR inhibitors appear to be non-specific, and we propose that the phototoxicity and expression of IL-6 and VEGF induced by A2E in RPE cells operates through the activation of PPAR or RXR rather than by RAR transactivation.
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