Discovery of sarolaner:A novel, Orally administered, broad-spectrum, Isoxazoline ectoparasiticide for dogs

AbstractThe novel isoxazoline ectoparasiticide, sarolaner, was identified during a lead optimization program for an orally-active compound with efficacy against fleas and ticks on dogs. The aim of the discovery program was to identify a novel isoxazoline specifically for use in companion animals, beginning with de novo synthesis in the Zoetis research laboratories. The sarolaner molecule has unique structural features important for its potency and pharmacokinetic (PK) properties, including spiroazetidine and sulfone moieties. The flea and tick activity resides in the chirally pure S-enantiomer, which was purified to alleviate potential off-target effects from the inactive enantiomer. The mechanism of action was established in electrophysiology assays using CHO-K1 cell lines stably expressing cat flea (Ctenocephalides felis) RDL (resistance-to-dieldrin) genes for assessment of GABA-gated chloride channel (GABACls) pharmacology. As expected, sarolaner inhibited GABA-elicited currents at both susceptible (CfRDL-A285) and resistant (CfRDL-S285) flea GABACls with similar potency. Initial whole organism screening was conducted in vitro using a blood feeding assay against C. felis. Compounds which demonstrated robust activity in the flea feed assay were subsequently tested in an in vitro ingestion assay against the soft tick, Ornithodoros turicata. Efficacious compounds which were confirmed safe in rodents at doses up to 30mg/kg were progressed to safety, PK and efficacy studies in dogs. In vitro sarolaner demonstrated an LC80 of 0.3μg/mL against C. felis and an LC100 of 0.003μg/mL against O. turicata. In a head-to-head comparative in vitro assay with both afoxolaner and fluralaner, sarolaner demonstrated superior flea and tick potency. In exploratory safety studies in dogs, sarolaner demonstrated safety in dogs≥8 weeks of age upon repeated monthly dosing at up to 20mg/kg. Sarolaner was rapidly and well absorbed following oral dosing. Time to maximum plasma concentration occurred within the first day post-dose. Bioavailability for sarolaner was calculated at >85% and the compound was highly protein bound (>99.9%). The half-life for sarolaner was calculated at 11–12 days. Sarolaner plasma concentrations indicated dose proportionality over the range 1.25–5mg/kg, and these same doses provided robust efficacy (>99%) for ≥35days against both fleas (C. felis) and multiple species of ticks (Rhipicephalus sanguineus, Ixodes ricinus and Dermacentor reticulatus) after oral administration to dogs. As a result of these exploratory investigations, sarolaner was progressed for development as an oral monthly dose for treatment and control of fleas and ticks on dogs

Nightside clouds and disequilibrium chemistry on the hot Jupiter WASP-43b

Hot Jupiters are among the best-studied exoplanets, but it is still poorly understood how their chemical composition and cloud properties vary with longitude. Theoretical models predict that clouds may condense on the nightside and that molecular abundances can be driven out of equilibrium by zonal winds. Here we report a phase-resolved emission spectrum of the hot Jupiter WASP-43b measured from 5 μm to 12 μm with the JWST’s Mid-Infrared Instrument. The spectra reveal a large day–night temperature contrast (with average brightness temperatures of 1,524 ± 35 K and 863 ± 23 K, respectively) and evidence for water absorption at all orbital phases. Comparisons with three-dimensional atmospheric models show that both the phase-curve shape and emission spectra strongly suggest the presence of nightside clouds that become optically thick to thermal emission at pressures greater than ~100 mbar. The dayside is consistent with a cloudless atmosphere above the mid-infrared photosphere. Contrary to expectations from equilibrium chemistry but consistent with disequilibrium kinetics models, methane is not detected on the nightside (2σ upper limit of 1–6 ppm, depending on model assumptions). Our results provide strong evidence that the atmosphere of WASP-43b is shaped by disequilibrium processes and provide new insights into the properties of the planet’s nightside clouds. However, the remaining discrepancies between our observations and our predictive atmospheric models emphasize the importance of further exploring the effects of clouds and disequilibrium chemistry in numerical models.Peer reviewe

Nightside clouds and disequilibrium chemistry on the hot Jupiter WASP-43b

Hot Jupiters are among the best-studied exoplanets, but it is still poorly understood how their chemical composition and cloud properties vary with longitude. Theoretical models predict that clouds may condense on the nightside and that molecular abundances can be driven out of equilibrium by zonal winds. Here we report a phase-resolved emission spectrum of the hot Jupiter WASP-43b measured from 5-12 μm with JWST's Mid-Infrared Instrument (MIRI). The spectra reveal a large day-night temperature contrast (with average brightness temperatures of 1524±35 and 863±23 Kelvin, respectively) and evidence for water absorption at all orbital phases. Comparisons with three-dimensional atmospheric models show that both the phase curve shape and emission spectra strongly suggest the presence of nightside clouds which become optically thick to thermal emission at pressures greater than ~100 mbar. The dayside is consistent with a cloudless atmosphere above the mid-infrared photosphere. Contrary to expectations from equilibrium chemistry but consistent with disequilibrium kinetics models, methane is not detected on the nightside (2σ upper limit of 1-6 parts per million, depending on model assumptions)

Nightside clouds and disequilibrium chemistry on the hot Jupiter WASP-43b

Hot Jupiters are among the best-studied exoplanets, but it is still poorly understood how their chemical composition and cloud properties vary with longitude. Theoretical models predict that clouds may condense on the nightside and that molecular abundances can be driven out of equilibrium by zonal winds. Here we report a phase-resolved emission spectrum of the hot Jupiter WASP-43b measured from 5-12 $\mu$m with JWST's Mid-Infrared Instrument (MIRI). The spectra reveal a large day-night temperature contrast (with average brightness temperatures of 1524$\pm$35 and 863$\pm$23 Kelvin, respectively) and evidence for water absorption at all orbital phases. Comparisons with three-dimensional atmospheric models show that both the phase curve shape and emission spectra strongly suggest the presence of nightside clouds which become optically thick to thermal emission at pressures greater than ~100 mbar. The dayside is consistent with a cloudless atmosphere above the mid-infrared photosphere. Contrary to expectations from equilibrium chemistry but consistent with disequilibrium kinetics models, methane is not detected on the nightside (2$\sigma$ upper limit of 1-6 parts per million, depending on model assumptions).Comment: 61 pages, 13 figures, 4 tables. This preprint has been submitted to and accepted in principle for publication in Nature Astronomy without significant change

Early Release Science of the Exoplanet WASP-39b with JWST NIRSpec G395H

Measuring the abundances of carbon and oxygen in exoplanet atmospheres is considered a crucial avenue for unlocking the formation and evolution of exoplanetary systems. Access to an exoplanet's chemical inventory requires high-precision observations, often inferred from individual molecular detections with low-resolution space-based and high-resolution ground-based facilities. Here we report the medium-resolution (R$\sim$600) transmission spectrum of an exoplanet atmosphere between 3-5 $\mu$m covering multiple absorption features for the Saturn-mass exoplanet WASP-39b, obtained with JWST NIRSpec G395H. Our observations achieve 1.46x photon precision, providing an average transit depth uncertainty of 221 ppm per spectroscopic bin, and present minimal impacts from systematic effects. We detect significant absorption from CO$_2$ (28.5$\sigma$) and H$_2$O (21.5$\sigma$), and identify SO$_2$ as the source of absorption at 4.1 $\mu$m (4.8$\sigma$). Best-fit atmospheric models range between 3 and 10x solar metallicity, with sub-solar to solar C/O ratios. These results, including the detection of SO$_2$, underscore the importance of characterising the chemistry in exoplanet atmospheres, and showcase NIRSpec G395H as an excellent mode for time series observations over this critical wavelength range.Comment: 44 pages, 11 figures, 3 tables. Resubmitted after revision to Natur

Educational Choice: The Stratifying Effects of Selecting Schools and Courses

The current political climate of educational reform very actively focuses on the positive aspects of increasing parental choice of children's schools, but there is little discussion of (and scant empirical research on) the potentially negative effects of increasing choice. This article examines the rich empirical base on another aspect of choice in education-curriculum choice-to draw parallels between the potentially harmful effects of both types of choice. Specifically, it has been shown that a wide latitude of student choice of courses in high school magnifies the social stratification of educational outcomes. This socially undesirable consequence results from two well-documented relationships: (a) Following a more demanding set of academic courses in high school is strongly and positively associated with higher academic achievement, and (b) less advantaged students are considerably less likely to select such a demanding course of study than are their more academically and socially advantaged counterparts. Additionally, academically and socially disadvantaged students and their families are less likely to seek out, or have access to, information about the consequences of their choices (of either schools or courses). If our society is unwilling to accept any educational reform that increases the inequitable distribution of educational outcomes among diverse social and racial groups, as is argued in this article, then we must take a hard look at the possible effects of school choice in this regard.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67622/2/10.1177_0895904893007002001.pd