Artemisinin activity-based probes identify multiple molecular targets within the asexual stage of the malaria parasites Plasmodium falciparum 3D7.

The artemisinin (ART)-based antimalarials have contributed significantly to reducing global malaria deaths over the past decade, but we still do not know how they kill parasites. To gain greater insight into the potential mechanisms of ART drug action, we developed a suite of ART activity-based protein profiling probes to identify parasite protein drug targets in situ. Probes were designed to retain biological activity and alkylate the molecular target(s) of Plasmodium falciparum 3D7 parasites in situ. Proteins tagged with the ART probe can then be isolated using click chemistry before identification by liquid chromatography-MS/MS. Using these probes, we define an ART proteome that shows alkylated targets in the glycolytic, hemoglobin degradation, antioxidant defense, and protein synthesis pathways, processes essential for parasite survival. This work reveals the pleiotropic nature of the biological functions targeted by this important class of antimalarial drugs.

Uranus's northern polar cap in 2014.

In October and November 2014, spectra covering the 1.436 - 1.863-µm wavelength range from the SINFONI Integral Field Unit Spectrometer on the Very Large Telescope showed the presence of a vast bright North polar cap on Uranus, extending northward from about 40°N and at all longitudes observed. The feature, first detected in August 2014 from Keck telescope images, has a morphology very similar to the southern polar cap that was seen to fade before the 2007 equinox. At strong methane-absorbing wavelengths (for which only the high troposphere or stratosphere is sampled) the feature is not visible, indicating that it is not a stratospheric phenomenon. We show that the observed northern bright polar cap results mainly from a decrease in the tropospheric methane mixing ratio, rather than from a possible latitudinal variation of the optical properties or abundance of aerosol, implying an increase in polar downwelling near the tropopause level.

Integrated transcriptomic and proteomic analyses uncover regulatory roles of Nrf2 in the kidney.

The transcription factor Nrf2 exerts protective effects in numerous experimental models of acute kidney injury, and is a promising therapeutic target in chronic kidney disease. To provide a detailed insight into the regulatory roles of Nrf2 in the kidney, we performed integrated transcriptomic and proteomic analyses of kidney tissue from wild-type and Nrf2 knockout mice treated with the Nrf2 inducer methyl-2-cyano-3,12-dioxooleano-1,9-dien-28-oate (CDDO-Me, also known as bardoxolone methyl). After 24 h, analyses identified 2561 transcripts and 240 proteins that were differentially expressed in the kidneys of Nrf2 knockout mice, compared with those of wild-type counterparts, and 3122 transcripts and 68 proteins that were differentially expressed in wild-type mice treated with CDDO-Me, compared with those of vehicle control. In the light of their sensitivity to genetic and pharmacological modulation of renal Nrf2 activity, genes/proteins that regulate xenobiotic disposition, redox balance, the intra/extracellular transport of small molecules, and the supply of NADPH and other cellular fuels were found to be positively regulated by Nrf2 in the kidney. This was verified by qPCR, immunoblotting, pathway analysis, and immunohistochemistry. In addition, the levels of NADPH and glutathione were found to be significantly decreased in the kidneys of Nrf2 knockout mice. Thus, Nrf2 regulates genes that coordinate homeostatic processes in the kidney, highlighting its potential as a novel therapeutic target.

Multiple Probe Measurements at Uranus Motivated by Spatial Variability.

A major motivation for multiple atmospheric probe measurements at Uranus is the understanding of dynamic processes that create and maintain spatial variation in thermal structure, composition, and horizontal winds. But origin questions-regarding the planet's formation and evolution, and conditions in the protoplanetary disk-are also major science drivers for multiprobe exploration. Spatial variation in thermal structure reveals how the atmosphere transports heat from the interior, and measuring compositional variability in the atmosphere is key to ultimately gaining an understanding of the bulk abundances of several heavy elements. We review the current knowledge of spatial variability in Uranus' atmosphere, and we outline how multiple probe exploration would advance our understanding of this variability. The other giant planets are discussed, both to connect multiprobe exploration of those atmospheres to open questions at Uranus, and to demonstrate how multiprobe exploration of Uranus itself is motivated by lessons learned about the spatial variation at Jupiter, Saturn, and Neptune. We outline the measurements of highest value from miniature secondary probes (which would complement more detailed investigation by a larger flagship probe), and present the path toward overcoming current challenges and uncertainties in areas including mission design, cost, trajectory, instrument maturity, power, and timeline.

Primordial argon isotope fractionation in the atmosphere of Mars measured by the SAM instrument on Curiosity and implications for atmospheric loss.

[1] The quadrupole mass spectrometer of the Sample Analysis at Mars (SAM) instrument on Curiosity rover has made the first high-precision measurement of the nonradiogenic argon isotope ratio in the atmosphere of Mars. The resulting value of 36Ar/38Ar = 4.2 ± 0.1 is highly significant for it provides excellent evidence that "Mars" meteorites are indeed of Martian origin, and it points to a significant loss of argon of at least 50% and perhaps as high as 85-95% from the atmosphere of Mars in the past 4 billion years. Taken together with the isotopic fractionations in N, C, H, and O measured by SAM, these results imply a substantial loss of atmosphere from Mars in the posthydrodynamic escape phase.

Isotopes of nitrogen on Mars: Atmospheric measurements by Curiosity's mass spectrometer.

[1] The Sample Analysis at Mars (SAM) instrument suite on the Mars Science Laboratory (MSL) measured a Mars atmospheric14N/15N ratio of 173 ± 11 on sol 341 of the mission, agreeing with Viking's measurement of 168 ± 17. The MSL/SAM value was based on Quadrupole Mass Spectrometer measurements of an enriched atmospheric sample, with CO2 and H2O removed. Doubly ionized nitrogen data at m/z 14 and 14.5 had the highest signal/background ratio, with results confirmed by m/z 28 and 29 data. Gases in SNC meteorite glasses have been interpreted as mixtures containing a Martian atmospheric component, based partly on distinctive14N/15N and40Ar/14N ratios. Recent MSL/SAM measurements of the40Ar/14N ratio (0.51 ± 0.01) are incompatible with the Viking ratio (0.35 ± 0.08). The meteorite mixing line is more consistent with the atmospheric composition measured by Viking than by MSL.

Hydrogen peroxide at the poles of Ganymede.

Ganymede is the only satellite in the solar system known to have an intrinsic magnetic field. Interactions between this field and the Jovian magnetosphere are expected to funnel most of the associated impinging charged particles, which radiolytically alter surface chemistry across the Jupiter system, to Ganymede's polar regions. Using observations obtained with JWST as part of the Early Release Science program exploring the Jupiter system, we report the discovery of hydrogen peroxide, a radiolysis product of water ice, specifically constrained to the high latitudes. This detection directly implies radiolytic modification of the polar caps by precipitation of Jovian charged particles along partially open field lines within Ganymede's magnetosphere. Stark contrasts between the spatial distribution of this polar hydrogen peroxide, those of Ganymede's other radiolytic oxidants, and that of hydrogen peroxide on neighboring Europa have important implications for understanding water-ice radiolysis throughout the solar system.

A low density of 0.8 g cm(-3) for the Trojan binary asteroid 617 Patroclus.

The Trojan population consists of two swarms of asteroids following the same orbit as Jupiter and located at the L4 and L5 stable Lagrange points of the Jupiter-Sun system (leading and following Jupiter by 60 degrees ). The asteroid 617 Patroclus is the only known binary Trojan. The orbit of this double system was hitherto unknown. Here we report that the components, separated by 680 km, move around the system's centre of mass, describing a roughly circular orbit. Using this orbital information, combined with thermal measurements to estimate the size of the components, we derive a very low density of 0.8(- 0.1)+0.2 g cm(-3). The components of 617 Patroclus are therefore very porous or composed mostly of water ice, suggesting that they could have been formed in the outer part of the Solar System.

The depth of Jupiter's Great Red Spot constrained by Juno gravity overflights.

Jupiter's Great Red Spot (GRS) is the largest atmospheric vortex in the Solar System and has been observed for at least two centuries. It has been unclear how deep the vortex extends beneath its visible cloud tops. We examined the gravity signature of the GRS using data from 12 encounters of the Juno spacecraft with the planet, including two direct overflights of the vortex. Localized density anomalies due to the presence of the GRS caused a shift in the spacecraft line-of-sight velocity. Using two different approaches to infer the GRS depth, which yielded consistent results, we conclude that the GRS is contained within the upper 500 kilometers of Jupiter's atmosphere.

A Survey of Small-Scale Waves and Wave-Like Phenomena in Jupiter's Atmosphere Detected by JunoCam.

In the first 20 orbits of the Juno spacecraft around Jupiter, we have identified a variety of wave-like features in images made by its public-outreach camera, JunoCam. Because of Juno's unprecedented and repeated proximity to Jupiter's cloud tops during its close approaches, JunoCam has detected more wave structures than any previous surveys. Most of the waves appear in long wave packets, oriented east-west and populated by narrow wave crests. Spacing between crests were measured as small as ~30 km, shorter than any previously measured. Some waves are associated with atmospheric features, but others are not ostensibly associated with any visible cloud phenomena and thus may be generated by dynamical forcing below the visible cloud tops. Some waves also appear to be converging, and others appear to be overlapping, possibly at different atmospheric levels. Another type of wave has a series of fronts that appear to be radiating outward from the center of a cyclone. Most of these waves appear within 5° of latitude from the equator, but we have detected waves covering planetocentric latitudes between 20°S and 45°N. The great majority of the waves appear in regions associated with prograde motions of the mean zonal flow. Juno was unable to measure the velocity of wave features to diagnose the wave types due to its close and rapid flybys. However, both by our own upper limits on wave motions and by analogy with previous measurements, we expect that the waves JunoCam detected near the equator are inertia-gravity waves.

Antimalarial activity of primaquine operates via a two-step biochemical relay.

Primaquine (PQ) is an essential antimalarial drug but despite being developed over 70 years ago, its mode of action is unclear. Here, we demonstrate that hydroxylated-PQ metabolites (OH-PQm) are responsible for efficacy against liver and sexual transmission stages of Plasmodium falciparum. The antimalarial activity of PQ against liver stages depends on host CYP2D6 status, whilst OH-PQm display direct, CYP2D6-independent, activity. PQ requires hepatic metabolism to exert activity against gametocyte stages. OH-PQm exert modest antimalarial efficacy against parasite gametocytes; however, potency is enhanced ca.1000 fold in the presence of cytochrome P450 NADPH:oxidoreductase (CPR) from the liver and bone marrow. Enhancement of OH-PQm efficacy is due to the direct reduction of quinoneimine metabolites by CPR with the concomitant and excessive generation of H2O2, leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles.

A New, Long-Lived, Jupiter Mesoscale Wave Observed at Visible Wavelengths.

Small-scale waves were observed along the boundary between Jupiter's North Equatorial Belt and North Tropical Zone, ~16.5° N planetographic latitude in Hubble Space Telescope data in 2012 and throughout 2015 to 2018, observable at all wavelengths from the UV to the near IR. At peak visibility, the waves have sufficient contrast (~10%) to be observed from ground-based telescopes. They have a typical wavelength of about 1.2° (1400 km), variable-length wave trains, and westward phase speeds of a few m/s or less. New analysis of Voyager 2 data shows similar wave trains over at least 300 hours. Some waves appear curved when over cyclones and anticyclones, but most are straight, but tilted, shifting in latitude as they pass vortices. Based on their wavelengths, phase speeds, and faint appearance at high-altitude sensitive passbands, the observed NEB waves are consistent with inertia-gravity waves at the 500-mbar pressure level, though formation altitude is not well constrained. Preliminary General Circulation Model simulations generate inertia-gravity waves from vortices interacting with the environment and can reproduce the observed wavelengths and orientations. Several mechanisms can generate these waves, and all may contribute: geostrophic adjustment of cyclones; cyclone/anticyclone interactions; wind interactions with obstructions or heat pulses from convection; or changing vertical wind shear. However, observations also show that the presence of vortices and/or regions of convection are not sufficient by themselves for wave formation, implying that a change in vertical structure may affect their stability, or that changes in haze properties may affect their visibility.

Background levels of methane in Mars' atmosphere show strong seasonal variations.

Variable levels of methane in the martian atmosphere have eluded explanation partly because the measurements are not repeatable in time or location. We report in situ measurements at Gale crater made over a 5-year period by the Tunable Laser Spectrometer on the Curiosity rover. The background levels of methane have a mean value 0.41 ± 0.16 parts per billion by volume (ppbv) (95% confidence interval) and exhibit a strong, repeatable seasonal variation (0.24 to 0.65 ppbv). This variation is greater than that predicted from either ultraviolet degradation of impact-delivered organics on the surface or from the annual surface pressure cycle. The large seasonal variation in the background and occurrences of higher temporary spikes (~7 ppbv) are consistent with small localized sources of methane released from martian surface or subsurface reservoirs.

A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance.

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.

Peering through Jupiter's clouds with radio spectral imaging.

Radio wavelengths can probe altitudes in Jupiter's atmosphere below its visible cloud layers. We used the Very Large Array to map this unexplored region down to ~8 bar, ~100 kilometers below the visible clouds. Our maps reveal a dynamically active planet at pressures less than 2 to 3 bar. A radio-hot belt exists, consisting of relatively transparent regions (a low ammonia concentration, NH3 being the dominant source of opacity) probing depths to over ~8 bar; these regions probably coincide with 5-micrometer hot spots. Just to the south we distinguish an equatorial wave, bringing up ammonia gas from Jupiter's deep atmosphere. This wave has been theorized to produce the 5-micrometer hot spots; we observed the predicted radio counterpart of such hot spots.

NEPTUNE'S DYNAMIC ATMOSPHERE FROM KEPLER K2 OBSERVATIONS: IMPLICATIONS FOR BROWN DWARF LIGHT CURVE ANALYSES.

Observations of Neptune with the Kepler Space Telescope yield a 49 day light curve with 98% coverage at a 1 minute cadence. A significant signature in the light curve comes from discrete cloud features. We compare results extracted from the light curve data with contemporaneous disk-resolved imaging of Neptune from the Keck 10-m telescope at 1.65 microns and Hubble Space Telescope visible imaging acquired nine months later. This direct comparison validates the feature latitudes assigned to the K2 light curve periods based on Neptune's zonal wind profile, and confirms observed cloud feature variability. Although Neptune's clouds vary in location and intensity on short and long timescales, a single large discrete storm seen in Keck imaging dominates the K2 and Hubble light curves; smaller or fainter clouds likely contribute to short-term brightness variability. The K2 Neptune light curve, in conjunction with our imaging data, provides context for the interpretation of current and future brown dwarf and extrasolar planet variability measurements. In particular we suggest that the balance between large, relatively stable, atmospheric features and smaller, more transient, clouds controls the character of substellar atmospheric variability. Atmospheres dominated by a few large spots may show inherently greater light curve stability than those which exhibit a greater number of smaller features.

Design and Synthesis of Irreversible Analogues of Bardoxolone Methyl for the Identification of Pharmacologically Relevant Targets and Interaction Sites.

Semisynthetic triterpenoids such as bardoxolone methyl (methyl-2-cyano 3,12-dioxooleano-1,9-dien-28-oate; CDDO-Me) (4) are potent inducers of antioxidant and anti-inflammatory signaling pathways, including those regulated by the transcription factor Nrf2. However, the reversible nature of the interaction between triterpenoids and thiols has hindered attempts to identify pharmacologically relevant targets and characterize the sites of interaction. Here, we report a shortened synthesis and SAR profiling of 4, enabling the design of analogues that react irreversibly with model thiols, as well as the model protein glutathione S-transferase P1, in vitro. We show that one of these analogues, CDDO-epoxide (13), is comparable to 4 in terms of cytotoxicity and potency toward Nrf2 in rat hepatoma cells and stably modifies specific cysteine residues (namely, Cys-257, -273, -288, -434, -489, and -613) within Keap1, the major repressor of Nrf2, both in vitro and in living cells. Supported by molecular modeling, these data demonstrate the value of 13 for identifying site(s) of interaction with pharmacologically relevant targets and informing the continuing development of triterpenoids as novel drug candidates.

Widespread morning drizzle on Titan.

Precipitation is expected in Titan's atmosphere, yet it has not been directly observed, and the geographical regions where rain occurs are unknown. Here we present near-infrared spectra from the Very Large Telescope and W. M. Keck Observatories that reveal an enhancement of opacity in Titan's troposphere on the morning side of the leading hemisphere. Retrieved extinction profiles are consistent with condensed methane in clouds at an altitude near 30 kilometers and concomitant methane drizzle below. The moisture encompasses the equatorial region over Titan's brightest continent, Xanadu. Diurnal temperature gradients that cause variations in methane relative humidity, winds, and topography may each be a contributing factor to the condensation mechanism. The clouds and precipitation are optically thin at 2.0 micrometers, and models of "subvisible" clouds suggest that the droplets are 0.1 millimeter or larger.