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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.

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 H 2 O 2 , leading to parasite killing. This detailed understanding of the mechanism paves the way to rationally re-designed 8-aminoquinolines with improved pharmacological profiles. Primaquine (PQ) is a widely used anti-malaria drug, but its mechanism of action is unclear. Here, Camarda et al. show that PQ’s activity against liver and sexual Plasmodium stages depends on generation of hydroxylated-PQ metabolites (OH-PQm), which, undergoing further reactions, results in production of H 2 O 2 .

We obtained high-resolution spectra of Jupiter between 4.6 and 5.4 µm using NIRSPEC on the Keck 2 telescope in February 2017. We measured the spatial variation of NH3, H2O, and the pressure level of deep (p > 3 bar) clouds using two geometries. We aligned the slit north–south on Jupiter’s Central Meridian to measure the spatial variation of the gas composition and cloud structure between 66°N and 70°S. With the slit aligned east–west, we also examined the longitudinal variation at two regions of the North Equatorial Belt (NEB) at 18°N and at 8°N near the latitude of the Galileo Probe entry site. We used the integrated line absorption, also known as the equivalent width, of deuterated methane (CH3D) at 4.66 µm to derive the pressure level of deep clouds between 3 and 7 bar. From thermochemical models, these are most likely water clouds. At the location of a deep cloud revealed by HST methane-band imaging, we found spectroscopic evidence for an opaque cloud at the 5 bar level. We also identified regions on Jupiter that lacked deep clouds but exhibited evidence for upper clouds and enhanced NH3. We estimated column-averaged mole fractions of H2O and NH3 above the opaque lower boundary of the deep cloud. The meridional scan exhibited significant belt-zone structure with retrieved NH3 abundances in the 200–400 ppm range above the opaque lower cloud, except for a depletion (down to 90 ppm) in the NEB. Water in Jupiter’s belts varies from a maximum of 7 ppm at 8°S to a minimum of 1.5 ppm at 23°S. We found evidence for water clouds and enhanced NH3 and H2O in the South Equatorial Belt Outbreak region at 13°S. The NEB is a heterogeneous region with significant variation in all of these quantities. The NH3 abundance at 18°N and 8°N varies with the longitude with mole fractions between 120 and 300 ppm. The H2O abundance at these same latitudes varies with the longitude with mole fractions between 3 and 10 ppm. Our volatile mole fractions apply to the 5 to 8 bar pressure range (or to the level of an opaque cloud top where found at shallower pressure); therefore, they imply a deeper gradient continuing to increase toward higher concentrations detected by the Galileo Probe Mass Spectrometer at 11 and 20 bar. Hot Spots in the NEB exhibit minimal cloud opacity; however, they lack prominent anomalies in the concentrations of NH3 or H2O.

Jupiter’s atmospheric water abundance is a highly important cosmochemical parameter that is linked to processes of planetary formation, weather, and circulation. Remote sensing and in situ measurement attempts still leave room for substantial improvements to our knowledge of Jupiter’s atmospheric water abundance. With the motivation to advance our understanding of water in Jupiter’s atmosphere, we investigate observations and models of deep clouds. We discuss deep clouds in isolated convective storms (including a unique storm site in the North Equatorial Belt that episodically erupted in 2021–2022), cyclonic vortices, and northern high-latitude regions, as seen in Hubble Space Telescope visible/near-infrared imaging data. We evaluate the imaging data in continuum and weak methane band (727 nm) filters by comparison with radiative transfer simulations, 5 micron imaging (Gemini), and 5 micron spectroscopy (Keck), and conclude that the weak methane band imaging approach mostly detects variation in the upper cloud and haze opacity, although sensitivity to deeper cloud layers can be exploited if upper cloud/haze opacity can be separately constrained. The cloud-base water abundance is a function of cloud-base temperature, which must be estimated by extrapolating 0.5-bar observed temperatures downward to the condensation region near 5 bar. For a given cloud base pressure, the largest source of uncertainty on the local water abundance comes from the temperature gradient used for the extrapolation. We conclude that spatially resolved spectra to determine cloud heights—collected simultaneously with spatially-resolved mid-infrared spectra to determine 500-mbar temperatures and with improved lapse rate estimates—would be needed to answer the following very challenging question: Can observations of deep water clouds on Jupiter be used to constrain the atmospheric water abundance?

Background: Pickleball is one of the fastest growing sports, and the use of virtual reality is also fast growing. Because the physiological responses in real life (IRL) vs. virtual reality are unknown, the purpose of this research was to compare heart rate, metabolic and pulmonary measures IRL vs. mixed reality (MR) during pickleball activity. Methods: Eleven adult participants were outfitted with a portable metabolic unit, heart rate monitor, and virtual reality headsets. Participants played simulated pickleball for 5 min IRL and 5 min in MR. Dependent variables included average heart rate (HR [beats per minute (bpm)], ventilation (VE [L/min]), tidal volume (VT [L]), respiratory frequency (Rf [breaths per min]), respiratory exchange ratio (RER), percent of calories from fat (FAT%), percent of calories from carbohydrate (CHO%), energy expenditure (EE [kilocalorie (kcal]), and VO2 (mL/kg/min). Data were analyzed using paired t-tests with significance accepted at p < 0.05. Effect size measurements were determined by interpretation of small (d = 0.2), medium (d = 0.5), and large (d = 0.8). Results: All metabolic and pulmonary variables except for FAT% were higher during IRL when compared with MR with effect sizes ranging from median to large. Conclusions: The results of this study provide evidence that playing pickleball IRL results in greater physiological responses in comparison to MR. Since MR demands less exertion and substrate use than IRL this result can be beneficial for training purposes with the added potential of reduced injury.

Metabolic analysis systems require binary sex input, conflating biological sex with gender, limiting inclusivity. This study aimed to determine whether sex input altered metabolic or pulmonary variables during self-paced walking and running. Twenty adults completed two 5-min walking and running trials under both female (FC) and male (MC) input conditions in randomized order. Dependent t-tests determined differences between conditions; p-values < 0.05 were considered significant, and effect sizes were calculated. No significant within-participant differences were found between FC and MC for any variable. During walking, mean relative VO2 (mL/kg/min) was 11.13 ± 2.73 (FC) and 10.81 ± 2.39 (MC), p = 0.08, R2 = 0.93; mean energy expenditure (kcal) was 18.28 ± 4.74 (FC) and 17.86 ± 4.33 (MC), p = 0.12, R2 = 0.94. During running, mean relative VO2 was 28.80 ± 5.89 (FC) and 28.82 ± 6.06 (MC), p = 0.90, R2 = 0.98; mean energy expenditure was 45.79 ± 13.08 (FC) and 45.55 ± 12.26 (MC), p = 0.99, R2 = 0.98. Binary sex input in the TrueOne 2400 system did not affect variables, supporting inclusive sex and gender data collection to improve research ethics, accuracy, and representation of gender-diverse people without compromising integrity.

Each of the giant planets, Jupiter, Saturn, Uranus, and Neptune, has been observed by at least one robotic spacecraft mission. However, these missions are infrequent; Uranus and Neptune have only had a single flyby by Voyager 2. The Hubble Space Telescope, particularly the Wide Field Camera 3 (WFC3) and Advanced Camera for Surveys (ACS) instruments, and large ground-based telescopes with adaptive optics systems have enabled high spatial resolution imaging at a higher cadence, and over a longer time, than can be achieved with targeted missions to these worlds. These facilities offer a powerful combination of high spatial resolution, often <0.05”, and broad wavelength coverage, from the ultraviolet through the near infrared, resulting in compelling studies of the clouds, winds, and atmospheric vertical structure. This coverage allows comparisons of atmospheric properties between the planets, as well as in different regions across each planet. Temporal variations in winds, cloud structure, and color over time scales of days to years, have been measured for all four planets. With several decades of data already obtained, we can now begin to investigate seasonal influences on dynamics and aerosol properties, despite orbital periods ranging from 12 to 165 years. Future facilities will enable even greater spatial resolution and, combined with our existing long record of data, will continue to advance our understanding of atmospheric evolution on the giant planets.

Background: Children with asthma may have a reduced ventilatory capacity, which could lead to symptoms and early termination of a cardiopulmonary exercise test (CPET). The purpose of this study was to examine the effects of short-acting beta agonist (albuterol) administration on estimated ventilatory capacity in children with asthma. Methods: Fifteen children (eleven boys, 10.6 ± 0.9 years) completed spirometry at baseline, after 180 µg of albuterol, and after the CPET in this cross-sectional study. Ventilatory capacity was calculated from forced vital capacity (FVC) and isovolume forced expiratory time from 25 to 75% of FVC (isoFET25–75) as follows: FVC/2 × [60/(2 × isoFET25–75)]. Differences in outcome variables between baseline, after albuterol administration, and after the CPET were detected with repeated measures mixed models with Bonferroni post hoc corrections. Results: Estimated ventilatory capacity was higher after albuterol (68.7 ± 21.2 L/min) and after the CPET (75.8 ± 25.6 L/min) when compared with baseline (60.9 ± 22.0 L/min; P = 0.003). Because forced vital capacity did not change, the increased ventilatory capacity was primarily due to a decrease in isoFET25–75 (i.e., an increase in mid-flows or isoFEF25–75). Conclusion: Albuterol administration could be considered prior to CPET for children with asthma with relatively well-preserved FEV1 values to increase ventilatory capacity pre-exercise and potentially avoid symptom-limited early termination of testing.

Although many bacterial lipases and PHA depolymerases have been identified, cloned, and characterized, there is very little information on the potential application of lipases and PHA depolymerases, especially intracellular enzymes, for the degradation of polyester polymers/plastics. We identified genes encoding an intracellular lipase (LIP3), an extracellular lipase (LIP4), and an intracellular PHA depolymerase (PhaZ) in the genome of the bacterium Pseudomonas chlororaphis PA23. We cloned these genes into Escherichia coli and then expressed, purified, and characterized the biochemistry and substrate preferences of the enzymes they encode. Our data suggest that the LIP3, LIP4, and PhaZ enzymes differ significantly in their biochemical and biophysical properties, structural-folding characteristics, and the absence or presence of a lid domain. Despite their different properties, the enzymes exhibited broad substrate specificity and were able to hydrolyze both short- and medium-chain length polyhydroxyalkanoates (PHAs), para-nitrophenyl (pNP) alkanoates, and polylactic acid (PLA). Gel Permeation Chromatography (GPC) analyses of the polymers treated with LIP3, LIP4, and PhaZ revealed significant degradation of both the biodegradable as well as the synthetic polymers poly(ε-caprolactone) (PCL) and polyethylene succinate (PES).

Hsp70 binding protein 1 (HspBP1) and Bcl2-associated athanogene 1 (BAG-1), the functional orthologous nucleotide exchange factors of the heat shock protein 70 kilodalton (Hsc70/Hsp70) chaperones, catalyze the release of ADP from Hsp70 while inducing different conformational changes of the ATPase domain of Hsp70. An appropriate exchange rate of ADP/ATP is crucial for chaperone-dependent protein folding processes. Among Hsp70 client proteins are steroid receptors such as the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR), and the androgen receptor (AR). BAG-1 diversely affects steroid receptor activity, while to date the influence of HspBP1 on steroid receptor function is mostly unknown. Here, we compared the influence of HspBP1 and BAG-1M on Hsp70-mediated steroid receptor folding complexes and steroid receptor activity. Coimmunoprecipitation studies indicated preferential binding of Hsp40 and the steroid receptors to BAG-1M as compared to HspBP1. Furthermore, Hsp70 binding to the ligand-binding domain of GR was reduced in the presence of HspBP1 but not in the presence of BAG-1M as shown by pull-down assays. Reporter gene experiments revealed an inhibitory effect on GR, MR, and AR at a wide range of HspBP1 protein levels and at hormone concentrations at or approaching saturation. BAG-1M exhibited a transition from stimulatory effects at low BAG-1M levels to inhibitory effects at higher BAG-1M levels. Overall, BAG-1M and HspBP1 had differential impacts on the dynamic composition of steroid receptor folding complexes and on receptor function with important implications for steroid receptor physiology.