Drug resistance remains a major obstacle to malaria control and eradication efforts, necessitating the development of novel therapeutic strategies to treat this disease. Drug combinations based on ...collateral sensitivity, wherein resistance to one drug causes increased sensitivity to the partner drug, have been proposed as an evolutionary strategy to suppress the emergence of resistance in pathogen populations. In this study, we explore collateral sensitivity between compounds targeting the Plasmodium dihydroorotate dehydrogenase (DHODH). We profiled the cross-resistance and collateral sensitivity phenotypes of several DHODH mutant lines to a diverse panel of DHODH inhibitors. We focus on one compound, TCMDC-125334, which was active against all mutant lines tested, including the DHODH C276Y line, which arose in selections with the clinical candidate DSM265. In six selections with TCMDC-125334, the most common mechanism of resistance to this compound was copy number variation of the dhodh locus, although we did identify one mutation, DHODH I263S, which conferred resistance to TCMDC-125334 but not DSM265. We found that selection of the DHODH C276Y mutant with TCMDC-125334 yielded additional genetic changes in the dhodh locus. These double mutant parasites exhibited decreased sensitivity to TCMDC-125334 and were highly resistant to DSM265. Finally, we tested whether collateral sensitivity could be exploited to suppress the emergence of resistance in the context of combination treatment by exposing wildtype parasites to both DSM265 and TCMDC-125334 simultaneously. This selected for parasites with a DHODH V532A mutation which were cross-resistant to both compounds and were as fit as the wildtype parent in vitro. The emergence of these cross-resistant, evolutionarily fit parasites highlights the mutational flexibility of the DHODH enzyme.
Returning humans to the Moon presents an unprecedented opportunity to determine the origin of volatiles stored in the permanently shaded regions (PSRs), which trace the history of lunar volcanic ...activity, solar wind surface chemistry, and volatile delivery to the Earth and Moon through impacts of comets, asteroids, and micrometeoroids. So far, the source of the volatiles sampled by the Lunar Crater Observation and Sensing Satellite (LCROSS) plume has remained undetermined. We show here that the source could not be volcanic outgassing and the composition is best explained by cometary impacts. Ruling out a volcanic source means that volatiles in the top 1-3 meters of the Cabeus PSR regolith may be younger than the latest volcanic outgassing event (~1 billion years ago; Gya).
The existence of methane in Titan's atmosphere (~6% level at the surface) presents a unique enigma, as photochemical models predict that the current inventory will be entirely depleted by ...photochemistry in a timescale of ~20 Myr. In this paper, we examine the clues available from isotopic ratios ( super(12)C/ super(13)C and D/H) in Titan's methane as to the past atmosphere history of this species. We first analyze recent infrared spectra of CH sub(4) collected by the Cassini Composite Infrared Spectrometer, measuring simultaneously for the first time the abundances of all three detected minor isotopologues: super(13)CH sub(4), super(12)CH sub(3)D, and super(13)CH sub(3)D. From these we compute estimates of super(12)C/ super(13)C = 86.5 + or - 8.2 and D/H = (1.59 + or - 0.33) x 10 super(-4), in agreement with recent results from the Huygens GCMS and Cassini INMS instruments. We also use the transition state theory to estimate the fractionation that occurs in carbon and hydrogen during a critical reaction that plays a key role in the chemical depletion of Titan's methane: CH sub(4) + C sub(2)H arrow right CH sub(3) + C sub(2)H sub(2). Using these new measurements and predictions we proceed to model the time evolution of super(12)C/ super(13)C and D/H in Titan's methane under several prototypical replenishment scenarios. In our Model 1 (no resupply of CH sub(4)), we find that the present-day super(12)C/ super(13)C implies that the CH sub(4) entered the atmosphere 60-1600 Myr ago if methane is depleted by chemistry and photolysis alone, but much more recently-most likely less than 10 Myr ago-if hydrodynamic escape is also occurring. On the other hand, if methane has been continuously supplied at the replenishment rate then the isotopic ratios provide no constraints, and likewise for the case where atmospheric methane is increasing. We conclude by discussing how these findings may be combined with other evidence to constrain the overall history of the atmospheric methane.
Comets play a dual role in understanding the formation and evolution of the solar system. First, the composition of comets provides information about the origin of the giant planets and their moons ...because comets formed early and their composition is not expected to have evolved significantly since formation. They, therefore serve as a record of conditions during the early stages of solar system formation. Once comets had formed, their orbits were perturbed allowing them to travel into the inner solar system and impact the planets. In this way they contributed to the volatile inventory of planetary atmospheres. We review here how knowledge of comet composition up to the time of the Rosetta mission has contributed to understanding the formation processes of the giant planets, their moons and small icy bodies in the solar system. We also discuss how comets contributed to the volatile inventories of the giant and terrestrial planets.
Effects of solar EUV on positive ions and heavy negative charge carriers (molecular ions, aerosol, and/or dust) in Titan's ionosphere are studied over the course of almost 12 years, including 78 ...flybys below 1400 km altitude between TA (October 2004) and T120 (June 2016). The Radio and Plasma Wave Science/Langmuir Probe‐measured ion charge densities (normalized by the solar zenith angle) show statistically significant variations with respect to the solar EUV flux. Dayside charge densities increase by a factor of ≈2 from solar minimum to maximum, while nightside charge densities are found to anticorrelate with the EUV flux and decrease by a factor of ≈3–4. The overall EUV dependence of the ion charge densities suggest inapplicability of the idealized Chapman theory below 1200 km in Titan's ionosphere. Nightside charge densities are also found to vary along Titan's orbit, with higher values in the sunward magnetosphere of Saturn compared to the magnetotail.
Key Points
Ion and dust grain charge densities near the ionospheric peak enhanced while the peak altitudes are decreased by higher solar EUV flux
Ionospheric nightside charge densities decrease with higher solar EUV flux
Chapman theory not applicable for Titan's (dayside) ionosphere below 1200 km altitude
Plain Language Summary
Satun's moon Titan hosts a fully developed atmosphere of nitrogen and methane extending up to almost an entire Titan radius above the surface. The top atmosphere is ionized primarily by the solar radiation on the dayside and energetic particles on the nightside, initiating a complex organic chemistry. Effects of solar radiation on Titan's ionosphere are studied over the course of almost 12 years, (October 2004 to June 2016). The dayside ionospheric plasma densities (ions and charged dust grains) cannot be described by the Chapman theory. On the nightside, the plasma densities anticorrelate with the solar radiation flux, possibly due to photochemistry of the upper atmosphere being altered by the higher flux. Nightside plasma densities are also found to vary along Titan's orbit, with higher values in the sunward magnetosphere of Saturn compared to the magnetotail.
A detailed overview of the knowledge gaps in our understanding of the heliospheric interaction with the largely unexplored Very Local Interstellar Medium (VLISM) are provided along with predictions ...of with the scientific discoveries that await. The new measurements required to make progress in this expanding frontier of space physics are discussed and include in-situ plasma and pick-up ion measurements throughout the heliosheath, direct sampling of the VLISM properties such as elemental and isotopic composition, densities, flows, and temperatures of neutral gas, dust and plasma, and remote energetic neutral atom (ENA) and Lyman-alpha (LYA) imaging from vantage points that can uniquely discern the heliospheric shape and bring new information on the interaction with interstellar hydrogen. The implementation of a pragmatic Interstellar Probe mission with a nominal design life to reach 375 Astronomical Units (au) with likely operation out to 550 au are reported as a result of a 4-year NASA funded mission study.
ABSTRACT
The abundances of the heavy elements and isotopic ratios in the present atmospheres of the giant planets can be used to trace the composition of volatiles that were present in the icy solid ...material that contributed to their formation. The first definitive measurements of noble gas abundances and isotope ratios at comet 67P/Churyumov–Gerasimenko (67P/C–G) were recently published by Marty et al. (2017) and Rubin et al. (2018, 2019). The implications of these abundances for the formation conditions of the 67P/C–G building blocks were then evaluated by Mousis et al. (2018a). We add here an analysis of the implications of these results for understanding the formation conditions of the building blocks of the Ice Giants and discuss how future measurements of Ice Giant atmospheric composition can be interpreted. We first evaluate the best approach for comparing comet observations with giant planet composition, and then determine what would be the current composition of the Ice Giant atmospheres based on four potential sources for their building blocks. We provide four scenarios for the origin of the Ice Giants building blocks based on four primary constraints for building block composition: (1) the bulk abundance of carbon relative to nitrogen, (2) noble gas abundances relative to carbon and nitrogen, (3) abundance ratios Kr/Ar and Xe/Ar, and (4) Xe isotopic ratios. In situ measurements of these quantities by a Galileo-like entry probe in the atmosphere(s) of Uranus and/or Neptune should place important constraints on the formation conditions of the Ice Giants.
We identify the Plasmodium falciparum acetyl-coenzyme A synthetase (PfAcAS) as a druggable target, using genetic and chemical validation. In vitro evolution of resistance with two antiplasmodial ...drug-like compounds (MMV019721 and MMV084978) selects for mutations in PfAcAS. Metabolic profiling of compound-treated parasites reveals changes in acetyl-CoA levels for both compounds. Genome editing confirms that mutations in PfAcAS are sufficient to confer resistance. Knockdown studies demonstrate that PfAcAS is essential for asexual growth, and partial knockdown induces hypersensitivity to both compounds. In vitro biochemical assays using recombinantly expressed PfAcAS validates that MMV019721 and MMV084978 directly inhibit the enzyme by preventing CoA and acetate binding, respectively. Immunolocalization studies reveal that PfAcAS is primarily localized to the nucleus. Functional studies demonstrate inhibition of histone acetylation in compound-treated wild-type, but not in resistant parasites. Our findings identify and validate PfAcAS as an essential, druggable target involved in the epigenetic regulation of gene expression.
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•Mutations in PfAcAS confer resistance to antiplasmodials MMV019721 and MMV084978•MMV019721 and MMV084978 specifically inhibit PfAcAS by competing with substrates•cKD and IFA show PfAcAS is an essential nuclear enzyme in blood-stage parasites•PfAcAS inhibitors deplete parasite acetyl-CoA and result in histone hypoacetylation
Using chemogenomics, Summers et al. identify PfAcAS as the target of two antimalarial compounds, MMV019721 and MMV084978. PfAcAS is an essential, nuclear-localized enzyme responsible for acetyl-CoA biosynthesis in blood-stage parasites. Both compounds inhibit PfAcAS competitively and act by depleting acetyl-CoA and disrupting histone acetylation in the parasite.
The importance of the heavy ions and dust grains for the chemistry and aerosol formation in Titan's ionosphere has been well established in the recent years of the Cassini mission. In this study we ...combine independent in situ plasma (Radio Plasma and Wave Science Langmuir Probe (RPWS/LP)) and particle (Cassini Plasma Science Electron Spectrometer, Cassini Plasma Science Ion Beam Spectrometer, and Ion and Neutral Mass Spectrometer) measurements of Titan's ionosphere for selected flybys (T16, T29, T40, and T56) to produce altitude profiles of mean ion masses including heavy ions and develop a Titan‐specific method for detailed analysis of the RPWS/LP measurements (applicable to all flybys) to further constrain ion charge densities and produce the first empirical estimate of the average charge of negative ions and/or dust grains. Our results reveal the presence of an ion‐ion (dusty) plasma below ~1100 km altitude, with charge densities exceeding the primary ionization peak densities by a factor ≥2 in the terminator and nightside ionosphere (ne/ni ≤ 0.1). We suggest that ion‐ion (dusty) plasma may also be present in the dayside ionosphere below 900 km (ne/ni < 0.5 at 1000 km altitude). The average charge of the dust grains (≥1000 amu) is estimated to be between −2.5 and −1.5 elementary charges, increasing toward lower altitudes.
Key Points
Detection of electron‐depleted dusty ion‐ion plasma in lower ionosphere with enhanced densities
First empirical estimate of the negative ion and dust grain charge
Context. Collisions between cometary neutrals in the inner coma of a comet and cometary ions that have been picked up into the solar wind flow and return to the coma lead to the formation of a broad ...inner boundary known as a collisionopause. This boundary is produced by a combination of charge transfer and chemical reactions, both of which are important at the location of the collisionopause boundary. Four spacecraft measured ion densities and velocities in the inner region of comets, exploring the part of the coma where an ion-neutral collisionopause boundary is expected to form. Aims. The aims are to determine the dominant physics behind the formation of the ion-neutral collisionopause and to evaluate where this boundary has been observed by spacecraft. Methods. We evaluated observations from three spacecraft at four different comets to determine if a collisionopause boundary was observed based on the reported ion velocities. We compared the measured location of the ion-neutral collisionopause with measurements of the collision cross sections to evaluate whether chemistry or charge exchange are more important at the location where the collisionopause is observed. Results. Based on measurements of the cross sections for charge transfer and for chemical reactions, the boundary observed by Rosetta appears to be the location where chemistry becomes the more probable result of a collision between H2O and H2O+ than charge exchange. Comparisons with ion observations made by Deep Space 1 at 19P/Borrelly and Giotto at 1P/Halley and 26P/Grigg-Skjellerup show that similar boundaries were observed at 19P/Borrelly and 1P/Halley. The ion composition measurements made by Giotto at Halley confirm that chemistry becomes more important inside of this boundary and that electron-ion dissociative recombination is a driver for the reported ion pileup boundary.
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