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A new analysis of aurora observations of Ganymede's atmosphere on the orbital leading and trailing hemispheres has been recently published by Roth et al. (2021), suggesting that water is its main constituent near noon. Here, we present two additional aurora observations of Ganymede's sub-Jovian and anti-Jovian hemispheres, which suggest a modulation of the atmospheric H2O/O2 ratio on the moon's orbital period, and analyze the orbital evolution of the atmosphere. For this, we propose a reconstruction of aurora observations based on a physical modelling of the exosphere taking into account its orbital variability (the Exospheric Global Model; Leblanc et al., 2017). The solution described in this paper agrees with Roth et al. (2021) that Ganymede's exosphere should be dominantly composed of water molecules. From Ganymede's position when its leading hemisphere is illuminated to when it is its trailing hemisphere, the column density of O2 may vary between 4.3 × 1014 and 3.6 × 1014 cm−2 whereas the H2O column density should vary between 5.6 × 1014 and 1.3 × 1015 cm−2. The water content of Ganymede's atmosphere is essentially constrained by its sublimation rate whereas the O2 component of Ganymede's atmosphere is controlled by the radiolytic yield. The other species, products of the water molecules, vary in a more complex way depending on their sources, either as ejecta from the surface and/or as product of the dissociation of the other atmospheric constituents. Electron impact on H2O and H2 molecules is shown to likely produce H Lyman-alpha emissions close to Ganymede, in addition to the observed extended Lyman-alpha corona from H resonant scattering. All these conclusions being highly dependent on our capability to accurately model the origins of the observed Ganymede auroral emissions, modelling these emissions remains poorly constrained without an accurate knowledge of the Jovian magnetospheric and Ganymede ionospheric electron populations.

We compute the diagrammatic expansion of the particle-particle susceptibility via algorithmic Matsubara integration and compute the correlated pairing susceptibility in the thermodynamic limit of the 2D Hubbard Model. We study the static susceptibility and its dependence on the pair momentum $\mathbf{q}$ for a range of temperature, interaction strength, and chemical potential. We show that $d_{x^2-y^2}$-wave pairing is expected in the model in the $U/t\to 0^+ $ limit from direct perturbation theory. From this, we identify key second and third-order diagrams that support pairing processes and note that the diagrams responsible are not a part of charge or spin susceptibility expansions. We find two key components for pairing at momenta $(0,0)$ and $(\pi,\pi)$ that can be well fit as separate bosonic modes. We extract amplitudes and correlation length scales where we find a predominantly local $(\pi,\pi)$ pairing and non-local $\mathbf{q}=(0,0)$ pairs and present the relative weights of these modes for variation in temperature, doping, and interaction strength., Comment: 9 pages - 10 figures

We study the weak-coupling limit of the $t-t^\prime-U$ Hubbard model on a two-dimensional square lattice using a direct perturbative approach. Aided by symbolic computational tools, we compute the longitudinal density-density correlation functions in the $\chi_{\uparrow \uparrow}$ and $\chi_{\uparrow \downarrow}$ basis from which we can obtain the dynamical spin and charge susceptibilities at arbitrary doping and temperature. We find that for non-zero $t^\prime$, the zero frequency commensurate $\mathbf{q} = (\pi, \pi)$ spin and charge excitations are each strongest at different densities and we observe a clear behavioral change that appears tied to the van Hove singularity of the non-interacting dispersion upon which the perturbative expansion is built. We find a strongly reduced compressibility in the vicinity of the van Hove singularity as well as a behavioral change in the double occupancy. For finite $t^\prime$, the observed van Hove singularity occurs away from half-filling leading us to conclude that that this reduction in compressibility is distinct from Mott insulating physics that one expects in the strong-coupling regime. We compute the full dynamical spin and charge excitations and observe distinct structure for electron and hole doped scenarios in agreement with experiments on cuprate materials. Finally, we observe a peculiar splitting in spin and charge excitations in the vicinity of the van Hove singularity, the origin of which is traced to a splitting near the bottom of the band., Comment: Supplemental PDF supplied

Precise calculations of dynamics in the homogeneous electron gas (jellium model) are of fundamental importance for design and characterization of new materials. We introduce a diagrammatic Monte Carlo technique based on algorithmic Matsubara integration that allows us to compute frequency and momentum resolved finite temperature response directly in the real frequency domain using series of connected Feynman diagrams. The data for charge response at moderate electron density are used to extract the frequency dependence of the exchange-correlation kernel at finite momenta and temperature. These results are as important for development of the time-dependent density functional theory for materials dynamics as ground state energies are for the density functional theory., Main text: 5 pages, 5 figures; Supplemental: 2 pages, 4 figures

Accurate prediction of human clearance (CL) and volume of distribution at steady state (V

Peripheral neurotoxicity is a debilitating toxicity that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically-engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells to oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventative strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.

Sodium and, in a lesser way, potassium atomic components of surface-bounded exospheres are among the brightest elements that can be observed from the Earth in our Solar System. Both species have been intensively observed around Mercury, the Moon and the Galilean Moons. During the last decade, new observations have been obtained thanks to space missions carrying remote and in situ instrumentation that provide a completely original view of these species in the exospheres of Mercury and the Moon. They challenged our understanding and modelling of these exospheres and opened new directions of research by suggesting the need to better take into account the relationship between the surface-exosphere and the magnetosphere. In this paper, we first review the large set of observations of Mercury and the Moon Sodium and Potassium exospheres. In the second part, we list what it tells us on the sources and sinks of these exospheres focusing in particular on the role of their magnetospheres of these objects and then discuss, in a third section, how these observations help us to understand and identify the key drivers of these exospheres.

We present a method to accelerate the numerical evaluation of spatial integrals of Feynman diagrams when expressed on the real frequency axis. This can be realized through use of a renormalized perturbation expansion with a constant but complex renormalization shift. The complex shift acts as a regularization parameter for the numerical integration of otherwise sharp functions. This results in an exponential speed up of stochastic numerical integration at the expense of evaluating additional counter-term diagrams. We provide proof of concept calculations within a difficult limit of the half-filled 2D Hubbard model on a square lattice.

International audience; We model the impact of an extreme solar flare on the Mg+, Na+, O+ and He+ ion density distribution in Mercury’s magnetosphere. The Flare Irradiance Spectral Model of the solar irradiance during the X9.3-class flare on 6 September 2017 is used as input to the time-dependent Latmos Ionized Exosphere ion density model. We find that the time-evolution of the planetary ion distribution differs with respect to energy, location and species. There exist two ion energy populations on the dayside that experience different dynamical evolution. The peak ion density in the nightside plasma sheet is delayed by ∼7 − 8 minutes compared to the dayside. The maximum Mg+ density occurs ∼ 4 minutes before He+ and O+ in the whole magnetosphere. The time delay between different species does not necessarily occur for solar flares that erupt near the apparent solar limb, where the optical depth is large.

Brillouin light scattering spectroscopy was used to probe the room-temperature elasticity of crystalline high-T c superconductor Bi2Sr2CaCu2O8+δ . A complete set of best-estimate elastic constants was obtained using established relationships between acoustic phonon velocities and elastic constants along with a simple expression relating crystal elastic constant C 22 to the corresponding constants of the constituent incommensurate sublattices. This latter relationship, which was derived and validated in the present work, has important implications for those studying incommensurate systems as it appears that it may be applied in its general form to any composite incommensurate crystal. The results obtained in this work are also consistent with sublattice assignments of Bi2Sr2O4 and CaCu2O4 reported in a previous Brillouin scattering study.

International audience; BepiColombo Mio (previously called MMO: Mercury Magnetospheric Orbiter) was successfully launched by Ariane 5 from Kourou, French Guiana on October 20, 2018. The Mercury Plasma/Particle Experiment (MPPE) is a comprehensive instrument package onboard Mio spacecraft used for plasma, high-energy particle and energetic neutral atom measurements. It consists of seven sensors including two Mercury Electron Analyzers (MEA1 and MEA2), Mercury Ion Analyzer (MIA), Mass Spectrum Analyzer (MSA), High Energy Particle instrument for electron (HEP-ele), High Energy Particle instrument for ion (HEP-ion), and Energetic Neutrals Analyzer (ENA). Significant efforts were made pre-flight to calibrate all of the MPPE sensors at the appropriate facilities on the ground. High voltage commissioning of MPPE analyzers was successfully performed between June and August 2019 and in February 2020 following the completion of the low voltage commissioning in November 2018. Although all of the MPPE analyzers are now ready to begin observation, the full service performance has been delayed until Mio’s arrival at Mercury. Most of the fields of view (FOVs) of the MPPE analyzers are blocked by the thermal shield surrounding the Mio spacecraft during the cruising phase. Together with other instruments on Mio including Magnetic Field Investigation (MGF) and Plasma Wave Investigation (PWI) that measure plasma field parameters, MPPE will contribute to the comprehensive understanding of the plasma environment around Mercury when BepiColombo/Mio begins observation after arriving at the planet Mercury in December 2025.

Background Perianal fistulising Crohn’s disease (CD) is an aggressive disease phenotype that can have a significant impact on patients’ quality of life. Current biological understanding of perianal fistulising CD remains inadequate and previous classification systems have not provided clear guidance on therapy in clinical practice nor on defining patient cohorts within clinical trials. To counter this unmet need, we propose a new classification system for perianal fistulising CD. Methods The proposed classification system was developed through a modified nominal group technique expert consensus process involving open discussion and formal voting on previously defined statements. Consensus agreement was defined a priori as 80% voting “strongly agree” or “agree with minor reservation”. Participants included gastroenterologists, radiologists, surgeons active in a tertiary IBD centre and a patient representative. Results The classification identifies four groups of patients with perianal fistulising CD. Key elements include stratification according to disease severity as well as disease outcome; synchronisation of patient and clinician goals in decision making, with a proactive, combined medical and surgical approach, on a ‘treat to patient goal’ basis; and identification of indications for curative fistula treatment, diverting ostomy and proctectomy. The new classification retains an element of flexibility, in which patients can cycle through different classes over time. Furthermore, with each specific class comes a paired treatment strategy suggestion and description of clinical trial suitability. Conclusion The proposed classification system is the first of its kind and is an important step towards tailored standardisation of clinical practice and research in patients with perianal fistulising CD.

Background Despite the advancement in pharmacological management of Inflammatory Bowel Disease (IBD), the efficacy and the side effects of the biologics are rarely studied in the elderly population. Our aim was to evaluate retrospectively the drug sustainability, efficacy, and safety of the biologic therapies in the elderly IBD population. Methods Consecutive elderly (> 60 years old) IBD patients, treated with biologics (infliximab, adalimumab, vedolizumab, ustekinumab) followed at the McGill University IBD Center were included between January 2000 and 2020. The efficacy of treatment was measured using clinical and biochemical parameters. Response and remission variables were measured at three distinct time points from the start date of the biologic agent, as in 3, 6–9 and 12–18 months. Patients required a minimal follow-up period of three months. Adverse events (AE) or serious adverse events (SAE) occurring within three months of the last biologic dose were considered to be related to the biologic agent. Results We identified a total of 147 elderly patients with IBD treated with biologic agents (109 Crohn’s disease (CD) and 38 ulcerative colitis (UC)). Disease location was predominantly ileocolonic (47.7%) in CD and pancolitis(63.2%) in UC. 47.6% of elderly IBD patients had attempted at least 1 biologic agent (Table1). The mean duration of biologic treatment was 157.5 (SD:148)weeks. Steroid exposure varied from 34% at the start of biologic therapy to 19% at 3 months, 16.3% at 6–9 months and 6.5% at 12–18 months.’ The remission rates at 3, 6–9 and 12–18 month were not significant between the biologic therapies. Kaplan-Meyer analysis did not show statistical difference for drug sustainability (p=0.195)(Figure1), time to adverse event (p=0.158) (Figure2) or infection rates (p=0.973) (Figure3) between all four biologics studied. The most common AEs led to discontinuation were loss of response, infusion or injection reaction and infection. Conclusion Current biologic therapies were not different with regards to drug sustainability and safety in the elderly IBD population. Based on these results, we are not able to suggest a preferred sequencing order among biologicals.

International audience

The ESA-JAXA BepiColombo mission to Mercury will provide simultaneous measurements from two spacecraft, offering an unprecedented opportunity to investigate magnetospheric and exospheric particle dynamics at Mercury as well as their interactions with solar wind, solar radiation, and interplanetary dust. The particle instrument suite SERENA (Search for Exospheric Refilling and Emitted Natural Abundances) is flying in space on-board the BepiColombo Mercury Planetary Orbiter (MPO) and is the only instrument for ion and neutral particle detection aboard the MPO. It comprises four independent sensors: ELENA for neutral particle flow detection, Strofio for neutral gas detection, PICAM for planetary ions observations, and MIPA, mostly for solar wind ion measurements. SERENA is managed by a System Control Unit located inside the ELENA box. In the present paper the scientific goals of this suite are described, and then the four units are detailed, as well as their major features and calibration results. Finally, the SERENA operational activities are shown during the orbital path around Mercury, with also some reference to the activities planned during the long cruise phase.

The original online version of this article was revised because a number of authors had the wrong affiliation number next to their names. © 2021, Springer Nature B.V.

Room-temperature optical constants of crystalline Bi$_2$Sr$_2$CaCu$_2$O$_{8+\delta}$ were determined using data extracted from Brillouin light scattering spectra. Optical extinction coefficient-to-refractive index ratios at a wavelength of 532 nm were obtained from bulk phonon peak linewidth and frequency shift measurements and range from $0.19 \leq 2\kappa/n \leq 0.29$ for directions close to the crystallographic $c$-axis. These ratios, and optical extinction coefficients, absorption coefficients, and imaginary parts of the dielectric function determined from these ratios and known refractive index, are in general agreement with values found in optical reflectance studies, but are 5-7 times larger than those extracted from optical interference measurements., Comment: 6 pages, 2 figures

The Solar Orbiter mission seeks to make connections between the physical processes occurring at the Sun or in the solar corona and the nature of the solar wind created by those processes which is subsequently observed at the spacecraft. The mission also targets physical processes occurring in the solar wind itself during its journey from its source to the spacecraft. To meet the specific mission science goals, Solar Orbiter will be equipped with both remote-sensing and in-situ instruments which will make unprecedented measurements of the solar atmosphere and the inner heliosphere. A crucial set of measurements will be provided by the Solar Wind Analyser (SWA) suite of instruments. This suite consists of an Electron Analyser System (SWA-EAS), a Proton and Alpha particle Sensor (SWA-PAS), and a Heavy Ion Sensor (SWA-HIS) which are jointly served by a central control and data processing unit (SWA-DPU). Together these sensors will measure and categorise the vast majority of thermal and suprathermal ions and electrons in the solar wind and determine the abundances and charge states of the heavy ion populations. The three sensors in the SWA suite are each based on the top hat electrostatic analyser concept, which has been deployed on numerous space plasma missions. The SWA-EAS uses two such heads, each of which have 360° azimuth acceptance angles and ±45° aperture deflection plates. Together these two sensors, which are mounted on the end of the boom, will cover a full sky field-of-view (FoV) (except for blockages by the spacecraft and its appendages) and measure the full 3D velocity distribution function (VDF) of solar wind electrons in the energy range of a few eV to ∼5 keV. The SWA-PAS instrument also uses an electrostatic analyser with a more confined FoV (−24° to +42° × ±22.5° around the expected solar wind arrival direction), which nevertheless is capable of measuring the full 3D VDF of the protons and alpha particles arriving at the instrument in the energy range from 200 eV/q to 20 keV/e. Finally, SWA-HIS measures the composition and 3D VDFs of heavy ions in the bulk solar wind as well as those of the major constituents in the suprathermal energy range and those of pick-up ions. The sensor resolves the full 3D VDFs of the prominent heavy ions at a resolution of 5 min in normal mode and 30 s in burst mode. Additionally, SWA-HIS measures 3D VDFs of alpha particles at a 4 s resolution in burst mode. Measurements are over a FoV of −33° to +66° × ±20° around the expected solar wind arrival direction and at energies up to 80 keV/e. The mass resolution (m/Δm) is > 5. This paper describes how the three SWA scientific sensors, as delivered to the spacecraft, meet or exceed the performance requirements originally set out to achieve the mission’s science goals. We describe the motivation and specific requirements for each of the three sensors within the SWA suite, their expected science results, their main characteristics, and their operation through the central SWA-DPU. We describe the combined data products that we expect to return from the suite and provide to the Solar Orbiter Archive for use in scientific analyses by members of the wider solar and heliospheric communities. These unique data products will help reveal the nature of the solar wind as a function of both heliocentric distance and solar latitude. Indeed, SWA-HIS measurements of solar wind composition will be the first such measurements made in the inner heliosphere. The SWA data are crucial to efforts to link the in situ measurements of the solar wind made at the spacecraft with remote observations of candidate source regions. This is a novel aspect of the mission which will lead to significant advances in our understanding of the mechanisms accelerating and heating the solar wind, driving eruptions and other transient phenomena on the Sun, and controlling the injection, acceleration, and transport of the energetic particles in the heliosphere.

Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion-transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes. The function of this transport system was inhibited by the tyrosine kinase inhibitor nilotinib through a noncompetitive mechanism, without compromising the anticancer properties of paclitaxel. Collectively, our findings reveal a pathway that explains the fundamental basis of paclitaxel-induced neurotoxicity, with potential implications for its therapeutic management.

Pesticides and other persistent organic pollutants are considered as risk factors for liver diseases. We treated the human hepatic cell line HepaRG with both 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) and the organochlorine pesticide, α-endosulfan, to evaluate their combined impact on the expression of hepatic genes involved in alcohol metabolism. We show that the combination of the two pollutants (25nM TCDD and 10μM α-endosulfan) led to marked decreases in the amounts of both the mRNA (up to 90%) and protein (up to 60%) of ADH4 and CYP2E1. Similar results were obtained following 24h or 8days of treatment with lower concentrations of these pollutants. Experiments with siRNA and AHR agonists and antagonist demonstrated that the genomic AHR/ARNT pathway is necessary for the dioxin effect. The PXR, CAR and estrogen receptor alpha transcription factors were not modulators of the effects of α-endosulfan, as assessed by siRNA transfection. In another human hepatic cell line, HepG2, TCDD decreased the expression of ADH4 and CYP2E1 mRNAs whereas α-endosulfan had no effect on these genes. Our results demonstrate that exposure to a mixture of pollutants may deregulate hepatic metabolism.

Local axonal protein synthesis plays a crucial role in the formation and function of neuronal circuits. Understanding the role of this mechanism in specific circuits requires identifying the protein composition and mRNA cargos of the ribonucleoprotein particles (RNPs) that form the substrate for axonal translation. FXGs (Fragile X granules) are axonal RNPs present in a stereotyped subset of mature axons in the intact brain that contain one or more of the Fragile X related (FXR) proteins (FMRP, FXR2P, and FXR1P) along with mRNA and ribosomes. Here we performed a systematic survey of the FXR protein composition and mRNA association of FXGs in the brain. We have identified four FXG types that can be categorized based on their FXR protein complement. All FXGs contain FXR2P, with FMRP and/or FXR1P present in circuit-selective subsets. Individual neuronal cell types predominantly express a single FXG type, with FMRP-containing FXGs the most prevalent in forebrain neurons. All FXG types associate with ribosomes and mRNA, but the specific mRNA cargos are a function of FXG type, brain region and neuron class. Transcripts for β-catenin and its regulator APC associate with a subset of forebrain FXGs. Moreover, both these transcripts can colocalize within individual FXGs, suggesting that the axonal translation of functionally related proteins may be coordinately regulated with high spatiotemporal resolution. Cell type-dependent expression of specific RNP types with distinct mRNA cargos, such as FXGs, presents a potential mechanism for regulating local translation and its output in a circuit-dependent manner.

Cisplatin is among the most widely used anticancer drugs and known to cause a dose-limiting nephrotoxicity, which is partially dependent on the renal uptake carrier OCT2. We here report a previously unrecognized, OCT2-independent pathway of cisplatin-induced renal injury that is mediated by the organic anion transporters OAT1 and OAT3. Using transporter-deficient mouse models, we found that this mechanism regulates renal uptake of a mercapturic acid metabolite of cisplatin that acts as a precursor of a potent nephrotoxin. The function of these two transport systems can be simultaneously inhibited by the tyrosine kinase inhibitor nilotinib through noncompetitive mechanisms, without compromising the anticancer properties of cisplatin. Collectively, our findings reveal a novel pathway that explains the fundamental basis of cisplatin-induced nephrotoxicity, with potential implications for its therapeutic management.

Individuals as well as entire ecosystems are exposed to mixtures of Persistent Organic Pollutants (POPs). Previously, we showed, by a non-targeted approach, that the expression of several genes involved in carbohydrate metabolism was almost completely inhibited in the human hepatic cell line HepaRG following exposure to a mixture of the organochlorine insecticide alpha-endosulfan and 2,3,7,8 tetrachlorodibenzo-p-dioxin. In this European HEALS project, which studies the effects of the exposome on human health, we used a Physiologically Based BioKinetic model to compare the concentrations previously used in vitro with in vivo exposures for humans. We investigated the effects of these POPs on the levels of proteins, on glycogen content, glucose production and the oxidation of glucose into CO2 and correlated them to the expression of genes involved in carbohydrate metabolism as measured by RT-qPCR. Exposure to individual POPs and the mixture decreased the expression of the proteins investigated as well as glucose output (up to 82%), glucose oxidation (up to 29%) and glycogen content (up to 48%). siRNAs that specifically inhibit the expression of several xenobiotic receptors were used to assess receptor involvement in the effects of the POPs. In the HepaRG model, we demonstrate that the effects are mediated by the aryl hydrocarbon receptor and the estrogen receptor alpha, but not the pregnane X receptor or the constitutive androstane receptor. These results provide evidence that exposure to combinations of POPs, acting through different signaling pathways, may affect, more profoundly than single pollutants alone, metabolic pathways such as carbohydrate/energy metabolism and play a potential role in pollutant associated metabolic disorders.

Much can be learned from terrestrial planets that appear to have had the potential to be habitable, but failed to realize that potential. Mars shows evidence of a once hospitable surface environment. The reasons for its current state, and in particular its thin atmosphere and dry surface, are of great interest for what they can tell us about habitable zone planet outcomes. A main goal of the MAVEN mission is to observe Mars’ atmosphere responses to solar and space weather influences, and in particular atmosphere escape related to space weather ‘storms’ caused by interplanetary coronal mass ejections (ICMEs). Numerical experiments with a data-validated MHD model suggest how the effects of an observed moderately strong ICME compare to what happens during a more extreme event. The results suggest the kinds of solar and space weather conditions that can have evolutionary importance at a planet like Mars.

Observations from the MESSENGER spacecraft have considerably enhanced our understanding of the plasma environment at Mercury. In particular, measurements from the Fast Imaging Plasma Spectrometer (FIPS) provide evidences of a variety of ion species of planetary origin (He+, O+, Na+) in the northern dayside cusp and in the nightside plasma sheet. A more comprehensive view of Mercury's plasma environment will be provided by the Bepi Colombo mission that will be launched in 2018. Onboard the Bepi Colombo MMO spacecraft, the MPPE (Mercury Plasma/Particle Experiment) consortium gathers different sensors dedicated to particle measurements. Among these sensors, the Mass Spectrum Analyzer (MSA) is the instrument dedicated to plasma composition analysis. It consists of a top-hat for energy analysis followed by a Time-Of-Flight (TOF) chamber to derive the ion mass. Taking advantage of the spacecraft rotation, MSA will measure three-dimensional distribution functions in one spin (4 s), from energies characteristic of exospheric populations (in the eV range) up to plasma sheet energies (up to ~38 keV/q). A notable feature of the MSA instrument is that the TOF chamber is polarized with a linear electric field that leads to isochronous TOFs and enhanced mass resolution (typically, m/∆m ≈ 40 for ions with energies up to 13 keV/q). At Mercury, this capability is of paramount importance to thoroughly characterize the wide variety of ion species originating from the planet surface. It is thus anticipated that MSA will provide unprecedented information on ion populations in the Hermean environment and hence improve our understanding of the coupling processes at work.

The mechanisms by which pollutants participate in the development of diverse pathologies are not completely understood. The pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activates the AhR (aryl hydrocarbon receptor) signaling pathway. We previously showed that TCDD (25 nM, 30 h) decreased the expression of several alcohol metabolism enzymes (cytochrome P450 2E1, alcohol dehydrogenases ADH1, 4 and 6) in differentiated human hepatic cells (HepaRG). Here, we show that, as rapidly as 8 h after treatment (25 nM TCDD) ADH expression decreased 40 % (p

BACKGROUND Peripheral neurotoxicity afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin therapy. Oxaliplatin preferentially accumulates in and causes toxicity to peripheral sensory neurons present in the dorsal root ganglia (DRG), but mechanistic details of the transporters involved in this process remain uncertain. In the present study, we set out to unambiguously identify these transporter(s) to support the notion that oxaliplatin accumulation in DRGs is a key trigger for the development of peripheral neurotoxicity. METHODS Engineered mouse models with transporter deficiency were used to assess peripheral neurotoxicity by the Von Frey Hair test. Immunofluorescence and primary ex vivo culture of DRGs were performed to determine localization, expression, and function. Pertinent findings were validated in Sprague‐Dawley rats as a secondary model organism, while the translational feasibility of using transport inhibitors to mitigate oxaliplatin‐induced peripheral neurotoxicity was demonstrated in preclinical models of colorectal cancer. RESULTS Comparative in vitro and in vivo association studies revealed that deficiency of OCT2 confers significant protection against acute and chronic peripheral neurotoxicity, but this was not observed for the putative oxaliplatin transporters OCT3, OCTN1, OATP1B2, OATP2B1, and MATE1. Within DRGs, OCT2 was localized to satellite glial cells (SGCs), and accumulation of oxaliplatin in ex vivo cultures of SGCs was prevented by pretreatment with the OCT2 inhibitor, dasatinib. The importance of this transport system was verified in rats, where pretreatment with dasatinib in wild‐type rats recapitulated paw sensitivity phenotypes observed in OCT2‐deficient rats. Dasatinib did not influence the systemic clearance of oxaliplatin, indicating that the observed neuroprotection is directly mediated by inhibition of neuronal transport. At the applied dose and schedule that afford neuroprotection, we found that dasatinib did not negatively affect the antitumor properties of oxaliplatin against colorectal cancer cells in vitro and in vivo. CONCLUSION We identified a previously unrecognized, SGC‐specific pathway of oxaliplatin‐induced neurological injury that is mediated by the organic cationic transporter, OCT2, which can be targeted pharmacologically without compromising the anticancer properties of oxaliplatin. These findings not only shed light on the etiology of oxaliplatin‐induced neurotoxicity, but also provide a rationale for the development of targeted interventions using transporter inhibitors to mitigate a debilitating side effect associated with conventional chemotherapy.