Astrocytes provide support for neurons, regulate metabolic processes, and influence neuronal communication in a variety of ways, including through the homeostatic regulation of glutamate. Following ...2-h cocaine or methamphetamine self-administration (SA) and extinction, rodents display decreased levels of basal glutamate in the nucleus accumbens core (NAcore), which transitions to elevated glutamate levels during drug seeking. We hypothesized that, like cocaine, this glutamate ‘overflow’ during methamphetamine seeking arises via decreased expression of the astroglial glutamate transporter GLT-1, and withdrawal of perisynaptic astroglial processes (PAPs) from synapses. As expected, methamphetamine self-administration and extinction decreased the level of contact made by PAPs in the NAcore, yet did not impact glutamate uptake, GLT-1 expression, or the general structural characteristics of astrocytes. Interestingly, systemic administration of N-acetylcysteine (NAC), a drug that both upregulates GLT-1 and promotes glial-glutamate release, reduced cued methamphetamine seeking. In order to test the impact of astrocyte activation and the induction of glial glutamate release within the NAcore, we employed astrocyte-specific expression of designer receptors exclusively activated by designer drugs (DREADDs). We show here that acute activation of Gq-coupled DREADDs in this region inhibited cued methamphetamine seeking. Taken together, these data indicate that cued methamphetamine seeking following two-hour SA is not mediated by deficient glutamate clearance in the NAcore, yet can be inhibited by engaging NAcore astrocytes.
•Two-hour methamphetamine self-administration and extinction does not alter glutamate uptake in the NAcore.•Two-hour methamphetamine self-administration and extinction decreases astrocytic insulation of NAcore synapses.•Chronic NAC treatment inhibits cued-methamphetamine seeking.•Acute activation of Gq-DREADD, specifically in NAcore astrocytes, inhibits cued-methamphetamine seeking.
The New Horizons spacecraft flew past the Kuiper Belt object (486958) Arrokoth (also known as 2014 MU69) in January 2019. Because of the great distance to the outer Solar System and limited ...bandwidth, it will take until late 2020 to downlink all the spacecraft's observations back to Earth. Three papers in this issue analyze recently downlinked data, including the highest-resolution images taken during the encounter (see the Perspective by Jewitt). Spencer et al. examined Arrokoth's geology and geophysics using stereo imaging, dated the surface using impact craters, and produced a geomorphological map. Grundy et al. investigated the composition of the surface using color imaging and spectroscopic data and assessed Arrokoth's thermal emission using microwave radiometry. McKinnon et al. used simulations to determine how Arrokoth formed: Two gravitationally bound objects gently spiraled together during the formation of the Solar System. Together, these papers determine the age, composition, and formation process of the most pristine object yet visited by a spacecraft.
The New Horizons spacecraft's encounter with the cold classical Kuiper Belt object (486958) Arrokoth (provisional designation 2014 MU
) revealed a contact-binary planetesimal. We investigated how ...Arrokoth formed and found that it is the product of a gentle, low-speed merger in the early Solar System. Its two lenticular lobes suggest low-velocity accumulation of numerous smaller planetesimals within a gravitationally collapsing cloud of solid particles. The geometric alignment of the lobes indicates that they were a co-orbiting binary that experienced angular momentum loss and subsequent merger, possibly because of dynamical friction and collisions within the cloud or later gas drag. Arrokoth's contact-binary shape was preserved by the benign dynamical and collisional environment of the cold classical Kuiper Belt and therefore informs the accretion processes that operated in the early Solar System.
The flyby of Pluto and Charon by the New Horizons spacecraft provided high-resolution images of cratered surfaces embedded in the Kuiper belt, an extensive region of bodies orbiting beyond Neptune. ...Impact craters on Pluto and Charon were formed by collisions with other Kuiper belt objects (KBOs) with diameters from ~40 kilometers to ~300 meters, smaller than most KBOs observed directly by telescopes. We find a relative paucity of small craters ≲13 kilometers in diameter, which cannot be explained solely by geological resurfacing. This implies a deficit of small KBOs (≲1 to 2 kilometers in diameter). Some surfaces on Pluto and Charon are likely ≳4 billion years old, thus their crater records provide information on the size-frequency distribution of KBOs in the early Solar System.
Gastrointestinal motility involves interactions between myogenic and neurogenic processes intrinsic to the gut wall. We have compared the presence of propagating myogenic contractions of the isolated ...colon in four experimental animals (guinea pig, mouse, rabbit, and rat), following blockade of enteric neural activity. Isolated colonic preparations were distended with fluid, with the anal end either closed or open. Spatiotemporal maps of changes in diameter were constructed from video recordings. Distension-induced peristaltic contractions were abolished by tetrodotoxin (TTX; 0.6 μM) in all animal species. Subsequent addition of carbachol (0.1-1 μM) did not evoke myogenic motor patterns in the mouse or guinea pig, although some activity was observed in rabbit and rat colon. These myogenic contractions propagated both orally and anally and differed from neurogenic propagating contractions in their frequency, extent of propagation, and polarity. Niflumic acid (300 μM), used to block myogenic activity, also blocked neural peristalsis and thus cannot be used to discriminate between these mechanisms. In all species, except the mouse colon, small myogenic "ripple" contractions were revealed in TTX, but in both rat and rabbit an additional, higher-frequency ripple-type contraction was superimposed. Following blockade of enteric nerve function, a muscarinic agonist can evoke propulsive myogenic peristaltic contractions in isolated rabbit and rat colon, but not in guinea pig or mouse colon. Marked differences between species exist in the ability of myogenic mechanisms to propel luminal content, but in all species there is normally a complex interplay between neurogenic and myogenic processes.
Surface compositions across Pluto and Charon Grundy, W. M.; Binzel, R. P.; Buratti, B. J. ...
Science (American Association for the Advancement of Science),
03/2016, Letnik:
351, Številka:
6279
Journal Article
Recenzirano
Odprti dostop
The Kuiper Belt hosts a swarm of distant, icy objects ranging in size from small, primordial planetesimals to much larger, highly evolved objects, representing a whole new class of previously ...unexplored cryogenic worlds. Pluto, the largest among them, along with its system of five satellites, has been revealed by NASAs New Horizons spacecraft flight through the system in July 2015, nearly a decade after its launch.
Interstellar neutral atoms, unlike charged particles, freely penetrate the heliosphere, allowing us to sample the physical state of the interstellar matter directly. Most interstellar hydrogen atoms ...are ionized before reaching the inner heliosphere and become energetic protons picked up by the solar wind and transported away from the Sun. Consequently, observations of interstellar hydrogen atoms by missions operating within a few astronomical units from the Sun are subject to significant systematic uncertainties. We analyze observations from the Solar Wind Around Pluto instrument on New Horizons, the first experiment to provide extensive measurements of the picked-up protons far from the Sun. Analyzing the density of these protons, we find an interstellar neutral hydrogen density at the termination shock of 0.127 0.015 cm−3, i.e., ∼40% higher than previously thought. We show that the Voyager observations of the slowdown of the solar wind further support this value. This result resolves a problem of why energetic neutral atom fluxes, created from pickup ions by charge exchange with hydrogen atoms, are roughly twice that expected from numerical models. Our result also implies higher charge exchange rates at the heliospheric boundaries and, consequently, a less asymmetric shape of the heliosphere. Based on a previous study of the atom filtration in the heliospheric boundaries, we estimate the neutral hydrogen density in the unperturbed local interstellar medium of 0.195 0.033 cm−3. This value agrees with astrophysical observations of the interstellar clouds in the Sun proximity.
The Cold Classical Kuiper Belt, a class of small bodies in undisturbed orbits beyond Neptune, is composed of primitive objects preserving information about Solar System formation. In January 2019, ...the New Horizons spacecraft flew past one of these objects, the 36-kilometer-long contact binary (486958) Arrokoth (provisional designation 2014 MU
). Images from the flyby show that Arrokoth has no detectable rings, and no satellites (larger than 180 meters in diameter) within a radius of 8000 kilometers. Arrokoth has a lightly cratered, smooth surface with complex geological features, unlike those on previously visited Solar System bodies. The density of impact craters indicates the surface dates from the formation of the Solar System. The two lobes of the contact binary have closely aligned poles and equators, constraining their accretion mechanism.
Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II ...study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and myeloma). In patients with leukemia and myeloid disorders, 60 mg was the MTD for weekly as well as biweekly panobinostat. In patients with lymphoma and myeloma, 40 mg was the recommended dose for phase II evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was the MTD for biweekly panobinostat. Overall, panobinostat-related grade 3-4 adverse events included thrombocytopenia (41.5%), fatigue (21%) and neutropenia (21%). Single-agent activity was observed in several indications, including Hodgkin lymphoma and myelofibrosis. This phase Ia/II study provided a broad analysis of the safety profile and efficacy of single-agent panobinostat in patients with hematologic malignancies.
Abstract
This study reports the first high-time-resolution observations of interstellar pickup ions (PUIs) in the outer heliosphere, including the first high-resolution observations of PUIs mediating ...shocks collected anywhere. These new data were enabled by a clever flight software reprogramming of the Solar Wind Around Pluto (SWAP) instrument on New Horizons to provide ∼30 minutes resolution as compared to the previous ∼24 hr time resolution. This time resolution is sufficient to resolve the shock structures and quantify the particle heating across these shocks. In the ∼10 months of initial data, we observed seven relatively small shocks, including one reverse shock. We find that the PUIs are preferentially compressed and heated across the shocks, indicating compression ratios from ∼1.2–1.8, with little heating for values less than ∼1.5 and progressively more PUI heating for larger compression ratios. In contrast, core solar wind properties did not show consistent changes across the shocks, indicating that these particles (1) participate little in the large-scale fluid-like interactions of the outer heliosphere’s combined solar wind and PUI plasma and (2) cannot be used to characterize PUI-mediated shocks as prior studies sought to do. All six forward shock crossings showed gradual increases in PUI pressure over shock widths of ∼0.05–0.13 au, which is roughly three decades larger than characteristic particle scales such as the PUI gyroradii. The new high-resolution observations and results described here are important for understanding shocks in the outer heliosphere, the termination shock, and more broadly for PUI-mediated shocks across many astrophysical systems.
PDF
