The ventral tegmental area (VTA) is a heterogeneous midbrain structure, containing neurons and astrocytes, that coordinates behaviors by integrating activity from numerous afferents. Within ...neuron-astrocyte networks, astrocytes control signals from distinct afferents in a circuit-specific manner, but whether this capacity scales up to drive motivated behavior has been undetermined. Using genetic and optical dissection strategies we report that VTA astrocytes tune glutamatergic signaling selectively on local inhibitory neurons to drive a functional circuit for learned avoidance. In this circuit, astrocytes facilitate excitation of VTA GABA neurons to increase inhibition of dopamine neurons, eliciting real-time and learned avoidance behavior that is sufficient to impede expression of preference for reward. Loss of one glutamate transporter (GLT-1) from VTA astrocytes selectively blocks these avoidance behaviors and spares preference for reward. Thus, VTA astrocytes selectively regulate excitation of local GABA neurons to drive a distinct avoidance circuit that opposes approach behavior.
Planar laser-plasma interaction (LPI) experiments at the National Ignition Facility (NIF) have allowed access for the first time to regimes of electron density scale length (∼500 to 700 μm), ...electron temperature (∼3 to 5 keV), and laser intensity (6 to 16×10^{14} W/cm^{2}) that are relevant to direct-drive inertial confinement fusion ignition. Unlike in shorter-scale-length plasmas on OMEGA, scattered-light data on the NIF show that the near-quarter-critical LPI physics is dominated by stimulated Raman scattering (SRS) rather than by two-plasmon decay (TPD). This difference in regime is explained based on absolute SRS and TPD threshold considerations. SRS sidescatter tangential to density contours and other SRS mechanisms are observed. The fraction of laser energy converted to hot electrons is ∼0.7% to 2.9%, consistent with observed levels of SRS. The intensity threshold for hot-electron production is assessed, and the use of a Si ablator slightly increases this threshold from ∼4×10^{14} to ∼6×10^{14} W/cm^{2}. These results have significant implications for mitigation of LPI hot-electron preheat in direct-drive ignition designs.
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Cross-beam energy transfer (CBET) results from two-beam energy exchange via seeded stimulated Brillouin scattering, which detrimentally reduces ablation pressure and implosion velocity in ...direct-drive inertial confinement fusion. Mitigating CBET is demonstrated for the first time in inertial-confinement implosions at the National Ignition Facility by detuning the laser-source wavelengths (±2.3 Å UV) of the interacting beams. We show that, in polar direct-drive, wavelength detuning increases the equatorial region velocity experimentally by 16% and alters the in-flight shell morphology. These experimental observations are consistent with design predictions of radiation-hydrodynamic simulations that indicate a 10% increase in the average ablation pressure.
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(Ultra) luminous infrared galaxies ((U)LIRGs) are objects characterized by their extreme infrared (8-1000 mu m) luminosities (L sub(LIRG) > 10 super(11) L sub(middot in circle) and L sub(ULIRG) > 10 ...super(12)L sub(middot in circle)). The Herschel Comprehensive ULIRG Emission Survey (PI: van der Werf) presents a representative flux-limited sample of 29 (U)LIRGs that spans the full luminosity range of these objects (10 super(11)L sub(middo t in circle) < or =, slant L sub(IR) < or =, slant 10 super(13) L sub(middot in circle)). With the Herschel Space Observatory, we observe CII 157 mu m, OI 63 mu m, and OI 145 mu m line emission with Photodetector Array Camera and Spectrometer, CO J = 4-3 through J = 13-12, CI 370 mu m, and CI 609 mu m with SPIRE, and low-J CO transitions with ground-based telescopes. The CO ladders of the sample are separated into three classes based on their excitation level. In 13 of the galaxies, the OI 63 mu m emission line is self absorbed. Comparing the CO excitation to the InfraRed Astronomical Satellite 60/100 mu m ratio and to far infrared luminosity, we find that the CO excitation is more correlated to the far infrared colors. We present cooling budgets for the galaxies and find fine-structure line flux deficits in the CII, SiII, OI, and CI lines in the objects with the highest far IR fluxes, but do not observe this for CO 4 < or =, slant J sub(upp) < or =, slant 13. In order to study the heating of the molecular gas, we present a combination of three diagnostic quantities to help determine the dominant heating source. Using the CO excitation, the CO J = 1-0 linewidth, and the active galactic nucleus (AGN) contribution, we conclude that galaxies with large CO linewidths always have high-excitation CO ladders, and often low AGN contributions, suggesting that mechanical heating is important.
Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated ...dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proof-of-principle phase II study in patients with p53 tumor suppressor gene ( TP53)-mutated ovarian cancer refractory or resistant (< 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies. Patients and Methods Patients were treated with carboplatin (area under the curve, 5 mg/mL⋅min) combined with AZD1775 225 mg orally twice daily over 2.5 days every 21-day cycle until disease progression. Results AZD1775 plus carboplatin demonstrated manageable toxicity; fatigue (87%), nausea (78%), thrombocytopenia (70%), diarrhea (70%), and vomiting (48%) were the most common adverse events. The most frequent grade 3 or 4 adverse events were thrombocytopenia (48%) and neutropenia (37%). Of 24 patients enrolled, 21 patients were evaluable for efficacy end points. The overall response rate was 43% (95% CI, 22% to 66%), including one patient (5%) with a prolonged complete response. Median progression-free and overall survival times were 5.3 months (95% CI, 2.3 to 9.0 months) and 12.6 months (95% CI, 4.9 to 19.7), respectively, with two patients with ongoing response for more than 31 and 42 months at data cutoff. Conclusion To our knowledge, this is the first report providing clinical proof that AZD1775 enhances carboplatin efficacy in TP53-mutated tumors. The encouraging antitumor activity observed in patients with TP53-mutated ovarian cancer who were refractory or resistant (< 3 months) to first-line therapy warrants further development.
Hot electrons generated by laser-plasma instabilities degrade the performance of laser-fusion implosions by preheating the DT fuel and reducing core compression. The hot-electron energy deposition in ...the DT fuel has been directly measured for the first time by comparing the hard x-ray signals between DT-layered and mass-equivalent ablator-only implosions. The electron energy deposition profile in the fuel is inferred through dedicated experiments using Cu-doped payloads of varying thickness. The measured preheat energy accurately explains the areal-density degradation observed in many OMEGA implosions. This technique can be used to assess the viability of the direct-drive approach to laser fusion with respect to the scaling of hot-electron preheat with laser energy.
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OBJECTIVES: Our purpose was to define the frequency and reasons for oral contraceptive discontinuation and subsequent contraceptive behavior.
STUDY DESIGN: A nationwide prospective study of 1657 ...women initiating or switching to the use of a new contraceptive from private practices, clinics, and a health maintenance organization was performed.
RESULTS: Six months after a new oral contraceptive prescription, 68% of new starts and 84% of switchers still used oral contraceptives. Of women who discontinued, 46% did so because of side effects, whereas 23% had no continuing need. More than four fifths of women who discontinued oral contraceptives but remained at risk of unintended pregnancy either failed to adopt another method or adopted a less effective method. Fifteen percent of women who discontinued oral contraceptives resumed their use within the 7-month follow-up period.
CONCLUSIONS: Counseling should emphasize the possibility of side effects, stressing the fact that most will be transient, and the need to identify a backup method. Follow-up visits should be scheduled for 1 to 2 months after a prescription is written. (Am J Obstet Gynecol 1998;179:577-82.)
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Monoenergetic-proton radiographs of laser-generated, high-Mach-number plasma jets colliding at various angles shed light on the structures and dynamics of these collisions. The observations compare ...favorably with results from 2D hydrodynamic simulations of multistream plasma jets, and also with results from an analytic treatment of electron flow and magnetic field advection. In collisions of two noncollinear jets, the observed flow structure is similar to the analytic model's prediction of a characteristic feature with a narrow structure pointing in one direction and a much thicker one pointing in the opposite direction. Spontaneous magnetic fields, largely azimuthal around the colliding jets and generated by the well-known ∇T(e)×∇n(e) Biermann battery effect near the periphery of the laser spots, are demonstrated to be "frozen in" the plasma (due to high magnetic Reynolds number Re(M)∼5×10(4)) and advected along the jet streamlines of the electron flow. These studies provide novel insight into the interactions and dynamics of colliding plasma jets.
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