The initial reinforcing properties of drugs of abuse, such as cocaine, are largely attributed to their ability to activate the mesolimbic dopamine system. Resulting increases in extracellular ...dopamine in the nucleus accumbens (NAc) are traditionally thought to result from cocaine's ability to block dopamine transporters (DATs). Here we demonstrate that cocaine also interacts with the immunosurveillance receptor complex, Toll-like receptor 4 (TLR4), on microglial cells to initiate central innate immune signaling. Disruption of cocaine signaling at TLR4 suppresses cocaine-induced extracellular dopamine in the NAc, as well as cocaine conditioned place preference and cocaine self-administration. These results provide a novel understanding of the neurobiological mechanisms underlying cocaine reward/reinforcement that includes a critical role for central immune signaling, and offer a new target for medication development for cocaine abuse treatment.
The MiniBooNE-DM Collaboration searched for vector-boson mediated production of dark matter using the Fermilab 8-GeV Booster proton beam in a dedicated run with 1.86×10^{20} protons delivered to a ...steel beam dump. The MiniBooNE detector, 490 m downstream, is sensitive to dark matter via elastic scattering with nucleons in the detector mineral oil. Analysis methods developed for previous MiniBooNE scattering results were employed, and several constraining data sets were simultaneously analyzed to minimize systematic errors from neutrino flux and interaction rates. No excess of events over background was observed, leading to a 90% confidence limit on the dark matter cross section parameter, Y=ε^{2}α_{D}(m_{χ}/m_{V})^{4}≲10^{-8}, for α_{D}=0.5 and for dark matter masses of 0.01<m_{χ}<0.3 GeV in a vector portal model of dark matter. This is the best limit from a dedicated proton beam dump search in this mass and coupling range and extends below the mass range of direct dark matter searches. These results demonstrate a novel and powerful approach to dark matter searches with beam dump experiments.
The MiniBooNE experiment at Fermilab reports results from an analysis of ν_{e} appearance data from 12.84×10^{20} protons on target in neutrino mode, an increase of approximately a factor of 2 over ...previously reported results. A ν_{e} charged-current quasielastic event excess of 381.2±85.2 events (4.5σ) is observed in the energy range 200<E_{ν}^{QE}<1250 MeV. Combining these data with the νover ¯_{e} appearance data from 11.27×10^{20} protons on target in antineutrino mode, a total ν_{e} plus νover ¯_{e} charged-current quasielastic event excess of 460.5±99.0 events (4.7σ) is observed. If interpreted in a two-neutrino oscillation model, ν_{μ}→ν_{e}, the best oscillation fit to the excess has a probability of 21.1%, while the background-only fit has a χ^{2} probability of 6×10^{-7} relative to the best fit. The MiniBooNE data are consistent in energy and magnitude with the excess of events reported by the Liquid Scintillator Neutrino Detector (LSND), and the significance of the combined LSND and MiniBooNE excesses is 6.0σ. A two-neutrino oscillation interpretation of the data would require at least four neutrino types and indicate physics beyond the three neutrino paradigm. Although the data are fit with a two-neutrino oscillation model, other models may provide better fits to the data.
Supramolecular synthesis is a powerful strategy for assembling complex molecules, but to do this by targeted design is challenging. This is because multicomponent assembly reactions have the ...potential to form a wide variety of products. High-throughput screening can explore a broad synthetic space, but this is inefficient and inelegant when applied blindly. Here we fuse computation with robotic synthesis to create a hybrid discovery workflow for discovering new organic cage molecules, and by extension, other supramolecular systems. A total of 78 precursor combinations were investigated by computation and experiment, leading to 33 cages that were formed cleanly in one-pot syntheses. Comparison of calculations with experimental outcomes across this broad library shows that computation has the power to focus experiments, for example by identifying linkers that are less likely to be reliable for cage formation. Screening also led to the unplanned discovery of a new cage topology-doubly bridged, triply interlocked cage catenanes.
This paper describes the operation of the Coherent CAPTAIN-Mills (CCM) detector located at the Los Alamos Neutron Science Center at Los Alamos National Laboratory. CCM is a 10-ton liquid argon ...detector located 20 meters from a high flux neutron/neutrino source and is designed to search for sterile neutrinos (νs’s) and light dark matter (LDM). An engineering run was performed in fall 2019 to study the characteristics of the CCM120 detector by searching for coherent scattering signals consistent with νs’s and LDM resulting from the production and decays of π+ and π0 in the tungsten target. New parameter space in a leptophobic dark matter (DM) model was excluded for DM masses between ~2.0 and 30 MeV. The lessons learned from this run have guided the development and construction of the new CCM200 detector that will begin operations in 2021 and significantly improve on these searches.
Human error poses significant risk for hospitalized patients causing an estimated 100,000 to 400,000 deaths in the USA annually. Medication errors contribute, with error occurring in 5.3% of ...medication administrations during surgery. In this study 70.3% of medication errors were deemed preventable. Given the paucity of randomized controlled studies, we undertook a rigorous review of the literature to identify recommendations supported by expert opinions. An extensive literature search pertaining to medication error, medication safety, operating room, and anaesthesia was performed. The National Guidelines Clearinghouse was searched for any anaesthesia or operating room medication safety guidelines.
A total of 74 articles were included. Recommendations were tabulated and assigned points based on a scale revised from a prior study. A total of 138 unique recommendations were identified, with point tallies ranging from 4 to 190. An in-person focus meeting occurred, where the 138 recommendations were reviewed, combined and condensed. A modified Delphi process was used to eliminate items found to be unimportant or those unable to be quantified (e.g. “minimize fatigue”). A total of 35 specific recommendations remained. Adverse events as a result of medication errors occur frequently in the operative setting. There are few rigorous studies to direct medication safety strategies, but this should not lead us to do nothing. The overwhelming consensus regarding best practices should be accepted, and the recommendations implemented. Our list of recommended strategies can hopefully be used to assess local vulnerabilities and institute system solutions.
A search for sub-GeV dark matter produced from collisions of the Fermilab 8 GeV Booster protons with a steel beam dump was performed by the MiniBooNE-DM Collaboration using data from 1.86 × 1020 ...protons on target in a dedicated run. The MiniBooNE detector, consisting of 818 tons of mineral oil and located 490 meters downstream of the beam dump, is sensitive to a variety of dark matter initiated scattering reactions. Three dark matter interactions are considered for this analysis: elastic scattering off nucleons, inelastic neutral pion production, and elastic scattering off electrons. Multiple data sets were used to constrain flux and systematic errors, and time-of-flight information was employed to increase sensitivity to higher dark matter masses. No excess from the background predictions was observed, and 90% confidence level limits were set on the vector portal and leptophobic dark matter models. New parameter space is excluded in the vector portal dark matter model with a dark matter mass between 5 and 50 MeV c−2 . The reduced neutrino flux allowed to test if the MiniBooNE neutrino excess scales with the production of neutrinos. No excess of neutrino oscillation events were measured ruling out models that scale solely by number of protons on target independent of beam configuration at 4.6σ.
We report the first measurement of coherent elastic neutrino-nucleus scattering (CEvNS) on argon using a liquid argon detector at the Oak Ridge National Laboratory Spallation Neutron Source. Two ...independent analyses prefer CEvNS over the background-only null hypothesis with greater than 3σ significance. The measured cross section, averaged over the incident neutrino flux, is (2.2±0.7)×10^{-39} cm^{2}-consistent with the standard model prediction. The neutron-number dependence of this result, together with that from our previous measurement on CsI, confirms the existence of the CEvNS process and provides improved constraints on nonstandard neutrino interactions.
Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, ...behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events.Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4-9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend novel insight to MPS neuropathology, suggesting that MPSIIIA and IIIB have more pronounced neuropathology than MPSI, yet all are still progressive, at least in some aspects of neuropathology, from 4-9 months.
The COHERENT experiment is well poised to test sub-GeV dark matter models using detectors sensitive to coherent elastic neutrino-nucleus scattering (CEvNS) in the π+ decay-at-rest (π-DAR) neutrino ...beam produced by the Spallation Neutron Source. We show a planned 750-kg single-phase liquid argon scintillation detector would place leading limits on scalar light dark matter models for dark matter particles produced through vector and leptophobic portals in the absence of other effects beyond the standard model. The characteristic timing profile of a π-DAR beam allows a unique opportunity for constraining systematic uncertainties on the standard model background using a time window where dark matter signal is not expected, enhancing expected sensitivity. Additionally, we discuss future prospects which show that an on-axis CEvNS detector would probe the thermal abundance for a scalar dark matter candidate for all couplings α′ ≤ 1 for 15 MeV dark matter with just 1.0 tonne-yr of exposure with increased exposure testing a wider range of dark matter masses and spins.
PDF
