Highlights • Adult rat CNS endothelial cells express functional TLR4. • The opioid receptor-inactive morphine metabolite M3G activates TLR4-dependent inflammatory signaling in endothelial cells. • ...Nalmefene is a mu opioid receptor antagonist without TLR4 activity, whereas CTAP is an antagonist at both receptors. • Stimulation of endothelial cells by M3G induces in vivo responses of decreased mechanical thresholds and vasodilation. • The putative glial inhibitors AV1013 and propentofylline also inhibit the inflammatory response of endothelial cells.
The Red MSX Source (RMS) survey has identified a sample of ∼1200 massive young stellar objects (MYSOs), compact and ultra-compact H ii regions from a sample of ∼2000 MSX and Two Micron All Sky Survey ...(2MASS) colour-selected sources. We have used the 100-m Green Bank Telescope to search for 22-24 GHz water maser and ammonia (1,1), (2,2) and (3,3) emission towards ∼600 RMS sources located within the northern Galactic plane. We have identified 308 H2O masers which corresponds to an overall detection rate of ∼50 per cent. We find no significant difference in the detection rate for H ii regions and MYSOs which would suggest that the conditions required to produce maser emission are equally likely in both phases. Comparing the detection rates as a function of luminosity, we find the H2O detection rate has a positive dependence on the source luminosity, with the detection rate increasing with increasing luminosity.
We detect ammonia emission towards 479 of these massive young stars, which corresponds to ∼80 per cent. Ammonia is an excellent probe of high-density gas allowing us to measure key parameters such as gas temperatures, opacities and column densities, as well as providing an insight into the gas kinematics. The average kinetic temperature, full width at half-maximum linewidth and total NH3 column density for the sample are approximately 22 K, 2 km s−1 and 2 × 1015 cm−2, respectively. We find that the NH3 (1,1) linewidth and kinetic temperature are correlated with luminosity, and finding no underlying dependence of these parameters on the evolutionary phase of the embedded sources, we conclude that the observed trends in the derived parameters are more likely to be due to the energy output of the central source and/or the linewidth-clump mass relationship.
The velocities of the peak H2O masers and the NH3 emission are in excellent agreement with each other, which would strongly suggest an association between the dense gas and the maser emission. Moreover, we find the bolometric luminosity of the embedded source and the isotropic luminosity of the H2O maser are also correlated. We conclude from the correlations of the cloud and water maser velocities and the bolometric and maser luminosity that there is a strong dynamical relationship between the embedded young massive star and the H2O maser.
Abstract Glutamate neurotransmission is highly regulated, largely by glutamate transporters. In the spinal cord, the glutamate transporter GLT-1 is primarily responsible for glutamate clearance. ...Downregulation of GLT-1 can occur in activated astrocytes, and is associated with increased extracellular glutamate and neuroexcitation. Among other conditions, astrocyte activation occurs following repeated opioids and in models of chronic pain. If GLT-1 downregulation occurs in these states, GLT-1 could be a pharmacological target for improving opioid efficacy and controlling chronic pain. The present studies explored whether daily intrathecal treatment of rats with ceftriaxone, a β-lactam antibiotic that upregulates GLT-1 expression, could prevent development of hyperalgesia and allodynia following repeated morphine, reverse pain arising from central or peripheral neuropathy, and reduce glial activation in these models. Ceftriaxone pre-treatment attenuated the development of hyperalgesia and allodynia in response to repeated morphine, and prevented associated astrocyte activation. In a model of multiple sclerosis (experimental autoimmune encephalomyelitis; EAE), ceftriaxone reversed tactile allodynia and halted the progression of motor weakness and paralysis. Similarly, ceftriaxone reversed tactile allodynia induced by chronic constriction nerve injury (CCI). EAE and CCI each significantly reduced the expression of membrane-bound, dimerized GLT-1 protein in lumbar spinal cord, an effect normalized by ceftriaxone. Lastly, ceftriaxone normalized CCI- and EAE-induced astrocyte activation in lumbar spinal cord. Together, these data indicate that increasing spinal GLT-1 expression attenuates opioid-induced paradoxical pain, alleviates neuropathic pain, and suppresses associated glial activation. GLT-1 therefore may be a therapeutic target that could improve available treatment options for patients with chronic pain.
Repeated outbreaks of emerging pathogens underscore the need for preparedness plans to prevent, detect, and respond. As countries develop and improve National Action Plans for Health Security, ...addressing subnational variation in preparedness is increasingly important. One facet of preparedness and mitigating disease transmission is health facility accessibility, linking infected persons with health systems and vice versa. Where potential patients can access care, local facilities must ensure they can appropriately diagnose, treat, and contain disease spread to prevent secondary transmission; where patients cannot readily access facilities, alternate plans must be developed. Here, we use travel time to link facilities and populations at risk of viral hemorrhagic fevers (VHFs) and identify spatial variation in these respective preparedness demands.
We used geospatial resources of travel friction, pathogen environmental suitability, and health facilities to determine facility accessibility of any at-risk location within a country. We considered in-country and cross-border movements of exposed populations and highlighted vulnerable populations where current facilities are inaccessible and new infrastructure would reduce travel times. We developed profiles for 43 African countries. Resulting maps demonstrate gaps in health facility accessibility and highlight facilities closest to areas at risk for VHF spillover. For instance, in the Central African Republic, we identified travel times of over 24 h to access a health facility. Some countries had more uniformly short travel times, such as Nigeria, although regional disparities exist. For some populations, including many in Botswana, access to areas at risk for VHF nationally was low but proximity to suitable spillover areas in bordering countries was high. Additional analyses provide insights for considering future resource allocation. We provide a contemporary use case for these analyses for the ongoing Ebola outbreak.
These maps demonstrate the use of geospatial analytics for subnational preparedness, identifying facilities close to at-risk populations for prioritizing readiness to detect, treat, and respond to cases and highlighting where gaps in health facility accessibility exist. We identified cross-border threats for VHF exposure and demonstrate an opportunity to improve preparedness activities through the use of precision public health methods and data-driven insights for resource allocation as part of a country's preparedness plans.
Sea-surface temperature (SST) warming events, which are projected to increase in frequency and intensity with climate change, represent major threats to coral reefs. How these events impact reef ...carbonate budgets, and thus the capacity of reefs to sustain vertical growth under rising sea levels, remains poorly quantified. Here we quantify the magnitude of changes that followed the ENSO-induced SST warming that affected the Indian Ocean region in mid-2016. Resultant coral bleaching caused an average 75% reduction in coral cover (present mean 6.2%). Most critically we report major declines in shallow fore-reef carbonate budgets, these shifting from strongly net positive (mean 5.92 G, where G = kg CaCO
m
yr
) to strongly net negative (mean -2.96 G). These changes have driven major reductions in reef growth potential, which have declined from an average 4.2 to -0.4 mm yr
. Thus these shallow fore-reef habitats are now in a phase of net erosion. Based on past bleaching recovery trajectories, and predicted increases in bleaching frequency, we predict a prolonged period of suppressed budget and reef growth states. This will limit reef capacity to track IPCC projections of sea-level rise, thus limiting the natural breakwater capacity of these reefs and threatening reef island stability.
We present a complete sample of molecular clumps containing compact and ultracompact H ii (UC H ii) regions between = 10° and 60° and |b| < 1°, identified by combining the APEX Telescope Large Area ...Survey of the Galaxy submm and CORNISH radio continuum surveys with visual examination of archival infrared data. Our sample is complete to optically thin, compact and UC H ii regions driven by a zero-age main-sequence star of spectral type B0 or earlier embedded within a 1000 M clump. In total we identify 213 compact and UC H ii regions, associated with 170 clumps. Unambiguous kinematic distances are derived for these clumps and used to estimate their masses and physical sizes, as well as the Lyman continuum fluxes and sizes of their embedded H ii regions. We find a clear lower envelope for the surface density of molecular clumps hosting massive star formation of 0.05 g cm−2, which is consistent with a similar sample of clumps associated with 6.7 GHz masers. The mass of the most massive embedded stars is closely correlated with the mass of their natal clump. Young B stars appear to be significantly more luminous in the ultraviolet than predicted by current stellar atmosphere models. The properties of clumps associated with compact and UC H ii regions are very similar to those associated with 6.7 GHz methanol masers and we speculate that there is little evolution in the structure of the molecular clumps between these two phases. Finally, we identify a significant peak in the surface density of compact and UC H ii-regions associated with the W49A star-forming complex, noting that this complex is truly one of the most massive and intense regions of star formation in the Galaxy.
We observed electronic K x rays emitted from muonic iron atoms using superconducting transition-edge sensor microcalorimeters. The energy resolution of 5.2 eV in FWHM allowed us to observe the ...asymmetric broad profile of the electronic characteristic K α and K β x rays together with the hypersatellite Khα x rays around 6 keV. This signature reflects the time-dependent screening of the nuclear charge by the negative muon and the L-shell electrons, accompanied by electron side feeding. Assisted by a simulation, these data clearly reveal the electronic K - and L-shell hole production and their temporal evolution on the 10–20 fs scale during the muon cascade process.
To compare effects of combinations of standard and intensive treatment of glycemia and either blood pressure (BP) or lipids in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
...ACCORD enrolled 10,251 type 2 diabetes patients aged 40-79 years at high risk for cardiovascular disease (CVD) events. Participants were randomly assigned to hemoglobin A1c goals of <6.0% (<42 mmol/mol; intensive glycemia) or 7.0-7.9% (53-63 mmol/mol; standard glycemia) and then randomized a second time to either 1) systolic BP goals of <120 mmHg (intensive BP) or <140 mmHg (standard BP) or 2) simvastatin plus fenofibrate (intensive lipid) or simvastatin plus placebo (standard lipid). Proportional hazards models were used to assess combinations of treatment assignments on the composite primary (deaths due to CVD, nonfatal myocardial infarction MI, and nonfatal stroke) and secondary outcomes.
In the BP trial, risk of the primary outcome was lower in the groups intensively treated for glycemia (hazard ratio HR 0.67; 95% CI 0.50-0.91), BP (HR 0.74; 95% CI 0.55-1.00), or both (HR 0.71; 95% CI 0.52-0.96) compared with combined standard BP and glycemia treatment. For secondary outcomes, MI was significantly reduced by intensive glycemia treatment and stroke by intensive BP treatment; most other HRs were neutral or favored intensive treatment groups. In the lipid trial, the general pattern of results showed no evidence of benefit of intensive regimens (whether single or combined) compared with combined standard lipid and glycemia treatment. The mortality HR was 1.33 (95% CI 1.02-1.74) in the standard lipid/intensive glycemia group compared with the standard lipid/standard glycemia group.
In the ACCORD BP trial, compared with combined standard treatment, intensive BP or intensive glycemia treatment alone improved major CVD outcomes, without additional benefit from combining the two. In the ACCORD lipid trial, neither intensive lipid nor glycemia treatment produced an overall benefit, but intensive glycemia treatment increased mortality.
To test bound-state quantum electrodynamics (BSQED) in the strong-field regime, we have performed high precision x-ray spectroscopy of the 5g-4f and 5f- 4d transitions (BSQED contribution of 2.4 and ...5.2 eV, respectively) of muonic neon atoms in the low-pressure gas phase without bound electrons. Muonic atoms have been recently proposed as an alternative to few-electron high-Z ions for BSQED tests by focusing on circular Rydberg states where nuclear contributions are negligibly small. We determined the 5g_{9/2}- 4f_{7/2} transition energy to be 6297.08±0.04(stat)±0.13(syst) eV using superconducting transition-edge sensor microcalorimeters (5.2-5.5 eV FWHM resolution), which agrees well with the most advanced BSQED theoretical prediction of 6297.26 eV.
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