Recovery of NMDA receptor currents from MK-801 blockade is accelerated by Mg2+ and memantine under conditions of agonist exposure

AbstractMK-801 is a use-dependent NMDA receptor open channel blocker with a very slow off-rate. These properties can be exploited to ‘pre-block’ a population of NMDARs, such as synaptic ones, enabling the selective activation of a different population, such as extrasynaptic NMDARs. However, the usefulness of this approach is dependent on the stability of MK-801 blockade after washout. We have revisited this issue, and confirm that recovery of NMDAR currents from MK-801 blockade is enhanced by channel opening by NMDA, and find that it is further increased when Mg2+ is also present. In the presence of Mg2+, 50% recovery from MK-801 blockade is achieved after 10′ of 100 μM NMDA, or 30′ of 15 μM NMDA exposure. In Mg2+-free medium, NMDA-induced MK-801 dissociation was found to be much slower. Memantine, another PCP-site antagonist, could substitute for Mg2+ in accelerating the unblock of MK-801 in the presence of NMDA. This suggests a model whereby, upon dissociation from its binding site in the pore, MK-801 is able to re-bind in a process antagonized by Mg2+ or another PCP-site antagonist. Finally we show that even when all NMDARs are pre-blocked by MK-801, incubation of neurons with 100 μM NMDA in the presence of Mg2+ for 2.5 h triggers sufficient unblocking to kill >80% of neurons. We conclude that while synaptic MK-801 ‘pre-block’ protocols are useful for pharmacologically assessing synaptic vs. extrasynaptic contributions to NMDAR currents, or studying short-term effects, it is problematic to use this technique to attempt to study the effects of long-term selective extrasynaptic NMDAR activation.This article is part of the Special Issue entitled ‘Glutamate Receptor-Dependent Synaptic Plasticity’

Estimating prevalence of overweight and obesity at the neighborhood level: the value of maternal height and weight data available on birth certificate records

<p>Abstract</p> <p>Objective</p> <p>To determine the value of maternal height and weight data on birth certificate records when estimating prevalence of overweight and obese adults at the neighborhood level.</p> <p>Research Design and Methods</p> <p>Regression analysis was used to determine how much variation in the percentage of the adult population with a body mass index (BMI) of ≥ 25 (based on survey data) could be accounted for by the percentage of mothers with BMI ≥ 25 (based on birth certificate data) -- alone and in combination with other sociodemographic characteristics of census tracts.</p> <p>Results</p> <p>Alone, the percentage of mothers with BMI ≥ 25 explained more than half (R²= .52) of the variation in the percentage of all residents in census tracts with BMI ≥ 25; in combination with several measures of the sociodemographic characteristics of the census tracts, 75% ( R²= 75.2) of the variation is explained.</p> <p>Conclusions</p> <p>Maternal height and weight data available from birth certificate records may be useful for identifying neighborhoods with relatively high or low prevalence of adult residents who are overweight or obese. This is especially true if used in combination with readily available census data.</p

A summary of the 6th international conference on coagulation in liver disease : discussion, debate, deliberations

Editor’s Preface from Nahum Mendez Sanchez: Below, the Editors of Annals of Hepatology provide a summary report from the 2015 multidisciplinary Coagulation in Liver Disease group meeting. This group which originated in 2005 is dedicated to issues of Coagulation, Hemostasis and Thrombosis in Liver Disease patients and includes members from diverse Specialties including representation from the fields of Hepatology, Hematology, Surgery, Anesthesiology, Pathology, Interventional Radiology, Laboratory Medicine, Transfusion Sciences and Blood Banking with a combined approach of basic and clinical Sciences. The aim of the symposium was to raise points of convergence of interest and research and to provide a forum to facilitate collaboration in order to advance the field. [Introduction]peer-reviewe

GBA variants in REM sleep behavior disorder: a multicenter study

To study the role of GBA variants in the risk for isolated rapid-eye-movement (REM)-sleep behavior disorder (iRBD) and conversion to overt neurodegeneration

The case for strategic international alliances to harness nutritional genomics for public and personal health

Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene-nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient-genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countrie

Provenance of Cretaceous through Eocene strata of the Four Corners region: Insights from detrital zircons in the San Juan Basin, New Mexico and Colorado

Cretaceous through Eocene strata of the Four Corners region provide an excellent record of changes in sediment provenance from Sevier thin-skinned thrusting through the formation of Laramide block uplifts and intra-foreland basins. During the ca. 125–50 Ma timespan, the San Juan Basin was flanked by the Sevier thrust belt to the west, the Mogollon highlands rift shoulder to the southwest, and was influenced by (ca. 75–50 Ma) Laramide tectonism, ultimately preserving a >6000 ft (>2000 m) sequence of continental, marginal-marine, and offshore marine sediments. In order to decipher the influences of these tectonic features on sediment delivery to the area, we evaluated 3228 U-Pb laser analyses from 32 detrital-zircon samples from across the entire San Juan Basin, of which 1520 analyses from 16 samples are newly reported herein. The detrital-zircon results indicate four stratigraphic intervals with internally consistent age peaks: (1) Lower Cretaceous Burro Canyon Formation, (2) Turonian (93.9–89.8 Ma) Gallup Sandstone through Campanian (83.6–72.1 Ma) Lewis Shale, (3) Campanian Pictured Cliffs Sandstone through Campanian Fruitland Formation, and (4) Campanian Kirtland Sandstone through Lower Eocene (56.0–47.8 Ma) San Jose Formation. Statistical analysis of the detrital-zircon results, in conjunction with paleocurrent data, reveals three distinct changes in sediment provenance. The first transition, between the Burro Canyon Formation and the Gallup Sandstone, reflects a change from predominantly reworked sediment from the Sevier thrust front, including uplifted Paleozoic sediments and Mesozoic eolian sandstones, to a mixed signature indicating both Sevier and Mogollon derivation. Deposition of the Pictured Cliffs Sandstone at ca. 75 Ma marks the beginning of the second transition and is indicated by the spate of near-depositional-age zircons, likely derived from the Laramide porphyry copper province of southern Arizona and southwestern New Mexico. Paleoflow indicators suggest the third change in provenance was complete by 65 Ma as recorded by the deposition of the Paleocene Ojo Alamo Sandstone. However, our new U-Pb detrital-zircon results indicate this transition initiated ∼8 m.y. earlier during deposition of the Campanian Kirtland Formation beginning ca. 73 Ma. This final change in provenance is interpreted to reflect the unroofing of surrounding Laramide basement blocks and a switch to local derivation. At this time, sediment entering the San Juan Basin was largely being generated from the nearby San Juan Mountains to the north-northwest, including uplift associated with early phases of Colorado mineral belt magmatism. Thus, the detrital-zircon spectra in the San Juan Basin document the transition from initial reworking of the Paleozoic and Mesozoic cratonal blanket to unroofing of distant basement-cored uplifts and Laramide plutonic rocks, then to more local Laramide uplifts.National Science Foundation (NSF grant EAR-1649254

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

The SuperCam Instrument Suite on the Mars 2020 Rover: Science Objectives and Mast-Unit Description

On the NASA 2020 rover mission to Jezero crater, the remote determination of the texture, mineralogy and chemistry of rocks is essential to quickly and thoroughly characterize an area and to optimize the selection of samples for return to Earth. As part of the Perseverance payload, SuperCam is a suite of five techniques that provide critical and complementary observations via Laser-Induced Breakdown Spectroscopy (LIBS), Time-Resolved Raman and Luminescence (TRR/L), visible and near-infrared spectroscopy (VISIR), high-resolution color imaging (RMI), and acoustic recording (MIC). SuperCam operates at remote distances, primarily 2-7 m, while providing data at sub-mm to mm scales. We report on SuperCam's science objectives in the context of the Mars 2020 mission goals and ways the different techniques can address these questions. The instrument is made up of three separate subsystems: the Mast Unit is designed and built in France; the Body Unit is provided by the United States; the calibration target holder is contributed by Spain, and the targets themselves by the entire science team. This publication focuses on the design, development, and tests of the Mast Unit; companion papers describe the other units. The goal of this work is to provide an understanding of the technical choices made, the constraints that were imposed, and ultimately the validated performance of the flight model as it leaves Earth, and it will serve as the foundation for Mars operations and future processing of the data.In France was provided by the Centre National d'Etudes Spatiales (CNES). Human resources were provided in part by the Centre National de la Recherche Scientifique (CNRS) and universities. Funding was provided in the US by NASA's Mars Exploration Program. Some funding of data analyses at Los Alamos National Laboratory (LANL) was provided by laboratory-directed research and development funds