Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus

Persistent activation of GABAA receptors by extracellular GABA (tonic inhibition) plays a critical role in signal processing and network excitability in the brain. In hippocampal principal cells, tonic inhibition has been reported to be mediated by {alpha}5-subunit-containing GABAA receptors ({alpha}5GABAARs). Pharmacological or genetic disruption of these receptors improves cognitive performance, suggesting that tonic inhibition has an adverse effect on information processing. Here, we show that {alpha}5GABAARs contribute to tonic currents in pyramidal cells only when ambient GABA concentrations increase (as may occur during increased brain activity). At low ambient GABA concentrations, activation of {delta}-subunit-containing GABAA receptors predominates. In epileptic tissue, {alpha}5GABAARs are downregulated and no longer contribute to tonic currents under conditions of raised extracellular GABA concentrations. Under these conditions, however, the tonic current is greater in pyramidal cells from epileptic tissue than in pyramidal cells from nonepileptic tissue, implying substitution of {alpha}5GABAARs by other GABAA receptor subtypes. These results reveal multiple components of tonic GABAA receptor-mediated conductance that are activated by low GABA concentrations. The relative contribution of these components changes after the induction of epilepsy, implying an adaptive plasticity of the tonic current in the presence of spontaneous seizures

Plasticity of GABA(B) receptor-mediated heterosynaptic interactions at mossy fibers after status epilepticus

Several neurotransmitters, including GABA acting at presynaptic GABAB receptors, modulate glutamate release at synapses between hippocampal mossy fibers and CA3 pyramidal neurons. This phenomenon gates excitation of the hippocampus and may therefore prevent limbic seizure propagation. Here we report that status epilepticus, triggered by either perforant path stimulation or pilocarpine administration, was followed 24 hr later by a loss of GABAB receptor-mediated heterosynaptic depression among populations of mossy fibers. This was accompanied by a decrease in the sensitivity of mossy fiber transmission to the exogenous GABAB receptor agonist baclofen. Autoradiography revealed a reduction in GABAB receptor binding in the stratum lucidum after status epilepticus. Failure of GABAB receptor-mediated modulation of mossy fiber transmission at mossy fibers may contribute to the development of spontaneous seizures after status epilepticus

The GEOSAT Follow-on (GFO) Altimeter

The NAVY GEOSAT Mission (1985-1990) demonstrated the ability of an altimeter equipped satellite to provide global measurements of mesoscale ocean features with 3 centimeter precision. The GEOSAT radar altimeter, developed by JHU/APL, was an enormous success. Built with early 1980\u27s technology, the GEOSAT altimeter weighed 191 pounds and consumed 146 watts. The GFO radar altimeter, under development by E-Systems Inc., will achieve the GEOSAT measurement capability, but at one-third the weight and one-half the power (48 pounds, excluding antenna, and 76 watts). The GFO altimeter uses the same proven linear FM waveform, pulse repetition frequency (PRF), pulse compression technique, and alpha-beta tracker design as the GEOSAT radar altimeter, but takes advantage of current RF and digital signal processing technologies to produce an instrument that is both light-weight and reliable. Also, thanks to a cooperative working relationship with JHU/APL, the GFO radar altimeter design encompasses lessons learned from both the GEOSAT and TOPEX programs. Analysis of the range, waveheight, and back-scattering cross section performance indicates that the GFO altimeter will achieve the GEOSAT performance in all areas. Finally, the GFO altimeter design encompasses features allowing economical expansion; including a C-band channel for improved range accuracy, and a 33% higher PRF for improved instrument noise performance. The GFO dual-channel altimeter would weigh 107 pounds and consume 156 watts

Structure of protease-cleaved escherichia coliα-2-macroglobulin reveals a putative mechanism of conformational activation for protease entrapment

Bacterial -2-macroglobulins have been suggested to function in defence as broad-spectrum inhibitors of host proteases that breach the outer membrane. Here, the X-ray structure of protease-cleaved Escherichia coli -2-macroglobulin is described, which reveals a putative mechanism of activation and conformational change essential for protease inhibition. In this competitive mechanism, protease cleavage of the bait-region domain results in the untethering of an intrinsically disordered region of this domain which disrupts native interdomain interactions that maintain E. coli -2-macroglobulin in the inactivated form. The resulting global conformational change results in entrapment of the protease and activation of the thioester bond that covalently links to the attacking protease. Owing to the similarity in structure and domain architecture of Escherichia coli -2-macroglobulin and human -2-macro­globulin, this protease-activation mechanism is likely to operate across the diverse members of this group

In-medium broadening of nucleon resonances

We analyze the effects of an in-medium broadening of nucleon resonances on the exclusive photoproduction of mesons on nuclei as well as on the total photoabsorption cross sections in a transport calculation. We show that the resonance widths observed in semi-inclusive photoproduction on nuclei are insensitive to an in-medium broadening of nucleon resonances. This is due to a simple effect: the sizeable width of the nuclear surface and Fermi motion.Comment: 4 pages, 3 figures, minor changes in the tex

Stability constants of U(VI) and U(IV)-humic acid complexes

Conditional stability constants have been determined for U(IV) and U(VI) Boom Clay humic acid (BCHA) and Aldrich humic acid (AHA) complexes, under anaerobic and carbonate free conditions. The constants are needed for nuclear waste repository performance assessment purposes. The U(IV) constants were obtained by developing an approach based on the solubility product of amorphous U(OH)4. The U(VI) constants were obtained by applying the Schubert ion exchange approach

Isotope dependence and quantum effects on atomic hydrogen diffusion in liquid water

Relative diffusion coefficients were determined in water for the D, H, and Mu isotopes of atomic hydrogen by measuring their diffusion-limited spin-exchange rate constants with Ni2+ as a function of temperature. H and D atoms were generated by pulse radiolysis of water and measured by time-resolved pulsed EPR. Mu atoms are detected by muonium spin resonance. To isolate the atomic mass effect from solvent isotope effect, we measured all three spin-exchange rates in 90% D2O. The diffusion depends on the atomic mass, demonstrating breakdown of Stokes−Einstein behavior. The diffusion can be understood using a combination of water “cavity diffusion” and “hopping” mechanisms, as has been proposed in the literature. The H/D isotope effect agrees with previous modeling using ring polymer molecular dynamics. The “quantum swelling” effect on muonium due to its larger de Broglie wavelength does not seem to slow its “hopping” diffusion as much as predicted in previous work. Quantum effects of both the atom mass and the water librations have been modeled using RPMD and a qTIP4P/f quantized flexible water model. These results suggest that the muonium diffusion is very sensitive to the Mu versus water potential used.Division of Chemical Sciences,Geosciences, and Biosciences, Office of Basic Energy Sciences of the U.S. Department of Energy through award DE-FC02-04ER15533.http://pubs.acs.org/journal/jpcafh2016-12-30hb201

Confined granular packings: structure, stress, and forces

The structure and stresses of static granular packs in cylindrical containers are studied using large-scale discrete element molecular dynamics simulations in three dimensions. We generate packings by both pouring and sedimentation and examine how the final state depends on the method of construction. The vertical stress becomes depth-independent for deep piles and we compare these stress depth-profiles to the classical Janssen theory. The majority of the tangential forces for particle-wall contacts are found to be close to the Coulomb failure criterion, in agreement with the theory of Janssen, while particle-particle contacts in the bulk are far from the Coulomb criterion. In addition, we show that a linear hydrostatic-like region at the top of the packings unexplained by the Janssen theory arises because most of the particle-wall tangential forces in this region are far from the Coulomb yield criterion. The distributions of particle-particle and particle-wall contact forces $P(f)$ exhibit exponential-like decay at large forces in agreement with previous studies.Comment: 11 pages, 11 figures, submitted to PRE (v2) added new references, fixed typo

The cost-effectiveness of prophylaxis strategies for individuals with advanced HIV starting treatment in Africa

Introduction: Many HIV-positive individuals in Africa have advanced disease when initiating antiretroviral therapy (ART) so have high risks of opportunistic infections and death. The REALITY trial found that an enhanced-prophylaxis package including fluconazole reduced mortality by 27% in individuals starting ART with CD4<100 cells/mm3. We investigated the cost-effectiveness of this enhanced-prophylaxis package versus other strategies, including using cryptococcal antigen (CrAg) testing, in individuals with CD4<200 cells/mm3 or <100 cells/mm3 at ART initiation and all individuals regardless of CD4 count. Methods: The REALITY trial enrolled from June 2013 to April 2015. A decision-analytic model was developed to estimate the cost-effectiveness of six management strategies in individuals initiating ART in the REALITY trial countries. Strategies included standard-prophylaxis, enhanced-prophylaxis, standard-prophylaxis with fluconazole; and three CrAg testing strategies, the first stratifying individuals to enhanced-prophylaxis (CrAg-positive) or standard-prophylaxis (CrAg-negative), the second to enhanced-prophylaxis (CrAg-positive) or enhanced-prophylaxis without fluconazole (CrAg-negative) and the third to standard-prophylaxis with fluconazole (CrAg-positive) or without fluconazole (CrAg-negative). The model estimated costs, life-years and quality-adjusted life-years (QALY) over 48 weeks using three competing mortality risks: cryptococcal meningitis; tuberculosis, serious bacterial infection or other known cause; and unknown cause. Results: Enhanced-prophylaxis was cost-effective at cost-effectiveness thresholds of US$300 and US$500 per QALY with an incremental cost-effectiveness ratio (ICER) of US$157 per QALY in the CD4<200 cells/mm3 population providing enhanced-prophylaxis components are sourced at lowest available prices. The ICER reduced in more severely immunosuppressed individuals (US$113 per QALY in the CD4<100 cells/mm3 population) and increased in all individuals regardless of CD4 count (US$722 per QALY). Results were sensitive to prices of the enhanced-prophylaxis components. Enhanced-prophylaxis was more effective and less costly than all CrAg testing strategies as enhanced-prophylaxis still conveyed health gains in CrAg-negative patients and savings from targeting prophylaxis based on CrAg status did not compensate for costs of CrAg testing. CrAg testing strategies did not become cost-effective unless the price of CrAg testing fell below US$2.30. Conclusions: The REALITY enhanced-prophylaxis package in individuals with advanced HIV starting ART reduces morbidity and mortality, is practical to administer and is cost-effective. Efforts should continue to ensure that components are accessed at lowest available prices. Funding REALITY was funded by the Joint Global Health Trials Scheme (JGHTS) of the UK Department for International Development (DFID), the Wellcome Trust and Medical Research Council (MRC)