The SV2A ligand levetiracetam inhibits presynaptic Ca2+ channels via an intracellular pathway

Levetiracetam (LEV) is a prominent antiepileptic drug (AED) which binds to neuronal synaptic vesicle glycoprotein 2A (SV2A) protein and has reported effects on ion channels, but retains a poorly-defined mechanism of action. Here, we investigate inhibition of voltage-dependent Ca2+ (CaV) channels as a potential mechanism by which LEV imparts effects on neuronal activity. We used electrophysiological methods to investigate the effects of LEV on cholinergic synaptic transmission and CaV channel activity in superior cervical ganglion neurons (SCGNs). In parallel, we investigated effects of the LEV ‘inactive’ R-enantiomer, UCB L060. Thus, LEV, but not UCB L060 (each 100 μM), inhibited synaptic transmission between SCGNs in long-term culture in a time-dependent manner, significantly reducing excitatory postsynaptic potentials (EPSP) following ≥30 min application. In isolated SCGNs, LEV pretreatment (≥1 h), but not acute (5 min) application, significantly inhibited whole-cell IBa amplitude. In current clamp recordings, LEV reduced the amplitude of the afterhyperpolarizing potential (AHP) in a Ca2+-dependent manner, but also increased action potential (AP) latency in a Ca2+-independent manner, suggesting further mechanisms associated with reduced excitability. Intracellular LEV application (4-5 min) caused a rapid inhibition of IBa amplitude to an extent comparable to that seen following extracellular LEV pretreatment ( ≥ 1 h). Neither pretreatment nor intracellular application of UCB L060 produced any inhibitory effects on IBa amplitude. These results identify a stereospecific intracellular pathway by which LEV inhibits presynaptic CaV channels; resultant reductions in neuronal excitability are proposed to contribute to the anticonvulsant effects of LEV.

A variational method to retrieve the extinction profile in liquid clouds using multiple field-of-view lidar

Liquid clouds play a profound role in the global radiation budget but it is difficult to remotely retrieve their vertical profile. Ordinary narrow field-of-view (FOV) lidars receive a strong return from such clouds but the information is limited to the first few optical depths. Wideangle multiple-FOV lidars can isolate radiation scattered multiple times before returning to the instrument, often penetrating much deeper into the cloud than the singly-scattered signal. These returns potentially contain information on the vertical profile of extinction coefficient, but are challenging to interpret due to the lack of a fast radiative transfer model for simulating them. This paper describes a variational algorithm that incorporates a fast forward model based on the time-dependent two-stream approximation, and its adjoint. Application of the algorithm to simulated data from a hypothetical airborne three-FOV lidar with a maximum footprint width of 600m suggests that this approach should be able to retrieve the extinction structure down to an optical depth of around 6, and total opticaldepth up to at least 35, depending on the maximum lidar FOV. The convergence behavior of Gauss-Newton and quasi-Newton optimization schemes are compared. We then present results from an application of the algorithm to observations of stratocumulus by the 8-FOV airborne “THOR” lidar. It is demonstrated how the averaging kernel can be used to diagnose the effective vertical resolution of the retrieved profile, and therefore the depth to which information on the vertical structure can be recovered. This work enables exploitation of returns from spaceborne lidar and radar subject to multiple scattering more rigorously than previously possible.

Preventing carbon contamination of optical devices for X-rays: the effect of oxygen on photon-induced dissociation of CO on platinum

Platinum is one of the most common coatings used to optimize mirror reflectivity in soft X-ray beamlines. Normal operation results in optics contamination by carbon-based molecules present in the residual vacuum of the beamlines. The reflectivity reduction induced by a carbon layer at the mirror surface is a major problem in synchrotron radiation sources. A time-dependent photoelectron spectroscopy study of the chemical reactions which take place at the Pt(111) surface under operating conditions is presented. It is shown that the carbon contamination layer growth can be stopped and reversed by low partial pressures of oxygen for optics operated in intense photon beams at liquidnitrogen temperature. For mirrors operated at room temperature the carbon contamination observed for equivalent partial pressures of CO is reduced and the effects of oxygen are observed on a long time scale.

Quantifying volcanic ash dispersal and impact of the Campanian Ignimbrite super-eruption

1] We apply a novel computational approach to assess, for the first time, volcanic ash dispersal during the Campanian Ignimbrite (Italy) super-eruption providing insights into eruption dynamics and the impact of this gigantic event. The method uses a 3D time-dependent computational ash dispersion model, a set of wind fields, and more than 100 thickness measurements of the CI tephra deposit. Results reveal that the CI eruption dispersed 250–300 km3 of ash over ∼3.7 million km2. The injection of such a large quantity of ash (and volatiles) into the atmosphere would have caused a volcanic winter during the Heinrich Event 4, the coldest and driest climatic episode of the Last Glacial period. Fluorine-bearing leachate from the volcanic ash and acid rain would have further affected food sources and severely impacted Late Middle-Early Upper Paleolithic groups in Southern and Eastern Europe

On the quantum mechanical scattering statistics of many particles

The probability of a quantum particle being detected in a given solid angle is determined by the S-matrix. The explanation of this fact in time-dependent scattering theory is often linked to the quantum flux, since the quantum flux integrated against a (detector-) surface and over a time interval can be viewed as the probability that the particle crosses this surface within the given time interval. Regarding many particle scattering, however, this argument is no longer valid, as each particle arrives at the detector at its own random time. While various treatments of this problem can be envisaged, here we present a straightforward Bohmian analysis of many particle potential scattering from which the S-matrix probability emerges in the limit of large distances.

Unprecedented coordination of dithiocarbimate in multinuclear and heteroleptic complexes

An uncommon coordination protocol induced by the p-tolylsulfonyl dithiocarbimate ligand (L) [L = p-CH(3)C(6)H(4)SO(2)N CS(2)(2-)] in conjunction with PPh(3) allowed the formation of novel homodimetallic, Cu(2)(PPh(3))(4)L (1), trinuclear heterometallic Cu(2)Ni(L)(2)(PPh(3))(4) (2) and heteroleptic complexes of general formula cis-[M(PPh(3))(2)L] [M = Pd(II) (3), Pt(II) (4)]. The complexes have been characterized by microanalysis, mass spectrometry, IR, (1)H, (13)C and (31)P NMR and electronic absorption spectra and single-crystal X-ray crystallography. 2 uniquely consists of square planar, trigonal planar and tetrahedral coordination spheres within the same molecule. In both heteroleptic complexes 3 and 4 the orientation of aromatic protons of PPh(3) ligand towards the Pd(II) and Pt(II) center reveals C-H center dot center dot center dot Pd and C-H center dot center dot center dot Pt rare intramolecular anagostic or preagostic interactions. These complexes exhibit photoluminescent properties in solution at room temperature arising mainly from intraligand charge transfer (ILCT) transitions. The assignment of electronic absorption bands has been corroborated by time dependent density functional theory (TD-DFT) calculations. Complexes 1 and 2 with sigma(rt) values similar to 10(-6) S cm(-1) show semi-conductor properties in the temperature range 313-403 K whereas 3 and 4 exhibit insulating behaviour.

Phosphorylation of the voltage-gated potassium channel Kv2.1 by AMP-activated protein kinase regulates membrane excitability

Firing of action potentials in excitable cells accelerates ATP turnover. The voltage-gated potassium channel Kv2.1 regulates action potential frequency in central neurons, whereas the ubiquitous cellular energy sensor AMP-activated protein kinase (AMPK) is activated by ATP depletion and protects cells by switching off energy-consuming processes. We show that treatment of HEK293 cells expressing Kv2.1 with the AMPK activator A-769662 caused hyperpolarizing shifts in the current-voltage relationship for channel activation and inactivation. We identified two sites (S440 and S537) directly phosphorylated on Kv2.1 by AMPK and, using phosphospecific antibodies and quantitative mass spectrometry, show that phosphorylation of both sites increased in A-769662-treated cells. Effects of A-769662 were abolished in cells expressing Kv2.1 with S440A but not with S537A substitutions, suggesting that phosphorylation of S440 was responsible for these effects. Identical shifts in voltage gating were observed after introducing into cells, via the patch pipette, recombinant AMPK rendered active but phosphatase-resistant by thiophosphorylation. Ionomycin caused changes in Kv2.1 gating very similar to those caused by A-769662 but acted via a different mechanism involving Kv2.1 dephosphorylation. In cultured rat hippocampal neurons, A-769662 caused hyperpolarizing shifts in voltage gating similar to those in HEK293 cells, effects that were abolished by intracellular dialysis with Kv2.1 antibodies. When active thiophosphorylated AMPK was introduced into cultured neurons via the patch pipette, a progressive, time-dependent decrease in the frequency of evoked action potentials was observed. Our results suggest that activation of AMPK in neurons during conditions of metabolic stress exerts a protective role by reducing neuronal excitability and thus conserving energy.

Transient climate change simulations with a coupled atmosphere–ocean GCM including the tropospheric sulfur cycle

The time-dependent climate response to changing concentrations of greenhouse gases and sulfate aerosols is studied using a coupled general circulation model of the atmosphere and the ocean (ECHAM4/OPYC3). The concentrations of the well-mixed greenhouse gases like CO2, CH4, N2O, and CFCs are prescribed for the past (1860–1990) and projected into the future according to International Panel on Climate Change (IPCC) scenario IS92a. In addition, the space–time distribution of tropospheric ozone is prescribed, and the tropospheric sulfur cycle is calculated within the coupled model using sulfur emissions of the past and projected into the future (IS92a). The radiative impact of the aerosols is considered via both the direct and the indirect (i.e., through cloud albedo) effect. It is shown that the simulated trend in sulfate deposition since the end of the last century is broadly consistent with ice core measurements, and the calculated radiative forcings from preindustrial to present time are within the uncertainty range estimated by IPCC. Three climate perturbation experiments are performed, applying different forcing mechanisms, and the results are compared with those obtained from a 300-yr unforced control experiment. As in previous experiments, the climate response is similar, but weaker, if aerosol effects are included in addition to greenhouse gases. One notable difference to previous experiments is that the strength of the Indian summer monsoon is not fundamentally affected by the inclusion of aerosol effects. Although the monsoon is damped compared to a greenhouse gas only experiment, it is still more vigorous than in the control experiment. This different behavior, compared to previous studies, is the result of the different land–sea distribution of aerosol forcing. Somewhat unexpected, the intensity of the global hydrological cycle becomes weaker in a warmer climate if both direct and indirect aerosol effects are included in addition to the greenhouse gases. This can be related to anomalous net radiative cooling of the earth’s surface through aerosols, which is balanced by reduced turbulent transfer of both sensible and latent heat from the surface to the atmosphere.

Using paleo-climate comparisons to constrain future projections in CMIP5

We present a description of the theoretical framework and "best practice" for using the paleo-climate model component of the Coupled Model Intercomparison Project (Phase 5) (CMIP5) to constrain future projections of climate using the same models. The constraints arise from measures of skill in hindcasting paleo-climate changes from the present over 3 periods: the Last Glacial Maximum (LGM) (21 thousand years before present, ka), the mid-Holocene (MH) (6 ka) and the Last Millennium (LM) (850–1850 CE). The skill measures may be used to validate robust patterns of climate change across scenarios or to distinguish between models that have differing outcomes in future scenarios. We find that the multi-model ensemble of paleo-simulations is adequate for addressing at least some of these issues. For example, selected benchmarks for the LGM and MH are correlated to the rank of future projections of precipitation/temperature or sea ice extent to indicate that models that produce the best agreement with paleoclimate information give demonstrably different future results than the rest of the models. We also find that some comparisons, for instance associated with model variability, are strongly dependent on uncertain forcing timeseries, or show time dependent behaviour, making direct inferences for the future problematic. Overall, we demonstrate that there is a strong potential for the paleo-climate simulations to help inform the future projections and urge all the modeling groups to complete this subset of the CMIP5 runs.

The formation of ice in a long-lived supercooled layer cloud

This article focuses on the characteristics of persistent thin single-layer mixed-phase clouds. We seek to answer two important questions: (i) how does ice continually nucleate and precipitate from these clouds, without the available ice nuclei becoming depleted? (ii) how do the supercooled liquid droplets persist in spite of the net flux of water vapour to the growing ice crystals? These questions are answered quantitatively using in situ and radar observations of a long-lived mixed-phase cloud layer over the Chilbolton Observatory. Doppler radar measurements show that the top 500 m of cloud (the top 250 m of which is mixed-phase, with ice virga beneath) is turbulent and well-mixed, and the liquid water content is adiabatic. This well-mixed layer is bounded above and below by stable layers. This inhibits entrainment of fresh ice nuclei into the cloud layer, yet our in situ and radar observations show that a steady flux of ≈100 m−2s−1 ice crystals fell from the cloud over the course of ∼1 day. Comparing this flux to the concentration of conventional ice nuclei expected to be present within the well-mixed layer, we find that these nuclei would be depleted within less than 1 h. We therefore argue that nucleation in these persistent supercooled clouds is strongly time-dependent in nature, with droplets freezing slowly over many hours, significantly longer than the few seconds residence time of an ice nucleus counter. Once nucleated, the ice crystals are observed to grow primarily by vapour deposition, because of the low liquid water path (21 g m−2) yet vapour-rich environment. Evidence for this comes from high differential reflectivity in the radar observations, and in situ imaging of the crystals. The flux of vapour from liquid to ice is quantified from in situ measurements, and we show that this modest flux (3.3 g m−2h−1) can be readily offset by slow radiative cooling of the layer to space.

Comparison of the open-closed separatrix in a global magnetospheric simulation with observations: the role of the ring current

The development of global magnetospheric models, such as Space Weather Modeling Framework (SWMF), which can accurately reproduce and track space weather processes has high practical utility. We present an interval on 5 June 1998, where the location of the polar cap boundary, or open-closed field line boundary (OCB), can be determined in the ionosphere using a combination of instruments during a period encompassing a sharp northward to southward interplanetary field turning. We present both point- and time-varying comparisons of the observed and simulated boundaries in the ionosphere and find that when using solely the coupled ideal magnetohydrodynamic magnetosphere-ionosphere model, the rate of change of the OCB to a southward turning of the interplanetary field is significantly faster than that computed from the observational data. However, when the inner magnetospheric module is incorporated, the modeling framework both qualitatively, and often quantitatively, reproduces many elements of the studied interval prior to an observed substorm onset. This result demonstrates that the physics of the inner magnetosphere is critical in shaping the boundary between open and closed field lines during periods of southward interplanetary magnetic field (IMF) and provides significant insight into the 3-D time-dependent behavior of the Earth's magnetosphere in response to a northward-southward IMF turning. We assert that during periods that do not include the tens of minutes surrounding substorm expansion phase onset, the coupled SWMF model may provide a valuable and reliable tool for estimating both the OCB and magnetic field topology over a wide range of latitudes and local times.

The stability of a two-dimensional vorticity filament under uniform strain

The quantitative effects of uniform strain and background rotation on the stability of a strip of constant vorticity (a simple shear layer) are examined. The thickness of the strip decreases in time under the strain, so it is necessary to formulate the linear stability analysis for a time-dependent basic flow. The results show that even a strain rate γ (scaled with the vorticity of the strip) as small as 0.25 suppresses the conventional Rayleigh shear instability mechanism, in the sense that the r.m.s. wave steepness cannot amplify by more than a certain factor, and must eventually decay. For γ < 0.25 the amplification factor increases as γ decreases; however, it is only 3 when γ e 0.065. Numerical simulations confirm the predictions of linear theory at small steepness and predict a threshold value necessary for the formation of coherent vortices. The results help to explain the impression from numerous simulations of two-dimensional turbulence reported in the literature that filaments of vorticity infrequently roll up into vortices. The stabilization effect may be expected to extend to two- and three-dimensional quasi-geostrophic flows.

On the 'downward control' of extratropical diabatic circulations by eddy-induced mean zonal forces

The situation considered is that of a zonally symmetric model of the middle atmosphere subject to a given quasi-steady zonal force F̄, conceived to be the result of irreversible angular momentum transfer due to the upward propagation and breaking of Rossby and gravity waves together with any other dissipative eddy effects that may be relevant. The model's diabatic heating is assumed to have the qualitative character of a relaxation toward some radiatively determined temperature field. To the extent that the force F̄ may be regarded as given, and the extratropical angular momentum distribution is realistic, the extratropical diabatic mass flow across a given isentropic surface may be regarded as controlled exclusively by the F̄ distribution above that surface (implying control by the eddy dissipation above that surface and not, for instance, by the frequency of tropopause folding below). This “downward control” principle expresses a critical part of the dynamical chain of cause and effect governing the average rate at which photochemical products like ozone become available for folding into, or otherwise descending into, the extratropical troposphere. The dynamical facts expressed by the principle are also relevant, for instance, to understanding the seasonal-mean rate of upwelling of water vapor to the summer mesopause, and the interhemispheric differences in stratospheric tracer transport. The robustness of the principle is examined when F̄ is time-dependent. For a global-scale, zonally symmetric diabatic circulation with a Brewer-Dobson-like horizontal structure given by the second zonally symmetric Hough mode, with Rossby height HR = 13 km in an isothermal atmosphere with density scale height H = 7 km, the vertical partitioning of the unsteady part of the mass circulation caused by fluctuations in F̄ confined to a shallow layer LF̄ is always at least 84% downward. It is 90% downward when the force fluctuates sinusoidally on twice the radiative relaxation timescale and 95% if five times slower. The time-dependent adjustment when F̄ is changed suddenly is elucidated, extending the work of Dickinson (1968), when the atmosphere is unbounded above and below. Above the forcing, the adjustment is characterized by decay of the meridional mass circulation cell at a rate proportional to the radiative relaxation rate τr−1 divided by {1 + (4H2/HR2)}. This decay is related to the boundedness of the angular momentum that can be taken up by the finite mass of air above LF̄ without causing an ever-increasing departure from thermal wind balance. Below the forcing, the meridional mass circulation cell penetrates downward at a speed τr−1 HR2/H. For the second Hough mode, the time for downward penetration through one density scale height is about 6 days if the radiative relaxation time is 20 days, the latter being representative of the lower stratosphere. At any given altitude, a steady state is approached. The effect of a rigid lower boundary on the time-dependent adjustment is also considered. If a frictional planetary boundary layer is present then a steady state is ultimately approached everywhere, with the mass circulation extending downward from LF̄ and closing via the boundary layer. Satellite observations of temperature and ozone are used in conjunction with a radiative transfer scheme to estimate the altitudes from which the lower stratospheric diabatic vertical velocity is controlled by the effective F̄ in the real atmosphere. The data appear to indicate that about 80% of the effective control is usually exerted from below 40 km but with significant exceptions up to 70 km (in the high latitude southern hemispheric winter). The implications for numerical modelling of chemical transport are noted.

Money enhances memory consolidation – but only for boring material

Money’s ability to enhance memory has received increased attention in recent research. However, previous studies have not directly addressed the time-dependent nature of monetary effects on memory, which are suggested to exist by research in cognitive neuroscience, and the possible detrimental effects of monetary rewards on learning interesting material, as indicated by studies in motivational psychology. By utilizing a trivia question paradigm, the current study incorporated these perspectives and examined the effect of monetary rewards on immediate and delayed memory performance for answers to uninteresting and interesting questions. Results showed that monetary rewards promote memory performance only after a delay. In addition, the memory enhancement effect of monetary rewards was only observed for uninteresting questions. These results are consistent with both the hippocampus-dependent memory consolidation model of reward learning and previous findings documenting the ineffectiveness of monetary rewards on tasks that have intrinsic value.

Fireball models for flares in AE Aquarii

We examine the flaring behaviour of the cataclysmic variable AE Aqr in the context of the `magnetic propeller' model for this system. The flares are thought to arise from collisions between high-density regions in the material expelled from the system after interaction with the rapidly rotating magnetosphere of the white dwarf. We calculate the first quantitative models for the flaring and calculate the time-dependent emergent optical spectra from the resulting hot, expanding ball of gas. We compare the results under different assumptions to observations and derive values for the mass, length-scale and temperature of the material involved in the flare. We see that the fits suggest that the secondary star in this system has Population II composition.