Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB 1 receptor-independent mechanism

BACKGROUND AND PURPOSE Epilepsy is the most prevalent neurological disease and is characterized by recurrent seizures. Here, we investigate (i) the anticonvulsant profiles of cannabis-derived botanical drug substances (BDSs) rich in cannabidivarin (CBDV) and containing cannabidiol (CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their components at cannabinoid CB 1 receptors. EXPERIMENTAL APPROACH The anticonvulsant profiles of two CBDV BDSs (50–422 mg·kg −1 ) were evaluated in three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an isobolographic study to evaluate potential pharmacological interactions. CBDV BDS effects on motor function were also investigated using static beam and grip strength assays. Binding of CBDV BDSs to cannabinoid CB 1 receptors was evaluated using displacement binding assays. KEY RESULTS CBDV BDSs exerted significant anticonvulsant effects in the pentylenetetrazole (≥100 mg·kg −1 ) and audiogenic seizure models (≥87 mg·kg −1 ), and suppressed pilocarpine-induced convulsions (≥100 mg·kg −1 ). The isobolographic study revealed that the anticonvulsant effects of purified CBDV and CBD were linearly additive when co-administered. Some motor effects of CBDV BDSs were observed on static beam performance; no effects on grip strength were found. The Δ 9 -tetrahydrocannabinol and Δ 9 -tetrahydrocannabivarin content of CBDV BDS accounted for its greater affinity for CB 1 cannabinoid receptors than purified CBDV. CONCLUSIONS AND IMPLICATIONS CBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB 1 cannabinoid receptor and were of comparable efficacy with purified CBDV. These findings strongly support the further clinical development of CBDV BDSs for the treatment of epilepsy.

How large is congressional dependence in agriculture. Bayesian inference about ‘scale’ and ‘scope’ in measuring a spatial externality

The political economy literature on agriculture emphasizes influence over political outcomes via lobbying conduits in general, political action committee contributions in particular and the pervasive view that political preferences with respect to agricultural issues are inherently geographic. In this context, ‘interdependence’ in Congressional vote behaviour manifests itself in two dimensions. One dimension is the intensity by which neighboring vote propensities influence one another and the second is the geographic extent of voter influence. We estimate these facets of dependence using data on a Congressional vote on the 2001 Farm Bill using routine Markov chain Monte Carlo procedures and Bayesian model averaging, in particular. In so doing, we develop a novel procedure to examine both the reliability and the consequences of different model representations for measuring both the ‘scale’ and the ‘scope’ of spatial (geographic) co-relations in voting behaviour.

Dependence of sea ice yield-curve shape on ice thickness

In this note, the authors discuss the contribution that frictional sliding of ice floes (or floe aggregates) past each other and pressure ridging make to the plastic yield curve of sea ice. Using results from a previous study that explicitly modeled the amount of sliding and ridging that occurs for a given global strain rate, it is noted that the relative contribution of sliding and ridging to ice stress depends upon ice thickness. The implication is that the shape and size of the plastic yield curve is dependent upon ice thickness. The yield-curve shape dependence is in addition to plastic hardening/weakening that relates the size of the yield curve to ice thickness. In most sea ice dynamics models the yield-curve shape is taken to be independent of ice thickness. The authors show that the change of the yield curve due to a change in the ice thickness can be taken into account by a weighted sum of two thickness-independent rheologies describing ridging and sliding effects separately. It would be straightforward to implement the thickness-dependent yield-curve shape described here into sea ice models used for global or regional ice prediction.

Pan-Arctic and regional sea ice predictability: initialization month dependence

Seasonal-to-interannual predictions of Arctic sea ice may be important for Arctic communities and industries alike. Previous studies have suggested that Arctic sea ice is potentially predictable but that the skill of predictions of the September extent minimum, initialized in early summer, may be low. The authors demonstrate that a melt season “predictability barrier” and two predictability reemergence mechanisms, suggested by a previous study, are robust features of five global climate models. Analysis of idealized predictions with one of these models [Hadley Centre Global Environment Model, version 1.2 (HadGEM1.2)], initialized in January, May and July, demonstrates that this predictability barrier exists in initialized forecasts as well. As a result, the skill of sea ice extent and volume forecasts are strongly start date dependent and those that are initialized in May lose skill much faster than those initialized in January or July. Thus, in an operational setting, initializing predictions of extent and volume in July has strong advantages for the prediction of the September minimum when compared to predictions initialized in May. Furthermore, a regional analysis of sea ice predictability indicates that extent is predictable for longer in the seasonal ice zones of the North Atlantic and North Pacific than in the regions dominated by perennial ice in the central Arctic and marginal seas. In a number of the Eurasian shelf seas, which are important for Arctic shipping, only the forecasts initialized in July have continuous skill during the first summer. In contrast, predictability of ice volume persists for over 2 yr in the central Arctic but less in other regions.

Surface chemistry of alanine on Cu{111}: Adsorption geometry and temperature dependence

Adsorption of l-alanine on the Cu{111} single crystal surface was investigated as a model system for interactions between small chiral modifier molecules and close-packed metal surfaces. Synchrotron-based X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine structure (NEXAFS) spectroscopy are used to determine the chemical state, bond coordination and out-of-plane orientation of the molecule on the surface. Alanine adsorbs in its anionic form at room temperature, whilst at low temperature the overlayer consists of anionic and zwitterionic molecules. NEXAFS spectra exhibit a strong angular dependence of the π ⁎ resonance associated with the carboxylate group, which allows determining the tilt angle of this group with respect to the surface plane (48° ± 2°) at room temperature. Low-energy electron diffraction (LEED) shows a p(2√13x2√13)R13° superstructure with only one domain, which breaks the mirror symmetry of the substrate and, thus, induces global chirality to the surface. Temperature-programmed XPS (TP-XPS) and temperature-programmed desorption (TPD) experiments indicate that the zwitterionic form converts into the anionic species (alaninate) at 293 K. The latter desorbs/decomposes between 435 K and 445 K.

The annual-cycle modulation of meridional asymmetry in ENSO’s atmospheric response and its dependence on ENSO zonal structure

Previous studies documented that a distinct southward shift of central-Pacific low-level wind anomalies occurring during the ENSO decaying phase, is caused by an interaction between the Western Pacific annual cycle and El Niño-Southern Oscillation (ENSO) variability. The present study finds that the meridional movement of the central-Pacific wind anomalies appears only during traditional Eastern-Pacific (or EP) El Niño events rather than in Central-Pacific (CP) El Niño events in which sea surface temperature (SST) anomalies are confined to the central Pacific. The zonal structure of ENSO-related SST anomalies therefore has an important effect on meridional asymmetry in the associated atmospheric response and its modulation by the annual cycle. In contrast to EP El Niño events, the SST anomalies of CP El Niño events extend further west towards to the warm pool region with its climatological warm SSTs. In the warm pool region, relatively small SST anomalies thus are able to excite convection anomalies on both sides of the equator, even with a meridionally asymmetric SST background state. Therefore, almost meridionally symmetric precipitation and wind anomalies are observed over the central Pacific during the decaying phase of CP El Niño events. The SST anomaly pattern of La Niña events is similar to CP El Niño events with a reversed sign. Accordingly, no distinct southward displacement of the atmospheric response occurs over the central Pacific during the La Niña decaying phase. These results have important implications for ENSO climate impacts over East Asia, since the anomalous low-level anticyclone over the western North Pacific is an integral part of the annual cycle-modulated ENSO response.

The dependence of radiative forcing and feedback on evolving patterns of surface temperature change in climate models

Experiments with CO2 instantaneously quadrupled and then held constant are used to show that the relationship between the global-mean net heat input to the climate system and the global-mean surface-air-temperature change is nonlinear in Coupled Model Intercomparison Project phase 5 (CMIP5) Atmosphere-Ocean General Circulation Models (AOGCMs). The nonlinearity is shown to arise from a change in strength of climate feedbacks driven by an evolving pattern of surface warming. In 23 out of the 27 AOGCMs examined the climate feedback parameter becomes significantly (95% confidence) less negative – i.e. the effective climate sensitivity increases – as time passes. Cloud feedback parameters show the largest changes. In the AOGCM-mean approximately 60% of the change in feedback parameter comes from the topics (30N-30S). An important region involved is the tropical Pacific where the surface warming intensifies in the east after a few decades. The dependence of climate feedbacks on an evolving pattern of surface warming is confirmed using the HadGEM2 and HadCM3 atmosphere GCMs (AGCMs). With monthly evolving sea-surface-temperatures and sea-ice prescribed from its AOGCM counterpart each AGCM reproduces the time-varying feedbacks, but when a fixed pattern of warming is prescribed the radiative response is linear with global temperature change or nearly so. We also demonstrate that the regression and fixed-SST methods for evaluating effective radiative forcing are in principle different, because rapid SST adjustment when CO2 is changed can produce a pattern of surface temperature change with zero global mean but non-zero change in net radiation at the top of the atmosphere (~ -0.5 Wm-2 in HadCM3).

Atmospheric electric field measurements in urban environment and the pollutant aerosol weekly dependence

The weekly dependence of pollutant aerosols in the urban environment of Lisbon (Portugal) is inferred from the records of atmospheric electric field at Portela meteorological station (38°47′N,9°08′W). Measurements were made with a Bendorf electrograph. The data set exists from 1955 to 1990, but due to the contaminating effect of the radioactive fallout during 1960 and 1970s, only the period between 1980 and 1990 is considered here. Using a relative difference method a weekly dependence of the atmospheric electric field is found in these records, which shows an increasing trend between 1980 and 1990. This is consistent with a growth of population in the Lisbon metropolitan area and consequently urban activity, mainly traffic. Complementarily, using a Lomb–Scargle periodogram technique the presence of a daily and weekly cycle is also found. Moreover, to follow the evolution of theses cycles, in the period considered, a simple representation in a colour surface plot representation of the annual periodograms is presented. Further, a noise analysis of the periodograms is made, which validates the results found. Two datasets were considered: all days in the period, and fair-weather days only.

Extended cusp-like regions and their dependence on the Polar orbit, seasonal variations, and interplanetary conditions

Extended cusp-like regions (ECRs) are surveyed, as observed by the Magnetospheric Ion Composition Sensor (MICS) of the Charge and Mass Magnetospheric Ion Composition Experiment (CAMMICE) instrument aboard Polar between 1996 and 1999. The first of these ECR events was observed on 29 May 1996, an event widely discussed in the literature and initially thought to be caused by tail lobe reconnection due to the coinciding prolonged interval of strong northward IMF. ECRs are characterized here by intense fluxes of magnetosheath-like ions in the energy-per-charge range of _1 to 10 keV e_1. We investigate the concurrence of ECRs with intervals of prolonged (lasting longer than 1 and 3 hours) orientations of the IMF vector and high solar wind dynamic pressure (PSW). Also investigated is the opposite concurrence, i.e., of the IMF and high PSW with ECRs. (Note that these surveys are asking distinctly different questions.) The former survey indicates that ECRs have no overall preference for any orientation of the IMF. However, the latter survey reveals that during northward IMF, particularly when accompanied by high PSW, ECRs are more likely. We also test for orbital and seasonal effects revealing that Polar has to be in a particular region to observe ECRs and that they occur more frequently around late spring. These results indicate that ECRs have three distinct causes and so can relate to extended intervals in (1) the cusp on open field lines, (2) the magnetosheath, and (3) the magnetopause indentation at the cusp, with the latter allowing magnetosheath plasma to approach close to the Earth without entering the magnetosphere.

The dependence of cusp ion signatures on the reconnection rate

The interpretation of structure in cusp ion dispersions is important for helping to understand the temporal and spatial structure of magnetopause reconnection. “Stepped” and “sawtooth” signatures have been shown to be caused by temporal variations in the reconnection rate under the same physical conditions for different satellite trajectories. The present paper shows that even for a single satellite path, a change in the amplitude of any reconnection pulses can alter the observed signature and even turn sawtooth into stepped forms and vice versa. On 20 August 1998, the Defense Meteorological Satellite Program (DMSP) craft F-14 crossed the cusp just to the south of Longyearbyen, returning on the following orbit. The two passes by the DMSP F-14 satellites have very similar trajectories and the open-closed field line boundary (OCB) crossings, as estimated from the SSJ/4 precipitating particle data and Polar UVI images, imply a similarly-shaped polar cap, yet the cusp ion dispersion signatures differ substantially. The cusp crossing at 08:54 UT displays a stepped ion dispersion previously considered to be typical of a meridional pass, whereas the crossing at 10:38 UT is a sawtooth form ion dispersion, previously considered typical of a satellite travelling longitudinally with respect to the OCB. It is shown that this change in dispersed ion signature is likely to be due to a change in the amplitude of the pulses in the reconnection rate, causing the stepped signature. Modelling of the low-energy ion cutoff under different conditions has reproduced the forms of signature observed.

Relationship between the near-Earth interplanetary field and the coronal source flux: dependence on timescale

The Ulysses spacecraft has shown that the radial component of the heliospheric magnetic field is approximately independent of latitude. This has allowed quantification of the total open solar flux from near-Earth observations of the interplanetary magnetic field. The open flux can also be estimated from photospheric magnetograms by mapping the fields up to the ‘‘coronal source surface’’ where the field is assumed to be radial and which is usually assumed to be at a heliocentric distance r = 2.5R_{S} (a mean solar radius, 1R_{S} = 6.96x10^{8} m). These two classes of open flux estimate will differ by the open flux that threads the heliospheric current sheet(s) inside Earth’s orbit at 2.5R_{S} < r < 1R{1} (where the mean Earth-Sun distance, 1R_{1} = 1 AU = 1.5 x 10^{11} m). We here use near-Earth measurements to estimate this flux and show that at sunspot minimum it causes only a very small (approximately 0.5%) systematic difference between the two types of open flux estimate, with an uncertainty that is of order ±24% in hourly values, ±16% in monthly averages, and between -6% and +2% in annual values. These fractions may be somewhat larger for sunspot maximum because of flux emerging at higher heliographic latitudes.

Dependence of convective flows and particle precipitation in the high-latitude dayside ionosphere on theXandYcomponents of the interplanetary magnetic field

The asymmetries in the convective flows, current systems, and particle precipitation in the high-latitude dayside ionosphere which are related to the equatorial plane components of the interplanetary magnetic field (IMF) are discussed in relation to the results of several recent observational studies. It is argued that all of the effects reported to date which are ascribed to the y component of the IMF can be understood, at least qualitatively, in terms of a simple theoretical picture in which the effects result from the stresses exerted on the magnetosphere consequent on the interconnection of terrestrial and interplanetary fields. In particular, relaxation under the action of these stresses allows, in effect, a partial penetration of the IMF into the magnetospheric cavity, such that the sense of the expected asymmetry effects on closed field lines can be understood, to zeroth order, in terms of the “dipole plus uniform field” model. In particular, in response to IMF By, the dayside cusp should be displaced in longitude about noon in the same sense as By in the northern hemisphere, and in the opposite sense to By in the southern hemisphere, while simultaneously the auroral oval as a whole should be shifted in the dawn-dusk direction in the opposite sense with respect to By. These expected displacements are found to be consistent with recently published observations. Similar considerations lead to the suggestion that the auroral oval may also undergo displacements in the noon-midnight direction which are associated with the x component of the IMF. We show that a previously published study of the position of the auroral oval contains strong initial evidence for the existence of this effect. However, recent results on variations in the latitude of the cusp are more ambiguous. This topic therefore requires further study before definitive conclusions can be drawn.

The dependence of high-latitude dayside ionospheric flows on the North-South component of the IMF: A high time resolution correlation analysis using EISCAT “Polar” and AMPTE UKS and IRM data

In 1984 and 1985 a series of experiments was undertaken in which dayside ionospheric flows were measured by the EISCAT “Polar” experiment, while observations of the solar wind and interplanetary magnetic field (IMF) were made by the AMPTE UKS and IRM spacecraft upstream from the Earth's bow shock. As a result, 40 h of simultaneous data were acquired, which are analysed in this paper to investigate the relationship between the ionospheric flow and the North-South (Bz) component of the IMF. The ionospheric flow data have 2.5 min resolution, and cover the dayside local time sector from ∼ 09:30 to ∼ 18:30 M.L.T. and the latitude range from 70.8° to 74.3°. Using cross-correlation analysis it is shown that clear relationships do exist between the ionospheric flow and IMF Bz, but that the form of the relations depends strongly on latitude and local time. These dependencies are readily interpreted in terms of a twinvortex flow pattern in which the magnitude and latitudinal extent of the flows become successively larger as Bz becomes successively more negative. Detailed maps of the flow are derived for a range of Bz values (between ± 4 nT) which clearly demonstrate the presence of these effects in the data. The data also suggest that the morning reversal in the East-West component of flow moves to earlier local times as Bz, declines in value and becomes negative. The correlation analysis also provides information on the ionospheric response time to changes in IMF Bz, it being found that the response is very rapid indeed. The most rapid response occurs in the noon to mid-afternoon sector, where the westward flows of the dusk cell respond with a delay of 3.9 ± 2.2 min to changes in the North-South field at the subsolar magnetopause. The flows appear to evolve in form over the subsequent ~ 5 min interval, however, as indicated by the longer response times found for the northward component of flow in this sector (6.7 ±2.2 min), and in data from earlier and later local times. No evidence is found for a latitudinal gradient in response time; changes in flow take place coherently in time across the entire radar field-of-view.

Non-thermal plasma observations using EISCAT: Aspect angle dependence

Recent observations with the EISCAT incoherent scatter radar have shown large rises in dayside, auroral plasma velocities (>2 km s^{−1}) over a wide range of latitudes and lasting about an hour. These are larger than the neutral thermal speed, and allow, for the first time, observations of a non-thermal plasma over a range of observing angles, revealing a clear angular dependence. The observed ion temperature anisotropy, deduced by assuming a Maxwellian line-of-sight ion velocity distribution, is at least 1.75, which exceeds the theoretical value for a bi-Maxwellian based on a realistic ion-neutral collision model. The aspect angle dependence of the signal spectra also indicates non-Maxwellian plasma.