Voltage-gated sodium (NaV) channel blockade by plant cannabinoids does not confer anticonvulsant effects per se

Cannabidiol (CBD) is a non-psychoactive, well-tolerated, anticonvulsant plant cannabinoid, although its mechanism(s) of seizure suppression remains unknown. Here, we investigate the effect of CBD and the structurally similar cannabinoid, cannabigerol (CBG), on voltage-gated Na+ (NaV) channels, a common anti-epileptic drug target. CBG’s anticonvulsant potential was also assessed in vivo. CBD effects on NaV channels were investigated using patch-clamp recordings from rat CA1 hippocampal neurons in brain slices, human SH-SY5Y (neuroblastoma) cells and mouse cortical neurons in culture. CBG effects were also assessed in SH-SY5Y cells and mouse cortical neurons. CBD and CBG effects on veratridine-stimulated human recombinant NaV1.1, 1.2 or 1.5 channels were assessed using a membrane potential-sensitive fluorescent dye high-throughput assay. The effect of CBG on pentyleneterazole-induced (PTZ) seizures was assessed in rat. CBD (10M) blocked NaV currents in SH-SY5Y cells, mouse cortical neurons and recombinant cell lines, and affected spike parameters in rat CA1 neurons; CBD also significantly decreased membrane resistance. CBG blocked NaV to a similar degree to CBD in both SH-SY5Y and mouse recordings, but had no effect (50-200mg/kg) on PTZ-induced seizures in rat. CBD and CBG are NaV channel blockers at micromolar concentrations in human and murine neurons and recombinant cells. In contrast to previous reports investigating CBD, CBG had no effect upon PTZ-induced seizures in rat, indicating that NaV blockade per se does not correlate with anticonvulsant effects.

Simulated climate and biomes of Africa during the Late Quaternary: comparison with pollen and lake status data

New compilations of African pollen and lake data are compared with climate (CCM1, NCAR, Boulder) and vegetation (BIOME 1.2, GSG, Lund) simulations for the last glacial maximum (LGM) and early to mid-Holocene (EMH). The simulated LGM climate was ca 4°C colder and drier than present, with maximum reduction in precipitation in semi-arid regions. Biome simulations show lowering of montane vegetation belts and expansion of southern xerophytic associations, but no change in the distribution of deserts and tropical rain forests. The lakes show LGM conditions similar or drier than present throughout northern and tropical Africa. Pollen data indicate lowering of montane vegetation belts, the stability of the Sahara, and a reduction of rain forest. The paleoenvironmental data are consistent with the simulated changes in temperature and moisture budgets, although they suggest the climate model underestimates equatorial aridity. EMH simulations show temperatures slightly less than present and increased monsoonal precipitation in the eastern Sahara and East Africa. Biome simulations show an upward shift of montane vegetation belts, fragmentation of xerophytic vegetation in southern Africa, and a major northward shift of the southern margin of the eastern Sahara. The lakes indicate conditions wetter than present across northern Africa. Pollen data show an upward shift of the montane forests, the northward shift of the southern margin of the Sahara, and a major extension of tropical rain forest. The lake and pollen data confirm monsoon expansion in eastern Africa, but the climate model fails to simulate the wet conditions in western Africa.

Deglacial changes of the southern margin of the southern westerly winds revealed by terrestrial records from SW Patagonia (52 degrees S)

Much of the ongoing discussion regarding synchrony or bipolar asynchrony of paleoclimate events has centered on the timing and structure of the last glacial termination in the southern mid- latitudes, in particular the southwestern Patagonian region (50�e55�S). Its location adjacent to the Drake Passage andnear the southern margin of the southern westerly winds (SWW) allows examining the postulated links between the Southern Oceane SWW coupled system and tmospheric CO2 variations through the last glacial termination. Results from two sites located in the Última Esperanza area (52�S) allow us to infer SWW-driven changes in hydrologic balance during this critical time interval. These findings indicate peatland development under temperate/wet conditions between 14,600 and 14,900 cal yr BP, followed by cooling and a lake transgressive phase that led to a shallow lake during the early part of the Antarctic Cold Reversal (ACR, 13,600-14,600 cal yr BP), followed in turn by a deeper lake and modest warming during Younger Dryas time (YD, 11,800-13,000 cal yr BP), superseded by terrestrialization and forest expansion at the beginning of the Holocene. We propose that the SWW (i) strengthened and shifted northward during ACR time causing a precipitation rise in northwestern and southwestern Patagonia coeval with mid- and high-latitude cooling and a halt in the deglacial atmospheric CO2 rise; (ii) shifted southward during YD time causing a precipitation decline/increase in NW/SW Patagonia, respectively, high-latitude warming, and invigorated CO2 release from the Southern Ocean; (iii) became weaker between 10,000 and 11,500 cal yr BP causing a precipitation decline throughout Patagonia, concurrent with peak mid- and high-latitude temperatures and atmospheric CO2 concentrations.

Control methodologies: Peak reduction algorithms for DNO owned storage devices on the Low Voltage network

The Distribution Network Operators (DNOs) role is becoming more difficult as electric vehicles and electric heating penetrate the network, increasing the demand. As a result it becomes harder for the distribution networks infrastructure to remain within its operating constraints. Energy storage is a potential alternative to conventional network reinforcement such as upgrading cables and transformers. The research presented here in this paper shows that due to the volatile nature of the LV network, the control approach used for energy storage has a significant impact on performance. This paper presents and compares control methodologies for energy storage where the objective is to get the greatest possible peak demand reduction across the day from a pre-specified storage device. The results presented show the benefits and detriments of specific types of control on a storage device connected to a single phase of an LV network, using aggregated demand profiles based on real smart meter data from individual homes. The research demonstrates an important relationship between how predictable an aggregation is and the best control methodology required to achieve the objective.

Enrichment and stability: a phenomenological coupling of energy value and carrying capacity

Simple predator–prey models with a prey-dependent functional response predict that enrichment (increased carrying capacity) destabilizes community dynamics: this is the ‘paradox of enrichment’. However, the energy value of prey is very important in this context. The intraspecific chemical composition of prey species determines its energy value as a food for the potential predator. Theoretical and experimental studies establish that variable chemical composition of prey affects the predator–prey dynamics. Recently, experimental and theoretical approaches have been made to incorporate explicitly the stoichiometric heterogeneity of simple predator–prey systems. Following the results of the previous experimental and theoretical advances, in this article we propose a simple phenomenological formulation of the variation of energy value at increased level of carrying capacity. Results of our study demonstrate that coupling the parameters representing the phenomenological energy value and carrying capacity in a realistic way, may avoid destabilization of community dynamics following enrichment. Additionally, under such coupling the producer–grazer system persists for only an intermediate zone of production—a result consistent with recent studies. We suggest that, while addressing the issue of enrichment in a general predator–prey model, the phenomenological relationship that we propose here might be applicable to avoid Rosenzweig’s paradox.

Enrichment and ecosystem stability: effect of toxic food

Enrichment in resource availability theoretically destabilizes predator–prey dynamics (the paradox of enrichment). However, a minor change in the resource stoichiometry may make a prey toxic for the predator, and the presence of toxic prey affects the dynamics significantly. Here, theoretically we explore how, at increased carrying capacity, a toxic prey affects the oscillation or destabilization of predator–prey dynamics, and how its presence influences the growth of the predator as well as that of a palatable prey. Mathematical analysis determines the bounds on the food toxicity that allow the coexistence of a predator along with a palatable and a toxic prey. The overall results demonstrate that toxic food counteracts oscillation (destabilization) arising from enrichment of resource availability. Moreover, our results show that, at increased resource availability, toxic food that acts as a source of extra mortality may increase the abundance of the predator as well as that of the palatable prey.

The stability of ecosystems: a brief overview of the paradox of enrichment

In theory, enrichment of resource in a predator-prey model leads to destabilization of the system, thereby collapsing the trophic interaction, a phenomenon referred to as "the paradox of enrichment". After it was first proposed by Rosenzweig (1971), a number of subsequent studies were carried out on this dilemma over many decades. In this article, we review these theoretical and experimental works and give a brief overview of the proposed solutions to the paradox. The mechanisms that have been discussed are modifications of simple predator-prey models in the presence of prey that is inedible, invulnerable, unpalatable and toxic. Another class of mechanisms includes an incorporation of a ratio-dependent functional form, inducible defence of prey and density-dependent mortality of the predator. Moreover, we find a third set of explanations based on complex population dynamics including chaos in space and time. We conclude that, although any one of the various mechanisms proposed so far might potentially prevent destabilization of the predator-prey dynamics following enrichment, in nature different mechanisms may combine to cause stability, even when a system is enriched. The exact mechanisms, which may differ among systems, need to be disentangled through extensive field studies and laboratory experiments coupled with realistic theoretical models.

A peak reduction scheduling algorithm for storage devices on the low voltage network

Reinforcing the Low Voltage (LV) distribution network will become essential to ensure it remains within its operating constraints as demand on the network increases. The deployment of energy storage in the distribution network provides an alternative to conventional reinforcement. This paper presents a control methodology for energy storage to reduce peak demand in a distribution network based on day-ahead demand forecasts and historical demand data. The control methodology pre-processes the forecast data prior to a planning phase to build in resilience to the inevitable errors between the forecasted and actual demand. The algorithm uses no real time adjustment so has an economical advantage over traditional storage control algorithms. Results show that peak demand on a single phase of a feeder can be reduced even when there are differences between the forecasted and the actual demand. In particular, results are presented that demonstrate when the algorithm is applied to a large number of single phase demand aggregations that it is possible to identify which of these aggregations are the most suitable candidates for the control methodology.

Long-term cultivation-independent microbial diversity analysis demonstrates that bacterial communities infecting the adult cystic fibrosis lung show stability and resilience.

Whilst not true in all cases, the microbial communities that chronically infect the airways of patients with CF can vary little over a year despite antibiotic perturbation. The species present tended to vary more between than within subjects, suggesting that each CF airway infection is unique, with relatively stable and resilient bacterial communities. The inverse relationship between community richness and disease severity is similar to findings reported in other mucosal infections.

Stability of dobutamine 500 mg in 50 ml syringes prepared using a Central Intravenous Additive Service

Objectives A pharmacy Central Intravenous Additives Service (CIVAS) provides ready to use injectable medicines. However, manipulation of a licensed injectable medicine may significantly alter the stability of drug(s) in the final product. The aim of this study was to develop a stability indicating assay for CIVAS produced dobutamine 500 mg in 50 ml dextrose 1% (w/v) prefilled syringes, and to allocate a suitable shelf life. Methods A stability indicating high performance liquid chromatography (HPLC) assay was established for dobutamine. The stability of dobutamine prefilled syringes was evaluated under storage conditions of 4°C (protected from light), room temperature (protected from light), room temperature (exposed to light) and 40°C (protected from light) at various time points (up to 42 days). Results An HPLC method employing a Hypersil column, mobile phase (pH=4.0) consisting of 82:12:6 (v/v/v) 0.05 M KH2PO4:acetonitrile:methanol plus 0.3% (v/v) triethylamine with UV detection at λ=280 nm was specific for dobutamine. Under different storage conditions only samples stored at 40°C showed greater than 5% degradation (5.08%) at 42 days and had the shortest T95% based on this criterion (44.6 days compared with 111.4 days for 4°C). Exposure to light also reduced dobutamine stability. Discolouration on storage was the limiting factor in shelf life allocation, even when dobutamine remained within 5% of the initial concentration. Conclusions A stability indicating HPLC assay for dobutamine was developed. The shelf life recommended for the CIVAS product was 42 days at 4°C and 35 days at room temperature when protected from light.

On the voltage and distance across the low latitude boundary layer

A pass of the AMPTE-UKS satellite through the low-latitude boundary layer (LLBL) at 8:30 MLT is studied in detail. The magnetosheath field is predominantly northward. It is shown that multiple transitions through part or all of the layer of antisunward flow lead to overestimation of both the voltage across this layer and its width. The voltage is estimated to be only about 3 kV and this implies that the full LLBL is about 1200 km thick, consistent with previous studies.

On flow reversal boundaries and transpolar voltage in average models of high-latitude convection

The implications of polar cap expansions, contractions and movements for empirical models of high-latitude plasma convection are examined. Some of these models have been generated by directly averaging flow measurements from large numbers of satellite passes or radar scans; others have employed more complex means to combine data taken at different times into large-scale patterns of flow. In all cases, the models have implicitly adopted the assumption that the polar cap is in steady state: they have all characterized the ionospheric flow in terms of the prevailing conditions (e.g. the interplanetary magnetic field and/or some index of terrestrial magnetic activity) without allowance for their history. On long enough time scales, the polar cap is indeed in steady state but on time scales shorter than a few hours it is not and can oscillate in size and position. As a result, the method used to combine the data can influence the nature of the convection reversal boundary and the transpolar voltage in the derived model. This paper discusses a variety of effects due to time-dependence in relation to some ionospheric convection models which are widely applied. The effects are shown to be varied and to depend upon the procedure adopted to compile the model.

The importance of loop length on the stability of i-motif structures

Using UV and srCD spectroscopy it is found that loop length within the i-motif structure is important for both thermal and pH stability, but in contrast to previous statements, it is the shorter loops that exhibit the highest stability.

Structure and stability of two polymorphs of creatine and its monohydrate

An experimental search for crystalline forms of creatine including a variable temperature X-ray powder diffraction study has produced three polymorphs and a formic acid solvate. The crystal structures of creatine forms I and II were determined from X-ray powder diffraction data plus the creatine formic acid (1 : 1) solvate structure was obtained by single crystal X-ray diffraction methods. Evidence of a third polymorphic form of creatine obtained by rapid desolvation of creatine monohydrate is also presented. The results highlight the role of automated parallel crystallisation, slurry experiments and VT-XRPD as powerful techniques for effective physical form screening. They also highlight the importance of various complementary analytical techniques in structural characterisation and in achieving better understanding of the relationship between various solid-state forms. The structural relationships between various solid-state forms of creatine using the XPac method provided a rationale for the different relative stabilities of forms I and II of creatine with respect to the monohydrate form.

The effect of the tensor force on the predicted stability of superheavy nuclei

The effect of the tensor component of the Skyrme effective nucleon-nucleon interaction on the single-particle structure in superheavy elements is studied. A selection of the available Skyrme forces has been chosen and their predictions for the proton and neutron shell closures investigated. The inclusion of the tensor term with realistic coupling strength parameters leads to a small increase in the spin-orbit splitting between the proton 2f7/2 and 2f5/2 partners, opening the Z=114 shell gap over a wide range of nuclei. The Z=126 shell gap, predicted by these models in the absence of the tensor term, is found to be stongly dependent on neutron number with a Z=138 gap opening for large neutron numbers, having a consequent implication for the synthesis of neutron-rich superheavy elements. The predicted neutron shell structures remain largely unchanged by inclusion of the tensor component.