Phytocannabinoids as novel therapeutic agents in CNS disorders

The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body's endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB1 receptors by the major pCB, Δ9-tetrahydrocannabinol (Δ9-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ9-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent. In this regard, research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ9tetrahydrocannabivarin (Δ9-THCV) and cannabidivarin (CBDV), some of which show potential as therapeutic agents in preclinical models of CNS disease. Moreover, it is becoming evident that these non-Δ9-THC pCBs act at a wide range of pharmacological targets, not solely limited to CB receptors. Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour. Here, we review pCB effects in preclinical models of CNS disease and, where available, clinical trial data that support therapeutic effects. Such developments may soon yield the first non-Δ9-THC pCB-based medicines.

Intelligent agents enabling negotiated control of pervasive environments

One of the important goals of the intelligent buildings especially in commercial applications is not only to minimize the energy consumption but also to enhance the occupant’s comfort. However, most of current development in the intelligent buildings focuses on an implementation of the automatic building control systems that can support energy efficiency approach. The consideration of occupants’ preferences is not adequate. To improve occupant’s wellbeing and energy efficiency in intelligent environments, we develop four types of agent combined together to form a multi-agent system to control the intelligent buildings. Users’ preferential conflicts are discussed. Furthermore, a negotiation mechanism for conflict resolution, has been proposed in order to reach an agreement, and has been represented in syntax directed translation schemes for future implementation and testing. Keywords: conflict resolution, intelligent buildings, multi-agent systems (MAS), negotiation strategy, syntax directed translation schemes (SDTS).

Probability of survival in a random exchange economy with dependent agents

In this paper I analyze the general equilibrium in a random Walrasian economy. Dependence among agents is introduced in the form of dependency neighborhoods. Under the uncertainty, an agent may fail to survive due to a meager endowment in a particular state (direct effect), as well as due to unfavorable equilibrium price system at which the value of the endowment falls short of the minimum needed for survival (indirect terms-of-trade effect). To illustrate the main result I compute the stochastic limit of equilibrium price and probability of survival of an agent in a large Cobb-Douglas economy.

Two macrocyclic pentaaza compounds containing pyridine evaluated as novel chelating agents in copper(II) and nickel(II) overload

Two pentaaza macrocycles containing pyridine in the backbone, namely 3,6,9,12,18-pentaazabicyclo[12.3.1] octadeca-1(18),14,16-triene ([15]pyN(5)), and 3,6,10,13,19-pentaazabicyclo[13.3.1]nonadeca-1(19),15,17-triene ([16]pyN(5)), were synthesized in good yields. The acid-base behaviour of these compounds was studied by potentiometry at 298.2 K in aqueous solution and ionic strength 0.10 M in KNO3. The protonation sequence of [15]pyN(5) was investigated by H-1 NMR titration that also allowed the determination of protonation constants in D2O. Binding studies of the two ligands with Ca2+, Ni2+, Cu2+, Zn2+, Cd2+, and Pb2+ metal ions were performed under the same experimental conditions. The results showed that all the complexes formed with the 15-membered ligand, particularly those of Cu2+ and especially Ni2+, are thermodynamically more stable than with the larger macrocycle. Cyclic voltammetric data showed that the copper(II) complexes of the two macrocycles exhibited analogous behaviour, with a single quasi-reversible one-electron transfer reduction process assigned to the Cu(II)/Cu(I) couple. The UV-visible-near IR spectroscopic and magnetic moment data of the nickel(II) complexes in solution indicated a tetragonal distorted coordination geometry for the metal centre. X-band EPR spectra of the copper(II) complexes are consistent with distorted square pyramidal geometries. The crystal structure of [Cu([15]pyN(5))](2+) determined by X-ray diffraction showed the copper(II) centre coordinated to all five macrocyclic nitrogen donors in a distorted square pyramidal environment.

Understanding the effects of anesthetic agents on the EEG through neural field theory

Anesthetic and analgesic agents act through a diverse range of pharmacological mechanisms. Existing empirical data clearly shows that such "microscopic" pharmacological diversity is reflected in their "macroscopic" effects on the human electroencephalogram (EEG). Based on a detailed mesoscopic neural field model we theoretically posit that anesthetic induced EEG activity is due to selective parametric changes in synaptic efficacy and dynamics. Specifically, on the basis of physiologically constrained modeling, it is speculated that the selective modification of inhibitory or excitatory synaptic activity may differentially effect the EEG spectrum. Such results emphasize the importance of neural field theories of brain electrical activity for elucidating the principles whereby pharmacological agents effect the EEG. Such insights will contribute to improved methods for monitoring depth of anesthesia using the EEG.

Understanding the transition to seizure by modeling the epileptiform activity of general anesthetic agents

A central difficulty in modeling epileptogenesis using biologically plausible computational and mathematical models is not the production of activity characteristic of a seizure, but rather producing it in response to specific and quantifiable physiologic change or pathologic abnormality. This is particularly problematic when it is considered that the pathophysiological genesis of most epilepsies is largely unknown. However, several volatile general anesthetic agents, whose principle targets of action are quantifiably well characterized, are also known to be proconvulsant. The authors describe recent approaches to theoretically describing the electroencephalographic effects of volatile general anesthetic agents that may be able to provide important insights into the physiologic mechanisms that underpin seizure initiation.

A refined sampling strategy for intra-tooth stable isotope analysis of mammalian enamel

Serial sampling and stable isotope analysis performed along the growth axis of vertebrate tooth enamel records differences attributed to seasonal variation in diet, climate or animal movement. Because several months are required to obtain mature enamel in large mammals, modifications in the isotopic composition of environmental parameters are not instantaneously recorded, and stable isotope analysis of tooth enamel returns a time-averaged signal attenuated in its amplitude relative to the input signal. For convenience, stable isotope profiles are usually determined on the side of the tooth where enamel is thickest. Here we investigate the possibility of improving the time resolution by targeting the side of the tooth where enamel is thinnest. Observation of developing third molars (M3) in sheep shows that the tooth growth rate is not constant but decreases exponentially, while the angle between the first layer of enamel deposited and the enamel–dentine junction increases as a tooth approaches its maximal length. We also noted differences in thickness and geometry of enamel growth between the mesial side (i.e., the side facing the M2) and the buccal side (i.e., the side facing the cheek) of the M3. Carbon and oxygen isotope variations were measured along the M3 teeth from eight sheep raised under controlled conditions. Intra-tooth variability was systematically larger along the mesial side and the difference in amplitude between the two sides was proportional to the time of exposure to the input signal. Although attenuated, the mesial side records variations in the environmental signal more faithfully than the buccal side. This approach can be adapted to other mammals whose teeth show lateral variation in enamel thickness and could potentially be used as an internal check for diagenesis.

Component-resolved bleaching spectra of quartz optically stimulated luminescence: preliminary results and implications for dating

Bleaching spectra of the ‘fast’ and ‘medium’ optically stimulated luminescence (OSL) components of quartz are reported. A dependence of photoionization cross-section, σ, on wavelength was observed for the fast and medium components and a significant difference in their responses to stimulation wavelength was found. The ratio of the fast and medium photoionization cross-sections, σfast/σmedium, varied from 30.6 when stimulated with View the MathML source light to 1.4 at View the MathML source. At View the MathML source the fast and medium photoionization cross-sections were found to be sufficiently different that infrared bleaching at raised temperatures allowed the selective removal of the fast component with negligible depletion of the medium. A method for optically separating the OSL components of quartz is suggested, based on the wavelength dependence of photoionization cross-sections.

Highly contrasting effects of different climate forcing agents on terrestrial ecosystem services

Many atmospheric constituents besides carbon dioxide (CO2) contribute to global warming, and it is common to compare their influence on climate in terms of radiative forcing, which measures their impact on the planetary energy budget. A number of recent studies have shown that many radiatively active constituents also have important impacts on the physiological functioning of ecosystems, and thus the ‘ecosystem services’ that humankind relies upon. CO2 increases have most probably increased river runoff and had generally positive impacts on plant growth where nutrients are non-limiting, whereas increases in near-surface ozone (O3) are very detrimental to plant productivity. Atmospheric aerosols increase the fraction of surface diffuse light, which is beneficial for plant growth. To illustrate these differences, we present the impact on net primary productivity and runoff of higher CO2, higher near-surface O3, and lower sulphate aerosols, and for equivalent changes in radiative forcing.We compare this with the impact of climate change alone, arising, for example, from a physiologically inactive gas such as methane (CH4). For equivalent levels of change in radiative forcing, we show that the combined climate and physiological impacts of these individual agents vary markedly and in some cases actually differ in sign. This study highlights the need to develop more informative metrics of the impact of changing atmospheric constituents that go beyond simple radiative forcing.

Controlling market power of vertically integrated firms in electricity networks: demand response of aggregator agents

This article reports the results of an experiment that examined how demand aggregators can discipline vertically-integrated firms - generator and distributor-retailer holdings-, which have a high share in wholesale electricity market with uniform price double auction (UPDA). We initially develop a treatment where holding members redistribute the profit based on the imposition of supra-competitive prices, in equal proportions (50%-50%). Subsequently, we introduce a vertical disintegration (unbundling) treatment with holding-s information sharing, where profits are distributed according to market outcomes. Finally, a third treatment is performed to introduce two active demand aggregators, with flexible interruptible loads in real time. We found that the introduction of responsive demand aggregators neutralizes the power market and increases market efficiency, even beyond what is achieved through vertical disintegration.

Power and control: managing agents for international student recruitment in higher education

This multiple case-based study investigates the relationship between recruiting agents and the UK universities who act as their principals. The current extensive use of agents in UK higher education may be seen as an indicator of the financial impact made by international students. The study analyses the practice of agent management and explores the manner in which power and control interact. The study employed semi-structured interviews and group discussions involving up to 6 respondents from each of the 20 UK case institutions. The qualitative data reveal a considerable variation in the manner in which the universities manage their agency relationships. Through the joint consideration of control measures and use of power, five distinctive approaches have been identified. The study also reveals that over-dependence on agents reduces the power of the principal, and consequently, the principal’s ability to exercise control, particularly in highly competitive global and national markets.