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.

Occasional publishers: producing and marketing books in England 1771–1844

Purpose – To investigate the way in which a series of related printing businesses, owned by members of the Gye and Balne families in Bath and London from 1771 to 1844, selected and marketed their titles when they ventured into book printing and publishing. Design/methodology/approach – The basis of this research is extensive archival research analyzing primary sources, mainly the books and ephemera printed by the various firms, supported by information in contemporary newspapers and journals and in biographies of printers and publishers. Findings – The focus of these businesses was not solely on production but that marketing was also considered, and that there was each title was conceived and produced with a particular market in mind. In doing so it provides evidence of relatively advanced marketing strategies in use before 1850 and thus questions the validity of the four-eras model of marketing history. Research limitations/implications – The available primary sources are limited; while a number of books and other printed items have survived there are no extant accounts, correspondence, or other records for any of the firms that were studied. Originality/value – There has been very little research into the way small businesses during this period approached the marketing of their products. This paper is a potential model for further such historical research and also provides an example of how research into specific companies can illuminate the larger history of marketing, potentially changing the way in which we understand the development of consumer society.

Pianos for the people: the manufacture, marketing and sale of pianos as consumer durables, 1850-1914

During the second half of the nineteenth century, British society experienced a rise in real incomes and a change in its composition, with the expansion of the middle classes. These two factors led to a consumer revolution, with a growing, but still segmented, demand for household goods that could express status and aspiration. At the same time technological changes and new ways of marketing and selling goods made these goods more affordable. This paper analyzes these themes and the process of mediation that took place between producers, retailers, and consumers, by looking at the most culturally symbolic of nineteenth century consumer goods, the piano.

Modulation of ion channels by hydrogen sulfide

Increasing current awareness and understanding of the roles and mechanisms of action of ion channel regulation by H(2)S will open opportunities for therapeutic intervention with clear clinical benefits, and inform future therapies. In addition, more sensitive methods for detecting relevant physiological concentrations of H(2)S will allow for clarification of specific ion channel regulation with reference to physiological or pathophysiological settings.

Ion channels as effectors in carbon monoxide signaling

A wealth of recent studies has highlighted the diverse and important influences of carbon monoxide (CO) on cellular signaling pathways. Such studies have implicated CO, and the enzymes from which it is derived (heme oxygenases) as potential therapeutic targets, particularly (although not exclusively) in inflammation, immunity and cardiovascular disease.1 In a recent study,2 we demonstrated that CO inhibited cardiac L-type Ca(2+) channels. This effect arose due to the ability of CO to bind to mitochondria (presumably at complex IV of the electron transport chain) and so cause electron leak, which resulted in increased production of reactive oxygen species. These modulated the channel's activity through interactions with three cysteine residues in the cytosolic C-terminus of the channel's major, pore-forming subunit. Our study provided a potential mechanism for the cardioprotective effects of CO and also highlighted ion channels as a major potential target group for this gasotransmitter.

Carbon monoxide inhibits L-type Ca2+ channels via redox modulation of key cysteine residues by mitochondrial reactive oxygen species

Conditions of stress, such as myocardial infarction, stimulate up-regulation of heme oxygenase (HO-1) to provide cardioprotection. Here, we show that CO, a product of heme catabolism by HO-1, directly inhibits native rat cardiomyocyte L-type Ca2+ currents and the recombinant alpha1C subunit of the human cardiac L-type Ca2+ channel. CO (applied via a recognized CO donor molecule or as the dissolved gas) caused reversible, voltage-independent channel inhibition, which was dependent on the presence of a spliced insert in the cytoplasmic C-terminal region of the channel. Sequential molecular dissection and point mutagenesis identified three key cysteine residues within the proximal 31 amino acids of the splice insert required for CO sensitivity. CO-mediated inhibition was independent of nitric oxide and protein kinase G but was prevented by antioxidants and the reducing agent, dithiothreitol. Inhibition of NADPH oxidase and xanthine oxidase did not affect the inhibitory actions of CO. Instead, inhibitors of complex III (but not complex I) of the mitochondrial electron transport chain and a mitochondrially targeted antioxidant (Mito Q) fully prevented the effects of CO. Our data indicate that the cardioprotective effects of HO-1 activity may be attributable to an inhibitory action of CO on cardiac L-type Ca2+ channels. Inhibition arises from the ability of CO to promote generation of reactive oxygen species from complex III of mitochondria. This in turn leads to redox modulation of any or all of three critical cysteine residues in the channel's cytoplasmic C-terminal tail, resulting in channel inhibition.

Food marketing technology and contingency market valuation

Marketing activities are introduced into a rational expectations model of the food marketing system. The model is used to evaluate effects of alternative marketing technologies on the distribution of the benefits of contingency markets in agriculture. Benefits depend on two parameters: the cost share of farm inputs and the elasticity of substitution between farm and nonfarm inputs in food marketing. Over a broad spectrum of technologies, consumers are likely to be the net beneficiaries and farmers the net losers from the provision of contingency markets

The potential inefficiency of using marketing margins in applied commodity price analysis, forecasting and risk management

This paper examines the implications of using marketing margins in applied commodity price analysis. The marketing-margin concept has a long and distinguished history, but it has caused considerable controversy. This is particularly the case in the context of analyzing the distribution of research gains in multi-stage production systems. We derive optimal tax schemes for raising revenues to finance research and promotion in a downstream market, derive the rules for efficient allocation of the funds, and compare the rules with an without the marketing-margin assumption. Applying the methodology to quarterly time series on the Australian beef-cattle sector and, with several caveats, we conclude that, during the period 1978:2 - 1988:4, the Australian Meat and Livestock Corporation optimally allocated research resources.

Maximin SNR beamforming strategies for two-way relay channels

In this letter, we consider beamforming strategies in amplified-and-forward (AF) two-way relay channels, where two terminals and the relay are equipped with multiple antennas. Our aim is to optimize the worse end-to-end signal-to-noise ratio of the two links so that the reliability of both terminals can be guaranteed. We show that the optimization problem can be recast as a generalized fractional programing and be solved by using the Dinkelbach-type procedure combined with semidefinite programming. Simulation results confirm the efficiency of the proposed strategies.

Building from scratch a marketing services giant by acquisition: case study and interview with Sir Martin Sorrell, Chief Executive of WPP

Purpose – Mergers and acquisitions are among the most intensely used strategic decisions. Yet research by both academics and consulting groups suggests that many mergers and acquisitions fail to add value. On the other hand there are many companies that successfully use mergers and acquisition to grow and add shareholder value. One such company is WPP. The aim of this paper is to explore why WPP has been successful in its acquisition strategy while so many other companies fail. Design/methodology/approach – The paper draws on documentary evidence and a semi-structured interview with Sir Martin Sorrell – Chief Executive and founder of WPP. Research limitations/implications – The case study offers a unique insight into thinking of a successful acquirer and sheds light on how mergers and acquisitions are managed by WPP. However, because of its design the findings are not generalisable. Originality/value – This case study sheds light on how mergers and acquisitions can be used to create a £9 billion company from a standing start. Furthermore, very few case studies offer insight into the thinking of entrepreneurial Chief Executives who established the business, grew it to become the largest and most profitable marketing services company in the world and engineered close to 300 acquisitions.