Desensitization properties of P2X3 receptors shaping pain signaling

ATP-gated P2X3 receptors are mostly expressed by nociceptive sensory neurons and participate in transduction of pain signals. P2X3 receptors show a combination of fast desensitization onset and slow recovery. Moreover, even low nanomolar agonist concentrations unable to evoke a response, can induce desensitization via a phenomenon called "high affinity desensitization." We have also observed that recovery from desensitization is agonist-specific and can range from seconds to minutes. The recovery process displays unusually high temperature dependence. Likewise, recycling of P2X3 receptors in peri-membrane regions shows unexpectedly large temperature sensitivity. By applying kinetic modeling, we have previously shown that desensitization characteristics of P2X3 receptor are best explained with a cyclic model of receptor operation involving three agonist molecules binding a single receptor and that desensitization is primarily developing from the open receptor state. Mutagenesis experiments suggested that desensitization depends on a certain conformation of the ATP binding pocket and on the structure of the transmembrane domains forming the ion pore. Further molecular determinants of desensitization have been identified by mutating the intracellular N- and C-termini of P2X3 receptor. Unlike other P2X receptors, the P2X3 subtype is facilitated by extracellular calcium that acts via specific sites in the ectodomain neighboring the ATP binding pocket. Thus, substitution of serine275 in this region (called "left flipper") converts the natural facilitation induced by extracellular calcium to receptor inhibition. Given their strategic location in nociceptive neurons and unique desensitization properties, P2X3 receptors represent an attractive target for development of new analgesic drugs via promotion of desensitization aimed at suppressing chronic pain. \ua9 2013 Giniatullin and Nistri

Biomass carbonization: process options and economics for small scale forestry farms

Bioenergy represents a unique opportunity for forestry companies to diversify the sources of income and create new stable business opportunities: a large number of initiatives has started in the last decades especially regarding decentralized power generation; nevertheless the conversion of the farmers to energy producers is not a trivial issue. The present work has focused on a possible alternative to biopower generation for forestry farms: the biomass carbonization (i.e. biomass slow pyrolysis). Charcoal making presents good prerequisite conditions for successful biomass based systems in the forestry sector: the system results incentive-independent, the power generation represents the co-product of a different primary production (resulting a real additional income), the plant capital cost is affordable for small scale farmers, operations requires technical skills normally available in the forestry sector and the reliability of the system is proven and credible, reducing the risks contained in business plans based on "number of hours of operation over several years". Moreover charcoal is a well known product, familiar to forestry companies for a very long time, the market is well defined, the technology is known but still offers opportunities for further improvements (in terms of efficiency, costs and environmental impacts), the technology does not present major risk, the investment is well suited to small farmers and the process and technology gives a great opportunity for small scale and local supply chain development. Based on these considerations, the present work investigated the technological opportunities for small scale charcoal making systems. Various process configurations have been examined, focusing on advantages and disadvantages representative of each solution in view of small scale application suitable for the Italian case and a designed pilot plant has been proposed

Integration of SRF and carbonization plant for small forestry farms

A continuous oxidative carbonization pilot unit, with a capacity of 50 kg/h,has been developed and builtby RE-CORD; reported performance data shows that the unit can produce high quality charcoal, suitable for BBQ, metallurgy of activated-carbon manufacturing, as well as biochar. Charcoal yield in excess of 24 wt% (dry) has been achieved, with a fixed carbon content higher than 85 wt% (dry). In this work,the up-scaled 250 kg/h demo plant has been designed, and the construction, operation and maintenancecosts estimated. It was assumed to feed the plant with a dedicated SRF of either poplar or robinia, which represents a very innovative and yet unexplored value chain. Performance data are reported along with economic evaluation of the whole chain. Results shows how aland management scheme based on SRF coupled to innovative small-scale biomass carbonization technology represents an appealing opportunity for business diversification in small and medium forestry enterprises

Bimodal action of protons on ATP currents of rat PC12 cells

The mode of action of extracellular protons on ATP-gated P2X2 receptors remains controversial as either enhancement or depression of ATP-mediated currents has been reported. By investigating, at different pH, the electrophysiological effect of ATP on P2X2 receptors and complementing it with receptor modelling, the present study suggests a unified mechanism for both potentiation and inactivation of ATP receptors by protons. Our experiments on patch-clamped PC12 cells showed that, on the same cell, mild acidification potentiated currents induced by low ATP concentrations (1 mM) with emergence of current fading and rebound. To clarify the nature of the ATP/H+ interaction, we used the Ding and Sachs's "loop" receptor model which best describes the behavior of such receptors with two open states linked via one inactivated state. No effects by protons could be ascribed to H+-mediated open channel block. However, by assuming that protons facilitated binding of ATP to resting as well as open receptors, the model could closely replicate H+-induced potentiation of currents evoked by low ATP doses plus fading and rebound induced by high ATP doses. The latter phenomenon was due to receptor transition to the inactive state. The present data suggest that the high concentration of protons released with ATP (and catecholamines) from secretory vesicles may allow a dual action of H+ on P2X2 receptors. This condition might also occur on P2X2 receptors of central neurons exposed to low pH during ischemia

From the sugar platform to biofuels and biochemicals. Final report for the European Commission Directorate-General Energy NENER

Numerous potential pathways to biofuels and biochemicals exist via the sugar platform1. This study uses literature surveys, market data and stakeholder input to provide a comprehensive evidence base for policymakers and industry – identifying the key benefits and development needs for the sugar platform. The study created a company database for 94 sugar-based products, with some already commercial, the majority at research/pilot stage, and only a few demonstration plants crossing the “valley of death”. Case studies describe the value proposition, market outlook and EU activity for ten value chains (acrylic, adipic & succinic acids, FDCA, BDO, farnesene, isobutene, PLA, PHAs and PE). Most can deliver significant greenhouse savings and drop-in (or improved) properties, but at an added cost to fossil alternatives. Whilst significant progress has been made, research barriers remain around lignocellulosic biomass fractionation, product separation energy, biological inhibition, chemical selectivity and monomer purity, plus improving whole chain process integration. An assessment of EU competitiveness highlights strengths in R&D, but a lack of strong commercial activity, due to the US, China and Brazil having more attractive feedstock and investment conditions. Further policy development, in particular for biochemicals, will be required to realise a competitive European sugar-based bioeconomy