Neurogenic responses mediated by vanilloid receptor-1 (TRPV1) are blocked by the high affinity antagonist, iodo-resiniferatoxin

(1) Stimulation of the vanilloid receptor-1 (TRPV1) results in the activation of nociceptive and neurogenic inflammatory responses. Poor specificity and potency of TRPV1 antagonists has, however, limited the clarification of the physiological role of TRPV1. (2) Recently, iodo-resiniferatoxin (I-RTX) has been reported to bind as a high affinity antagonist at the native and heterologously expressed rat TRPV1. Here we have studied the ability of I-RTX to block a series of TRPV1 mediated nociceptive and neurogenic inflammatory responses in different species (including transfected human TRPV1). (3) We have demonstrated that I-RTX inhibited capsaicin-induced mobilization of intracellular Ca(2+) in rat trigeminal neurons (IC(50) 0.87 nM) and in HEK293 cells transfected with the human TRPV1 (IC(50) 0.071 nM). (4) Furthermore, I-RTX significantly inhibited both capsaicin-induced CGRP release from slices of rat dorsal spinal cord (IC(50) 0.27 nM) and contraction of isolated guinea-pig and rat urinary bladder (pK(B) of 10.68 and 9.63, respectively), whilst I-RTX failed to alter the response to high KCl or SP. (5) Finally, in vivo I-RTX significantly inhibited acetic acid-induced writhing in mice (ED(50) 0.42 micro mol kg(-1)) and plasma extravasation in mouse urinary bladder (ED(50) 0.41 micro mol kg(-1)). (6) In in vitro and in vivo TRPV1 activated responses I-RTX was approximately 3 log units and approximately 20 times more potent than capsazepine, respectively. This high affinity antagonist, I-RTX, may be an important tool for future studies in pain and neurogenic inflammatory models.

Mast cell tryptase and proteinase-activated receptor 2 induce hyperexcitability of guinea-pig submucosal neurons

Mast cells that are in close proximity to autonomic and enteric nerves release several mediators that cause neuronal hyperexcitability. This study examined whether mast cell tryptase evokes acute and long-term hyperexcitability in submucosal neurons from the guinea-pig ileum by activating proteinase-activated receptor 2 (PAR2) on these neurons. We detected the expression of PAR2 in the submucosal plexus using RT-PCR. Most submucosal neurons displayed PAR2 immunoreactivity, including those colocalizing VIP. Brief (minutes) application of selective PAR2 agonists, including trypsin, the activating peptide SL-NH2 and mast cell tryptase, evoked depolarizations of the submucosal neurons, as measured with intracellular recording techniques. The membrane potential returned to resting values following washout of agonists, but most neurons were hyperexcitable for the duration of recordings (> 30 min-hours) and exhibited an increased input resistance and amplitude of fast EPSPs. Trypsin, in the presence of soybean trypsin inhibitor, and the reverse sequence of the activating peptide (LR-NH2) had no effect on neuronal membrane potential or long-term excitability. Degranulation of mast cells in the presence of antagonists of established excitatory mast cell mediators (histamine, 5-HT, prostaglandins) also caused depolarization, and following washout of antigen, long-term excitation was observed. Mast cell degranulation resulted in the release of proteases, which desensitized neurons to other agonists of PAR2. Our results suggest that proteases from degranulated mast cells cleave PAR2 on submucosal neurons to cause acute and long-term hyperexcitability. This signalling pathway between immune cells and neurons is a previously unrecognized mechanism that could contribute to chronic alterations in visceral function.

Presence and bronchomotor activity of protease-activated receptor-2 in guinea pig airways

The protease activated receptor-2 (PAR-2) belongs to a family of G-protein-coupled receptors that are activated by proteolysis. Trypsin cleaves PAR-2, exposing an N-terminal tethered ligand (SLIGRL) that activates the receptor. Messenger RNA (mRNA) for PAR-2 was found in guinea pig airway tissue by reverse transcription-polymerase chain reaction, and PAR-2 was found by immunohistochemistry in airway epithelial and smooth-muscle cells. In anesthetized guinea pigs, trypsin and SLIGRL-NH(2) (given intratracheally or intravenously) caused a bronchoconstriction that was inhibited by the combination of tachykinin-NK(1) and -NK(2) receptor antagonists and was potentiated by inhibition of nitric oxide synthase (NOS). Trypsin and SLIGRL-NH(2) relaxed isolated trachea and main bronchi, and contracted intrapulmonary bronchi. Relaxation of main bronchi was abolished or reversed to contraction by removal of epithelium, administration of indomethacin, and NOS inhibition. PAR-1, PAR-3, and PAR-4 were not involved in the bronchomotor action of either trypsin or SLIGRL-NH(2), because ligands of these receptors were inactive either in vitro or in vivo, and because thrombin (a PAR-1 and PAR-3 agonist) did not show cross-desensitization with PAR-2 agonists in vivo. Thus, we have localized PAR-2 to the guinea-pig airways, and have shown that activation of PAR-2 causes multiple motor effects in these airways, including in vivo bronchoconstriction, which is in part mediated by a neural mechanism.

The effect of the Madden-Julian Oscillation on station rainfall and river level in the Fly River system, Papua New Guinea

The Madden-Julian oscillation (MJO) is the dominant mode of intraseasonal variability in tropical rainfall on the large scale, but its signal is often obscured in individual station data, where effects are most directly felt at the local level. The Fly River system, Papua New Guinea, is one of the wettest regions on Earth and is at the heart of the MJO envelope. A 16 year time series of daily precipitation at 15 stations along the river system exhibits strong MJO modulation in rainfall. At each station, the difference in rainfall rate between active and suppressed MJO conditions is typically 40% of the station mean. The spread of rainfall between individual MJO events was small enough such that the rainfall distributions between wet and dry phases of the MJO were clearly separated at the catchment level. This implies that successful prediction of the large-scale MJO envelope will have a practical use for forecasting local rainfall. In the steep topography of the New Guinea Highlands, the mean and MJO signal in station precipitation is twice that in the satellite Tropical Rainfall Measuring Mission 3B42HQ product, emphasizing the need for ground-truthing satellite-based precipitation measurements. A clear MJO signal is also present in the river level, which peaks simultaneously with MJO precipitation input in its upper reaches but lags the precipitation by approximately 18 days on the flood plains.

Teleconnections between Ethiopian summer rainfall and sea surface temperature: part I. Observation and modelling

In this study, the oceanic regions that are associated with anomalous Ethiopian summer rains were identified and the teleconnection mechanisms that give rise to these associations have been investigated. Because of the complexities of rainfall climate in the horn of Africa, Ethiopia has been subdivided into six homogeneous rainfall zones and the influence of SST anomalies was analysed separately for each zone. The investigation made use of composite analysis and modelling experiments. Two sets of composites of atmospheric fields were generated, one based on excess/deficit rainfall anomalies and the other based on warm/cold SST anomalies in specific oceanic regions. The aim of the composite analysis was to determine the link between SST and rainfall in terms of large scale features. The modelling experiments were intended to explore the causality of these linkage. The results show that the equatorial Pacific, the midlatitude northwest Pacific and the Gulf of Guinea all exert an influence on the summer rainfall in various part of the country. The results demonstrate that different mechanisms linked to sea surface temperature control variations in rainfall in different parts of Ethiopia. This has important consequences for seasonal forecasting models which are based on statistical correlations between SST and seasonal rainfall totals. It is clear that such statistical models should take account of the local variations in teleconnections.

Breeding distribution and population decline of globally threatened Grey-necked Picathartes Picathartes oreas in Mbam Minkom Mountain Forest, southern Cameroon

The Grey-necked Picathartes Picathartes oreas, considered 'Vulnerable', is an enigmatic ground-dwelling bird endemic to the central African equatorial rainforest and belongs to a family of only two species. Its distribution extends to the two Endemic Bird Areas within Cameroon (Guinea Congo forest biome and Cameroon mountain arc) and its population is thought to be in decline throughout its range due to increasing habitat fragmentation and disturbance. During March-April 2003 and June and October 2007 we surveyed Grey-necked Picathartes in the north-western region of the Mbam Minkom Mountain Forest. In January-March 2006 we surveyed the entire mountain range and found go breeding and 24 potential breeding sites, mostly located on the western slopes. From the complete survey, we estimated the population at 44 breeding individuals. Populations were highest in the north-west region but had apparently declined from 40 breeding individuals in 2003 to 20 in 2007. This region accounted for 41% of the entire population on the mountain range during the 2006 survey. The Mbam Minkom/Kala Important Bird Area was designated based on the presence of Grey-necked Picathartes but is under high pressure of imminent destruction from agricultural encroachment and illegal timber exploitation. These results have important implications for decision making in delimiting forest boundaries and core areas for protection in the development of management plans. We suggest possible remedial actions, appropriate repeatable methods for future monitoring and opportunities for community involvement in the management and conservation of the site.

Phylogeny, biogeography, and ecology of Ficus section Malvanthera (Moraceae)

We conducted the first molecular phylogenetic study of Ficus section Malvanthera (Moraceae; subgenus Urostigma) based on 32 Malvanthera accessions and seven outgroups representing other sections of Ficus subgenus Urostigma. We used DNA sequences from the nuclear ribosomal internal and external transcribed spacers (ITS and ETS), and the glyceraldehyde-3-phosphate dehydrogenase (G3pdh) region. Phylogenetic analysis using maximum parsimony, maximum likelihood and Bayesian methods recovered a monophyletic section Malvanthera to the exclusion of the rubber fig, Ficus elastica. The results of the phylogenetic analyses do not conform to any previously proposed taxonomic subdivision of the section and characters used for previous classification are homoplasious. Geographic distribution, however, is highly conserved and Melanesian Malvanthera are monophyletic. A new subdivision of section Malvanthera reflecting phylogenetic relationships is presented. Section Malvanthera likely diversified during a period of isolation in Australia and subsequently colonized New Guinea. Two Australian series are consistent with a pattern of dispersal out of rainforest habitat into drier habitats accompanied by a reduction in plant height during the transition from hemi-epiphytic trees to lithophytic trees and shrubs. In contradiction with a previous study of Pleistodontes phylogeny suggesting multiple changes in pollination behaviour, reconstruction of changes in pollination behaviour on Malvanthera, suggests only one or a few gains of active pollination within the section. (C) 2008 Elsevier Inc. All rights reserved.

Generation, description and storage of dendritic morphology data

It is generally assumed that the variability of neuronal morphology has an important effect on both the connectivity and the activity of the nervous system, but this effect has not been thoroughly investigated. Neuroanatomical archives represent a crucial tool to explore structure–function relationships in the brain. We are developing computational tools to describe, generate, store and render large sets of three–dimensional neuronal structures in a format that is compact, quantitative, accurate and readily accessible to the neuroscientist. Single–cell neuroanatomy can be characterized quantitatively at several levels. In computer–aided neuronal tracing files, a dendritic tree is described as a series of cylinders, each represented by diameter, spatial coordinates and the connectivity to other cylinders in the tree. This ‘Cartesian’ description constitutes a completely accurate mapping of dendritic morphology but it bears little intuitive information for the neuroscientist. In contrast, a classical neuroanatomical analysis characterizes neuronal dendrites on the basis of the statistical distributions of morphological parameters, e.g. maximum branching order or bifurcation asymmetry. This description is intuitively more accessible, but it only yields information on the collective anatomy of a group of dendrites, i.e. it is not complete enough to provide a precise ‘blueprint’ of the original data. We are adopting a third, intermediate level of description, which consists of the algorithmic generation of neuronal structures within a certain morphological class based on a set of ‘fundamental’, measured parameters. This description is as intuitive as a classical neuroanatomical analysis (parameters have an intuitive interpretation), and as complete as a Cartesian file (the algorithms generate and display complete neurons). The advantages of the algorithmic description of neuronal structure are immense. If an algorithm can measure the values of a handful of parameters from an experimental database and generate virtual neurons whose anatomy is statistically indistinguishable from that of their real counterparts, a great deal of data compression and amplification can be achieved. Data compression results from the quantitative and complete description of thousands of neurons with a handful of statistical distributions of parameters. Data amplification is possible because, from a set of experimental neurons, many more virtual analogues can be generated. This approach could allow one, in principle, to create and store a neuroanatomical database containing data for an entire human brain in a personal computer. We are using two programs, L–NEURON and ARBORVITAE, to investigate systematically the potential of several different algorithms for the generation of virtual neurons. Using these programs, we have generated anatomically plausible virtual neurons for several morphological classes, including guinea pig cerebellar Purkinje cells and cat spinal cord motor neurons. These virtual neurons are stored in an online electronic archive of dendritic morphology. This process highlights the potential and the limitations of the ‘computational neuroanatomy’ strategy for neuroscience databases.

Contesting Thistlewood: slavery, agency and the limits of representation

This piece is a contribution to the exhibition catalogue of Barbadian / Canadian artist Joscelyn Gardner's exhibition, 'Bleeding & Breeding' curated by Olexander Wlasenko, January 14-February 12, 2012 in the Station Gallery, Whitby, Ontario, Canada. The piece examines the ways in which Gardner's Creole Portraits II (2007) and Creole Portraits III (2009) issue a provocative and carefully crafted contestation to the journals of the slave-owner and amateur botanist Thomas Thistlewood. It argues that while Thistlewood’s journals make raced and gendered bodies seemingly available to knowledge, incorporating them within the colonial archive as signs of subjection, Gardener’s portraits disrupt these acts of history and knowledge. Her artistic response marks a radical departure from the significant body of scholarship that has drawn on the Thistlewood journals to date. Creatively contesting his narratives’ dispossession of Creole female subjects and yet aware of the problems of innocent recovery, her works style representations that retain the consciousness and effect of historical erasure. Through an oxymoronic aesthetic that assembles a highly crafted verisimilitude alongside the condition of invisibility and brings atrocity into the orbit of the aesthetic, these portraits force us to question what stakes are involved in bringing the lives of the enslaved and violated back into regimes of representation.

Pungent general anesthetics activate transient receptor potential-A1 to produce hyperalgesia and neurogenic bronchoconstriction

BACKGROUND: Volatile anesthetics such as isoflurane and halothane have been in clinical use for many years and represent the group of drugs most commonly used to maintain general anesthesia. However, despite their widespread use, the molecular mechanisms by which these drugs exert their effects are not completely understood. Recently, a seemingly paradoxical effect of general anesthetics has been identified: the activation of peripheral nociceptors by irritant anesthetics. This mechanism may explain the hyperalgesic actions of inhaled anesthetics and their adverse effects in the airways. METHODS: To test the hypothesis that irritant inhaled anesthetics activate the excitatory ion-channel transient receptor potential (TRP)-A1 and thereby contribute to hyperalgesia and irritant airway effects, we used the measurement of intracellular calcium concentration in isolated cells in culture. For our functional experiments, we used models of isolated guinea pig bronchi to measure bronchoconstriction and withdrawal threshold to mechanical stimulation with von Frey filaments in mice. RESULTS: Irritant inhaled anesthetics activate TRPA1 expressed in human embryonic kidney cells and in nociceptive neurons. Isoflurane induces mechanical hyperalgesia in mice by a TRPA1-dependent mechanism. Isoflurane also induces TRPA1-dependent constriction of isolated bronchi. Nonirritant anesthetics do not activate TRPA1 and fail to produce hyperalgesia and bronchial constriction. CONCLUSIONS: General anesthetics induce a reversible loss of consciousness and render the patient unresponsive to painful stimuli. However, they also produce excitatory effects such as airway irritation and they contribute to postoperative pain. Activation of TRPA1 may contribute to these adverse effects, a hypothesis that remains to be tested in the clinical setting.

Cigarette smoke-induced neurogenic inflammation is mediated by α,β-unsaturated aldehydes and the TRPA1 receptor in rodents

Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 alpha,beta-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce neurogenic inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca2+ in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. These responses were abolished by a TRPA1-selective antagonist and by the aldehyde scavenger glutathione but not by the TRPV1 antagonist capsazepine or by ROS scavengers. Treatment with CSE or aldehydes increased Ca2+ influx in TRPA1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE and aldehydes on Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify alpha,beta-unsaturated aldehydes as the main causative agents in CS that via TRPA1 stimulation mediate airway neurogenic inflammation and suggest a role for TRPA1 in the pathogenesis of CS-induced diseases.

Simulated changes in the relationship between tropical ocean temperatures and the western African monsoon during the mid-Holocene

Results from nine coupled ocean-atmosphere simulations have been used to investigate changes in the relationship between the variability of monsoon precipitation over western Africa and tropical sea surface temperatures (SSTs) between the mid-Holocene and the present day. Although the influence of tropical SSTs on the African monsoon is generally overestimated in the control simulations, the models reproduce aspects of the observed modes of variability. Thus, most models reproduce the observed negative correlation between western Sahelian precipitation and SST anomalies in the eastern tropical Pacific, and many of them capture the positive correlation between SST anomalies in the eastern tropical Atlantic and precipitation over the Guinea coastal region. Although the response of individual model to the change in orbital forcing between 6 ka and present differs somewhat, eight of the models show that the strength of the teleconnection between SSTs in the eastern tropical Pacific and Sahelian precipitation is weaker in the mid-Holocene. Some of the models imply that this weakening was associated with a shift towards longer time periods (from 3–5 years in the control simulations toward 4–10 years in the mid-Holocene simulations). The simulated reduction in the teleconnection between eastern tropical Pacific SSTs and Sahelian precipitation appears to be primarily related to a reduction in the atmospheric circulation bridge between the Pacific and West Africa but, depending on the model, other mechanisms such as increased importance of other modes of tropical ocean variability or increased local recycling of monsoonal precipitation can also play a role.

Propagation of the Madden-Julian Oscillation through the Maritime Continent and scale interaction with the diurnal cycle of precipitation

The convectively active part of the Madden-Julian Oscillation (MJO) propagates eastward through the warm pool, from the Indian Ocean through the Maritime Continent (the Indonesian archipelago) to the western Pacific. The Maritime Continent's complex topography means the exact nature of the MJO propagation through this region is unclear. Model simulations of the MJO are often poor over the region, leading to local errors in latent heat release and global errors in medium-range weather prediction and climate simulation. Using 14 northern winters of TRMM satellite data it is shown that, where the mean diurnal cycle of precipitation is strong, 80% of the MJO precipitation signal in the Maritime Continent is accounted for by changes in the amplitude of the diurnal cycle. Additionally, the relationship between outgoing long-wave radiation (OLR) and precipitation is weakened here, such that OLR is no longer a reliable proxy for precipitation. The canonical view of the MJO as the smooth eastward propagation of a large-scale precipitation envelope also breaks down over the islands of the Maritime Continent. Instead, a vanguard of precipitation (anomalies of 2.5 mm day^-1 over 10^6 km^2) jumps ahead of the main body by approximately 6 days or 2000 km. Hence, there can be enhanced precipitation over Sumatra, Borneo or New Guinea when the large-scale MJO envelope over the surrounding ocean is one of suppressed precipitation. This behaviour can be accommodated into existing MJO theories. Frictional and topographic moisture convergence and relatively clear skies ahead of the main convective envelope combine with the low thermal inertia of the islands, to allow a rapid response in the diurnal cycle which rectifies onto the lower-frequency MJO. Hence, accurate representations of the diurnal cycle and its scale interaction appear to be necessary for models to simulate the MJO successfully.