The Ca(v)2.3 calcium channel antagonist SNX-482 reduces dorsal horn neuronal responses in a rat model of chronic neuropathic pain

Neuropathic pain is a difficult state to treat, characterized by alterations in sensory processing that can include allodynia (touch-evoked pain). Evidence exists for nerve damage-induced plasticity in both transmission and modulatory systems, including changes in voltage-dependent calcium channel (VDCC) expression and function; however, the role of Ca(v)2.3 calcium channels has not clearly been defined. Here, the effects of SNX-482, a selective Ca(v)2.3 antagonist, on sensory transmission at the spinal cord level have been investigated in the rat. The spinal nerve ligation (SNL) model of chronic neuropathic pain [Kim & Chung, (1992) Pain, 50, 355-363] was used to induce mechanical allodynia, as tested on the ipsilateral hindpaw. In vivo electrophysiological measurements of dorsal horn neuronal responses to innocuous and noxious electrical and natural stimuli were made after SNL and compared to sham-operated animals. Spinal SNX-482 (0.5-4 mu g/50 mu L) exerted dose-related inhibitions of noxious C-fibre- and A delta-fibre-mediated neuronal responses in conditions of neuropathy, but not in sham-operated animals. Measures of spinal cord hyperexcitability and nociception were most susceptible to SNX-482. In contrast, non-noxious A beta-mediated responses were not affected by SNX-482. Moreover, responses to innocuous mechanical and also thermal stimuli were more sensitive to SNX-482 in SNL than control animals. This study is the first to demonstrate an antinociceptive role for SNX-482-sensitive channels in dorsal horn neurons during neuropathy. These data are consistent with plasticity in Ca(V)2.3 calcium channel expression and suggest a potential selective target to reduce nociceptive transmission during conditions of nerve damage.

Evidence that GABA rho subunits contribute to functional ionotropic GABA receptors in mouse cerebellar Purkinje cells

Ionotropic gamma-amino butyric acid (GABA) receptors composed of heterogeneous molecular subunits are major mediators of inhibitory responses in the adult CNS. Here, we describe a novel ionotropic GABA receptor in mouse cerebellar Purkinje cells (PCs) using agents reported to have increased affinity for rho subunit-containing GABA(C) over other GABA receptors. Exogenous application of the GABA(C)-preferring agonist cis-4-aminocrotonic acid (CACA) evoked whole-cell currents in PCs, whilst equimolar concentrations of GABA evoked larger currents. CACA-evoked currents had a greater sensitivity to the selective GABA(C) antagonist (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) than GABA-evoked currents. Focal application of agonists produced a differential response profile; CACA-evoked currents displayed a much more pronounced attenuation with increasing distance from the PC soma, displayed a slower time-to-peak and exhibited less desensitization than GABA-evoked currents. However, CACA-evoked currents were also completely blocked by bicuculline, a selective agent for GABA(A) receptors. Thus, we describe a population of ionotropic GABA receptors with a mixed GABA(A)/GABA(C) pharmacology. TPMPA reduced inhibitory synaptic transmission at interneurone-Purkinje cell (IN-PC) synapses, causing clear reductions in miniature inhibitory postsynaptic current (mIPSC) amplitude and frequency. Combined application of NO-711 (a selective GABA transporter subtype 1 (GAT-1) antagonist) and SNAP-5114 (a GAT-(2)/3/4 antagonist) induced a tonic GABA conductance in PCs; however, TPMPA had no effect on this current. Immunohistochemical studies suggest that rho subunits are expressed predominantly in PC soma and proximal dendritic compartments with a lower level of expression in more distal dendrites; this selective immunoreactivity contrasted with a more uniform distribution of GABA(A) alpha 1 subunits in PCs. Finally, co-immunoprecipitation studies suggest that rho subunits can form complexes with GABA(A) receptor alpha 1 subunits in the cerebellar cortex. Overall, these data suggest that rho subunits contribute to functional ionotropic receptors that mediate a component of phasic inhibitory GABAergic transmission at IN-PC synapses in the cerebellum.

Experimental evidence for a partially dissociated water bilayer on Ru{0001}

Core-level photoelectron spectra, in excellent agreement with ab initio calculations, confirm that the stable wetting layer of water on Ru{0001} contains O-H and H2O in roughly 3:5 proportion, for OHx coverages between 0.25 and 0.7 ML, and T<170 K. Proton disorder explains why the wetting structure looks to low energy electron diffraction (LEED) to be an ordered p(root3xroot3)R30degrees adlayer, even though approximate to3/8 of its molecules are dissociated. Complete dissociation to atomic oxygen starts near 190 K. Low photon flux in the synchrotron experiments ensured that the diagnosis of the nature of the wetting structure quantified by LEED is free of beam-induced damage.

Speech perception and phonological short-term memory capacity in language impairment: preliminary evidence from adolescents with specific language impairment (SLI) and autism spectrum disorders (ASD)

Background: The cognitive bases of language impairment in specific language impairment (SLI) and autism spectrum disorders (ASD) were investigated in a novel non-word comparison task which manipulated phonological short-term memory (PSTM) and speech perception, both implicated in poor non-word repetition. Aims: This study aimed to investigate the contributions of PSTM and speech perception in non-word processing and whether individuals with SLI and ASD plus language impairment (ALI) show similar or different patterns of deficit in these cognitive processes. Method & Procedures: Three groups of adolescents (aged 14–17 years), 14 with SLI, 16 with ALI, and 17 age and non-verbal IQ matched typically developing (TD) controls, made speeded discriminations between non-word pairs. Stimuli varied in PSTM load (two- or four-syllables) and speech perception load (mismatches on a word-initial or word-medial segment). Outcomes & Results: Reaction times showed effects of both non-word length and mismatch position and these factors interacted: four-syllable and word-initial mismatch stimuli resulted in the slowest decisions. Individuals with language impairment showed the same pattern of performance as those with typical development in the reaction time data. A marginal interaction between group and item length was driven by the SLI and ALI groups being less accurate with long items than short ones, a difference not found in the TD group. Conclusions & Implications: Non-word discrimination suggests that there are similarities and differences between adolescents with SLI and ALI and their TD peers. Reaction times appear to be affected by increasing PSTM and speech perception loads in a similar way. However, there was some, albeit weaker, evidence that adolescents with SLI and ALI are less accurate than TD individuals, with both showing an effect of PSTM load. This may indicate, at some level, the processing substrate supporting both PSTM and speech perception is intact in adolescents with SLI and ALI, but also in both there may be impaired access to PSTM resources.

Observations of ice multiplication in a weakly convective cell embedded in supercooled mid-level stratus

Simultaneous observations of cloud microphysical properties were obtained by in-situ aircraft measurements and ground based Radar/Lidar. Widespread mid-level stratus cloud was present below a temperature inversion (~5 °C magnitude) at 3.6 km altitude. Localised convection (peak updraft 1.5 m s−1) was observed 20 km west of the Radar station. This was associated with convergence at 2.5 km altitude. The convection was unable to penetrate the inversion capping the mid-level stratus. The mid-level stratus cloud was vertically thin (~400 m), horizontally extensive (covering 100 s of km) and persisted for more than 24 h. The cloud consisted of supercooled water droplets and small concentrations of large (~1 mm) stellar/plate like ice which slowly precipitated out. This ice was nucleated at temperatures greater than −12.2 °C and less than −10.0 °C, (cloud top and cloud base temperatures, respectively). No ice seeding from above the cloud layer was observed. This ice was formed by primary nucleation, either through the entrainment of efficient ice nuclei from above/below cloud, or by the slow stochastic activation of immersion freezing ice nuclei contained within the supercooled drops. Above cloud top significant concentrations of sub-micron aerosol were observed and consisted of a mixture of sulphate and carbonaceous material, a potential source of ice nuclei. Particle number concentrations (in the size range 0.13.0 μm) were measured above and below cloud in concentrations of ~25 cm−3. Ice crystal concentrations in the cloud were constant at around 0.2 L−1. It is estimated that entrainment of aerosol particles into cloud cannot replenish the loss of ice nuclei from the cloud layer via precipitation. Precipitation from the mid-level stratus evaporated before reaching the surface, whereas rates of up to 1 mm h−1 were observed below the convective feature. There is strong evidence for the Hallett-Mossop (HM) process of secondary ice particle production leading to the formation of the precipitation observed. This includes (1) Ice concentrations in the convective feature were more than an order of magnitude greater than the concentration of primary ice in the overlaying stratus, (2) Large concentrations of small pristine columns were observed at the ~−5 °C level together with liquid water droplets and a few rimed ice particles, (3) Columns were larger and increasingly rimed at colder temperatures. Calculated ice splinter production rates are consistent with observed concentrations if the condition that only droplets greater than 24 μm are capable of generating secondary ice splinters is relaxed. This case demonstrates the importance of understanding the formation of ice at slightly supercooled temperatures, as it can lead to secondary ice production and the formation of precipitation in clouds which may not otherwise be considered as significant precipitation sources.

Appraiser behaviour and appraisal smoothing: some qualitative and quantitative evidence

There is a substantial literature which suggests that appraisals are smoothed and lag the true level of prices. This study combines a qualitative interview survey of the leading fund manager/owners in the UK and their appraisers with a empirical study of the number of appraisals which change each month within the IPD Monthly Index. The paper concentrates on how the appraisal process operates for commercial property performance measurement purposes. The survey interviews suggest that periodic appraisal services are consolidating in fewer firms and, within these major firms, appraisers adopt different approaches to changing appraisals on a period by period basis, with some wanting hard transaction evidence while others act on "softer' signals. The survey also indicates a seasonal effect with greater effort and information being applied to annual and quarterly appraisals than monthly. The analysis of the appraisals within the Investment Property Databank Monthly Index confirms this effect with around 5% more appraisals being moved at each quarter day than the other months. January and August have significantly less appraisal changes than other months.

Unusual isotope effect in the reaction of chlorosilylene with trimethylsilane-1-d: Absolute rate studies and quantum chemical and Rice–Ramsperger–Kassel–Marcus calculations provide strong evidence for the involvement of an intermediate complex

Time-resolved studies of chlorosilylene, ClSiH, generated by the 193 nm laser flash photolysis of 1-chloro-1- silacyclopent-3-ene, have been carried out to obtain rate constants for its bimolecular reaction with trimethylsilane-1-d, Me3SiD, in the gas phase. The reaction was studied at total pressures up to 100 Torr (with and without added SF6) over the temperature range of 295−407 K. The rate constants were found to be pressure independent and gave the following Arrhenius equation: log[(k/(cm3 molecule−1 s−1)] = (−13.22 ± 0.15) + [(13.20 ± 1.00) kJ mol−1]/(RT ln 10). When compared with previously published kinetic data for the reaction of ClSiH with Me3SiH, kinetic isotope effects, kD/kH, in the range from 7.4 (297 K) to 6.4 (407 K) were obtained. These far exceed values of 0.4−0.5 estimated for a single-step insertion process. Quantum chemical calculations (G3MP2B3 level) confirm not only the involvement of an intermediate complex, but also the existence of a low-energy internal isomerization pathway which can scramble the D and H atom labels. By means of Rice−Ramsperger−Kassel−Marcus modeling and a necessary (but small) refinement of the energy surface, we have shown that this mechanism can reproduce closely the experimental isotope effects. These findings provide the first experimental evidence for the isomerization pathway and thereby offer the most concrete evidence to date for the existence of intermediate complexes in the insertion reactions of silylenes.

Progressive palaeoenvironmental change during the Late Barremian-Early Aptian as prelude to Oceanic Anoxic Event 1a: Evidence from the Gorgo a Cerbara section (Umbria-Marche basin, central Italy)

During Oceanic Anoxic Event 1a (OAE 1a, 120 Ma; Li et al., 2008), organic carbon-rich layers were deposited in marine environments under anoxic conditions on a global scale. In this study, palaeoenvironmental conditions leading to this event are characterised by studying the Upper Barremian to the Lower Aptian succession of the Gorgo a Cerbara section (central Italy). For this, an integrated multi-proxy approach (δ13Ccarb; δ13Corg; δ18O; phosphorus; Total Organic Carbon, TOC; bulk-rock mineralogy, as well as redox-sensitive trace elements — RSTEs) has been applied. During the LateBarremian, thin organic-rich layers occur episodically, and associated Corg:Ptot ratios indicate the presence of intermittent dysoxic to anoxic conditions. Coarse correlations are observed between TOC, P and biogenic silica contents, indicating links between P availability, productivity, and TOC preservation. However, the corresponding δ13Ccarb and δ18O records remain quite stable, indicating that these brief periods of enhanced TOC preservation did not have sufficient impact on the marine carbon reservoir to deviate δ13C records. Around the Barremian–Aptian boundary, TOC-enriched layers become more frequent. These layers correlate with negative excursions in the δ13Ccarb and δ13Corg records, possibly due to a warming period as indicated by the δ18O record. During the earliest Aptian, this warming trend is reverted into a cooling trend, which is then followed by an important warming step near the onset of Oceanic Anoxic Event 1a (OAE 1a). During this time period, organic-rich intervals occur, which are characterised by the progressive increase in RSTE. The warming step prior the onset of OAE 1a is associated with the well-known negative spike in δ13Ccarb and δ13Corg records, an important peak in P accumulation, RSTE enrichments and Corg:Ptot ratios indicating the prevalence of anoxic conditions. The Selli Level itself may document a cooling phase. RSTE enrichments and Corg:Ptot ratios confirm the importance of anoxic conditions during OAE 1a at this site. The Gorgo a Cerbara section is interpreted to reflect the progressive impact of palaeoenvironmental change related to the formation of the Ontong-Java plate-basalt plateau, which started already around the Barremian–Aptian boundary and culminated into OAE 1a.

Glycogen synthase kinase 3 (GSK3) in the heart: a point of integration in hypertrophic signalling and a therapeutic target? A critical analysis

Glycogen synthase kinase 3 (GSK3, of which there are two isoforms, GSK3alpha and GSK3beta) was originally characterized in the context of regulation of glycogen metabolism, though it is now known to regulate many other cellular processes. Phosphorylation of GSK3alpha(Ser21) and GSK3beta(Ser9) inhibits their activity. In the heart, emphasis has been placed particularly on GSK3beta, rather than GSK3alpha. Importantly, catalytically-active GSK3 generally restrains gene expression and, in the heart, catalytically-active GSK3 has been implicated in anti-hypertrophic signalling. Inhibition of GSK3 results in changes in the activities of transcription and translation factors in the heart and promotes hypertrophic responses, and it is generally assumed that signal transduction from hypertrophic stimuli to GSK3 passes primarily through protein kinase B/Akt (PKB/Akt). However, recent data suggest that the situation is far more complex. We review evidence pertaining to the role of GSK3 in the myocardium and discuss effects of genetic manipulation of GSK3 activity in vivo. We also discuss the signalling pathways potentially regulating GSK3 activity and propose that, depending on the stimulus, phosphorylation of GSK3 is independent of PKB/Akt. Potential GSK3 substrates studied in relation to myocardial hypertrophy include nuclear factors of activated T cells, beta-catenin, GATA4, myocardin, CREB, and eukaryotic initiation factor 2Bvarepsilon. These and other transcription factor substrates putatively important in the heart are considered. We discuss whether cardiac pathologies could be treated by therapeutic intervention at the GSK3 level but conclude that any intervention would be premature without greater understanding of the precise role of GSK3 in cardiac processes.

Generic strategies and performance: evidence from manufacturing firms

Purpose – The purpose of this study is to examine the relationship between business-level strategy and organisational performance and to test the applicability of Porter's generic strategies in explaining differences in the performance of organisations. Design/methodology/approach – The study was focussed on manufacturing firms in the UK belonging to the electrical and mechanical engineering sectors. Data were collected through a postal survey using the survey instrument from 124 organisations and the respondents were all at CEO level. Both objective and subjective measures were used to assess performance. Non-response bias was assessed statistically and it was not found to be a major problem affecting this study. Appropriate measures were taken to ensure that common method variance (CMV) does not affect the results of this study. Statistical tests indicated that CMV problem does not affect the results of this study. Findings – The results of this study indicate that firms adopting one of the strategies, namely cost-leadership or differentiation, perform better than “stuck-in-the-middle” firms which do not have a dominant strategic orientation. The integrated strategy group has lower performance compared with cost-leaders and differentiators in terms of financial performance measures. This provides support for Porter's view that combination strategies are unlikely to be effective in organisations. However, the cost-leadership and differentiation strategies were not strongly correlated with the financial performance measures indicating the limitations of Porter's generic strategies in explaining performance heterogeneity in organisations. Originality/value – This study makes an important contribution to the literature by identifying some of the gaps in the literature through a systematic literature review and addressing those gaps.

Pediastrum species as potential indicators of lake-level change in tropical South America

We explored the potential for using Pediastrum (Meyen), a genus of green alga commonly found in palaeoecological studies, as a proxy for lake-level change in tropical South America. The study site, Laguna La Gaiba (LLG) (17°45′S, 57°40′W), is a broad, shallow lake located along the course of the Paraguay River in the Pantanal, a 135,000-km2 tropical wetland located mostly in western Brazil, but extending into eastern Bolivia. Fourteen surface sediment samples were taken from LLG across a range of lake depths (2-5.2 m) and analyzed for Pediastrum. We found seven species, of which P. musteri (Tell et Mataloni), P. argentiniense (Bourr. et Tell), and P. cf. angulosum (Ehrenb.) ex Menegh. were identified as potential indicators of lake level. Results of the modern dataset were applied to 31 fossil Pediastrum assemblages spanning the early Holocene (12.0 kyr BP) to present to infer past lake level changes qualitatively. Early Holocene (12.0-9.8 kyr BP) assemblages do not show a clear signal, though abundance of P. simplex (Meyen) suggests relatively high lake levels. Absence of P. musteri, characteristic of deep, open water, and abundance of macrophyte-associated taxa indicate lake levels were lowest from 9.8 to 3.0 kyr BP. A shift to wetter conditions began at 4.4 kyr BP, indicated by the appearance of P. musteri, though inferred lake levels did not reach modern values until 1.4 kyr BP. The Pediastrum-inferred mid-Holocene lowstand is consistent with lower precipitation, previously inferred using pollen from this site, and is also in agreement with evidence for widespread drought in the South American tropics during the middle Holocene. An inference for steadily increasing lake level from 4.4 kyr BP to present is consistent with diatom-inferred water level rise at Lake Titicaca, and demonstrates coherence with the broad pattern of increasing monsoon strength from the late Holocene until present in tropical South America.

Processing reflexives in a second language: the timing of structural and discourse-level information

We report the results from two eye-movement monitoring experiments examining the processing of reflexive pronouns by proficient German-speaking learners of second language (L2) English. Our results show that the nonnative speakers initially tried to link English argument reflexives to a discourse-prominent but structurally inaccessible antecedent, thereby violating binding condition A. Our native speaker controls, in contrast, showed evidence of applying condition A immediately during processing. Together, our findings show that L2 learners’ initial focusing on a structurally inaccessible antecedent cannot be due to first language influence and is also independent of whether the inaccessible antecedent c-commands the reflexive. This suggests that unlike native speakers, nonnative speakers of English initially attempt to interpret reflexives through discourse-based coreference assignment rather than syntactic binding.

Ecosystem effects of CO2 concentration: evidence from past climates

Atmospheric CO2 concentration has varied from minima of 170-200 ppm in glacials to maxima of 280-300 ppm in the recent interglacials. Photosynthesis by C-3 plants is highly sensitive to CO2 concentration variations in this range. Physiological consequences of the CO2 changes should therefore be discernible in palaeodata. Several lines of evidence support this expectation. Reduced terrestrial carbon storage during glacials, indicated by the shift in stable isotope composition of dissolved inorganic carbon in the ocean, cannot be explained by climate or sea-level changes. It is however consistent with predictions of current process-based models that propagate known physiological CO2 effects into net primary production at the ecosystem scale. Restricted forest cover during glacial periods, indicated by pollen assemblages dominated by non-arboreal taxa, cannot be reproduced accurately by palaeoclimate models unless CO2 effects on C-3-C-4 plant competition are also modelled. It follows that methods to reconstruct climate from palaeodata should account for CO2 concentration changes. When they do so, they yield results more consistent with palaeoclimate models. In conclusion, the palaeorecord of the Late Quaternary, interpreted with the help of climate and ecosystem models, provides evidence that CO2 effects at the ecosystem scale are neither trivial nor transient.

Costing conservation: an expert appraisal of the pollinator habitat benefits of England’s entry level stewardship

Pollination services provided by insects play a key role in English crop production and wider ecology. Despite growing evidence of the negative effects of habitat loss on pollinator populations, limited policy support is available to reverse this pressure. One measure that may provide beneficial habitat to pollinators is England’s entry level stewardship agri-environment scheme. This study uses a novel expert survey to develop weights for a range of models which adjust the balance of Entry Level Stewardship options within the current area of spending. The annual costs of establishing and maintaining these option compositions were estimated at £59.3–£12.4 M above current expenditure. Although this produced substantial reduction in private cost:benefit ratios, the benefits of the scheme to pollinator habitat rose by 7–140 %; significantly increasing the public cost:benefit ratio. This study demonstrates that the scheme has significant untapped potential to provide good quality habitat for pollinators across England, even within existing expenditure. The findings should open debate on the costs and benefits of specific entry level stewardship management options and how these can be enhanced to benefit both participants and biodiversity more equitably.