Currents mediated by non-NMDA glutamate receptors in rat magnocellular basal forebrain neurones in primary culture

Patch-clamp techniques were used to record glutamate receptor-mediated responses from magnocellular rat basal forebrain neurones maintained in dissociated culture. Both NMDA and non-NMDA receptor-mediated responses were observed and could be distinguished pharmacologically. AMPA and kainate elicited inward currents. Responses to AMPA but not to kainate showed rapid desensitization. EC50S for steady-state responses to AMPA and kainate were 2.7 and 138µM respectively. Responses were potentiated by cyclothiazide but not by Concanavalin A and were inhibited by GYKI 53655. These data indicate that non-NMDA receptor-mediated responses result predominantly from activation of an AMPA receptor. In the presence of GYKI 53655 small inward currents were observed upon kainate application. Responses decreased in amplitude during prolonged application, were insensitive to cyclothiazide and potentiated by Concanavalin A. These responses probably reflect kainate receptor activation. Steady-state current-voltage relationships were examined in nucleated patches. With 30µM spermine in the pipette mildly outwardly rectifying through linear to strongly doubly-rectifying relationships were observed, suggesting a range of calcium permeabilities. AMPA receptor calcium permeabilities were quantitated using constant field theory to interpret the effects of solution exchanges on reversal potentials in acutely dissociated neurones. Relative calcium:sodium permeability ranged from 0.26 to 3.6, median 1.27. Extracellular calcium ions also reduced current amplitude, an effect mimicked by cadmium and by cobalt ions. The effect of cadmium was dose-dependent (EC50 44µM) and voltage-sensitive. Kainate application to acutely dissociated neurones resulted in calcium current inhibition. GYKI 53655 sensitivity indicated that the probable mechanism is calcium-dependent inactivation of calcium channels following calcium influx through AMPA receptors. These data may explain the sensitivity of magnocellular cholinergic basal forebrain neurones to non-NMDA receptor agonists in vivo and are consistent with the suggestion that glutamate-induced calcium influx may contribute to selective loss of cholinergic neurones in dementia

Non-conventional monetary policies: QE and the DSGE literature

At the zero lower bound, the scale and scope of non-conventional monetary policies have become the key decision variables for monetary policy makers. In the UK, quantitative easing has involved the creation of a fund to purchase medium term dated government bonds with borrowed central bank reserves and so has increased the liquidity of the non-bank financial sector and temporarily eased the budget constraint of HMT. Some of these reserves have been used to increase the extent of capital held by banks and there have also been direct injections of capital into the banking system. We assess some of the issues arising from the three policies by using three separate DSGE models, which take seriously the role of financial frictions. We find that it is possible to correct the effects of a lower zero bound in DSGE models, by (i) offsetting the liquidity premium embedded in long term bonds and/or (ii) adopting countercyclical subsidies to bank capital able and/or (iii) the creation of central bank reserves that reduce the costs of loan supply. But the correct quantitative response and ongoing interaction with standard monetary policy remains an open question

Differential expression of cytokine transcripts in neonatal and adult ovine alveolar macrophages in response to respiratory syncytial virus or toll-like receptor ligation

Alveolar macrophages (AMϕs) secrete regulatory molecules that are believed to be critical in maintaining normal lung homeostasis. However, in response to activating signals, AMϕs have been shown to become highly phagocytic cells capable of secreting significant levels of pro-inflammatory cytokines. There is evidence to suggest that susceptibility of Mϕ subpopulations to viral infection, and their subsequent cytokine/chemokine response, is dependent on age of the host. In the present study, we compared bovine respiratory syncytial virus (BRSV) replication and induction of cytokine responses in neonatal ovine AMϕs to those cells isolated from adult animals. While neonatal AMϕs could be infected with BRSV, viral replication was limited as previously shown for AMϕs from mature animals. Interestingly, following BRSV infection, peak mRNA levels of IL-1β and IL-8 in neonatal AMϕ were several fold higher than levels induced in adult AMϕs. In addition, peak mRNA expression for the cytokines examined occurred at earlier time points in neonatal AMϕs compared to adult AMϕs. However, the data indicated that viral replication was not required for the induction of specific cytokines in either neonatal or adult AMϕs. TLR3 and TLR4 agonists induced significantly higher levels of cytokine transcripts than BRSV in both neonatal and adult AMϕs. It was recently proposed that immaturity of the neonatal immune system extends from production of pro-inflammatory cytokines to regulation of such responses. Differential regulation of cytokines in neonatal AMϕs compared to adult AMϕs in response to RSV could be a contributory factor to more severe clinical episodes seen in neonates

Trajectory Mapping and Applications to Data from the Upper Atmosphere Research Satellite

The problem of creating synoptic maps from asynoptically gathered trace gas data has prompted the development of a number of schemes. Most notable among these schemes are the Kalman filter, the Salby-Fourier technique, and constituent reconstruction. This paper explores a new technique called trajectory mapping. Trajectory mapping creates synoptic maps from asynoptically gathered data by advecting measurements backward or forward in time using analyzed wind fields. A significant portion of this work is devoted to an analysis of errors in synoptic trajectory maps associated with the calculation of individual parcel trajectories. In particular, we have considered (1) calculational errors; (2) uncertainties in the values and locations of constituent measurements, (3) errors incurred by neglecting diabatic effects, and (4) sensitivity to differences in wind field analyses. These studies reveal that the global fields derived from the advection of large numbers of measurements are relatively insensitive to the errors in the individual trajectories. The trajectory mapping technique has been successfully applied to a variety of problems. In this paper, the following two applications demonstrate the usefulness of the technique: an analysis of dynamical wave-breaking events and an examination of Upper Atmosphere Research Satellite data accuracy

Hand-to-Face Remapping But No Differences in Temporal Discrimination Observed on the Intact Hand Following Unilateral Upper Limb Amputation

Unilateral major limb amputation causes changes in sensory perception. Changes may occur within not only the residual limb but also the intact limb as well as the brain. We tested the hypothesis that limb amputation may result in the detection of hand sensation during stimulation of a non-limb-related body region. We further investigated the responses of unilateral upper limb amputees and individuals with all limbs intact to temporally based sensory tactile testing of the fingertips to test the hypothesis that changes in sensory perception also have an effect on the intact limb. Upper extremity amputees were assessed for the presence of referred sensations (RSs)—experiencing feelings in the missing limb when a different body region is stimulated, to determine changes within the brain that occur due to an amputation. Eight of 19 amputees (42.1%) experienced RS in the phantom limb with manual tactile mapping on various regions of the face. There was no correlation between whether someone had phantom sensations or phantom limb pain and where RS was found. Six of the amputees had either phantom sensation or pain in addition to RS induced by facial stimulation. Results from the tactile testing showed that there were no significant differences in the accuracy of participants in the temporal order judgment tasks (p = 0.702), whereby participants selected the digit that was tapped first by a tracking paradigm that resulted in correct answers leading to shorter interstimulus intervals (ISIs) and incorrect answers increasing the ISI. There were also no significant differences in timing perception, i.e., the threshold accuracy of the duration discrimination task (p = 0.727), in which participants tracked which of the two digits received a longer stimulus. We conclude that many, but not all, unilateral upper limb amputees experience phantom hand sensation and/or pain with stimulation of the face, suggesting that there could be postamputation changes in neuronal circuitry in somatosensory cortex. However, major unilateral limb amputation does not lead to changes in temporal order judgment or timing perception tasks administered via the tactile modality of the intact hand in upper limb amputees

The Effect of PRRS Viral Level and Isolate on Tonsil Gene Expression

Porcine Reproductive and Respiratory Syndrome virus (PRRSV) can persist in tonsil tissue for \u3e150 days post infection (dpi) without clinical signs.This can occur even when PRRSV is cleared from serumand can result insecondary outbreaks. Tonsil tissue from commercial crossbred pigs that were experimentally infected with one of two PRRSV isolates, NVSL-97-7985 (NVSL) or KS-2006-72109 (KS06),was used to identify genes that were differentially expressed in pigs with extreme high or low tonsil PRRS viremia at 42 dpi. Results provide insighton the mechanisms of PRRSV persistence in tonsils and help to identify bio-markers for PRRSV persistence in tonsil tissue.This maylead tothe development of more effective strategies to reduce the chance of PRRS re-breaks

Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase

BACKGROUND: BACE1 is one of the two enzymes that cleave amyloid precursor protein to generate Alzheimer's disease (AD) beta amyloid peptides. It is widely believed that BACE1 initiates APP processing in endosomes, and in the brain this cleavage is known to occur during axonal transport of APP. In addition, BACE1 accumulates in dystrophic neurites surrounding brain senile plaques in individuals with AD, suggesting that abnormal accumulation of BACE1 at presynaptic terminals contributes to pathogenesis in AD. However, only limited information is available on BACE1 axonal transport and targeting. RESULTS: By visualizing BACE1-YFP dynamics using live imaging, we demonstrate that BACE1 undergoes bi-directional transport in dynamic tubulo-vesicular carriers along axons in cultured hippocampal neurons and in acute hippocampal slices of transgenic mice. In addition, a subset of BACE1 is present in larger stationary structures, which are active presynaptic sites. In cultured neurons, BACE1-YFP is preferentially targeted to axons over time, consistent with predominant in vivo localization of BACE1 in presynaptic terminals. Confocal analysis and dual-color live imaging revealed a localization and dynamic transport of BACE1 along dendrites and axons in Rab11-positive recycling endosomes. Impairment of Rab11 function leads to a diminution of total and endocytosed BACE1 in axons, concomitant with an increase in the soma. Together, these results suggest that BACE1 is sorted to axons in endosomes in a Rab11-dependent manner. CONCLUSION: Our results reveal novel information on dynamic BACE1 transport in neurons, and demonstrate that Rab11-GTPase function is critical for axonal sorting of BACE1. Thus, we suggest that BACE1 transcytosis in endosomes contributes to presynaptic BACE1 localization

Access to primary percutaneous coronary intervention for ST-segment elevation myocardial infarction in Canada: a geographic analysis

Ye

Identifying Molecular Differences in Pigs with Extreme Phenotypes for Weight Gain and Viral Load in Response to PRRS

Blood transcriptome analyses in the early phase after infection with the Porcine Reproductive and Respiratory Syndrome virus (PRRSv) revealed differential gene expression patterns and regulatory networks between pigs with extreme phenotypes for weight gain and viral load. Understanding these differences could lead to identifying biomarkers that would predict which pigs would be more resistant to PRRS

Use of fecal volatile organic compound analysis to discriminate between nonvaccinated and BCG-Vaccinated cattle prior to and after \u3ci\u3eMycobacterium bovis\u3c/i\u3e challenge

Bovine tuberculosis is a zoonotic disease of global public health concern. Development of diagnostic tools to improve test accuracy and efficiency in domestic livestock and enable surveillance of wildlife reservoirs would improve disease management and eradication efforts. Use of volatile organic compound analysis in breath and fecal samples is being developed and optimized as a means to detect disease in humans and animals. In this study we demonstrate that VOCs present in fecal samples can be used to discriminate between non-vaccinated and BCG-vaccinated cattle prior to and after Mycobacterium bovis challenge