The Elite: A high speed, low-cost general aviation aircraft for Aeroworld

The Elite is a six passenger, general aviation aircraft targeted at the upper middle class private pilot. The Elite is a low wing, conventional monoplane utilizing rudder, ailerons, and a stabilator. The Elite will create a new class of aircraft in Aeroworld. This class of aircraft will demonstrate a substantial improvement in cruise speed over the current existing commercial fleet of aircraft in Aeroworld. This new class will be capable of servicing all existing airstrips in Aeroworld, including rough and short airways. The drivers of this design were aesthetics, a high cruise speed, and take-off distance

CpG and UpA dinucleotides in both coding and non-coding regions of echovirus 7 inhibit replication initiation post-entry

Funding: Wellcome (WT103767MA) Peter Simmonds.Most vertebrate and plant RNA and small DNA viruses suppress genomic CpG and UpA dinucleotide frequencies, apparently mimicking host mRNA composition. Artificially increasing CpG/UpA dinucleotides attenuates viruses through an entirely unknown mechanism. Using the echovirus 7 (E7) model in several cell types, we show that the restriction in E7 replication in mutants with increased CpG/UpA dinucleotides occurred immediately after viral entry, with incoming virions failing to form replication complexes. Sequences of CpG/UpA-high virus stocks showed no evidence of increased mutational errors that would render them replication defective, these viral RNAs were not differentially sequestered in cytoplasmic stress granules nor did they induce a systemic antiviral state. Importantly, restriction was not mediated through effects on translation efficiency since replicons with high CpG/UpA sequences inserted into a non-coding region were similarly replication defective. Host-cells thus possess intrinsic defence pathways that prevent replication of viruses with increased CpG/UpA frequencies independently of codon usage.Publisher PDFPeer reviewe

[11C]CHIBA-1001 as a Novel PET Ligand for α7 Nicotinic Receptors in the Brain: A PET Study in Conscious Monkeys

BACKGROUND: The alpha7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. However, there are currently no suitable positron emission tomography (PET) radioligands for imaging alpha7 nAChRs in the intact human brain. Here we report the novel PET radioligand [11C]CHIBA-1001 for in vivo imaging of alpha7 nAChRs in the non-human primate brain. METHODOLOGY/PRINCIPAL FINDINGS: A receptor binding assay showed that CHIBA-1001 was a highly selective ligand at alpha7 nAChRs. Using conscious monkeys, we found that the distribution of radioactivity in the monkey brain after intravenous administration of [11C]CHIBA-1001 was consistent with the regional distribution of alpha7 nAChRs in the monkey brain. The distribution of radioactivity in the brain regions after intravenous administration of [11C]CHIBA-1001 was blocked by pretreatment with the selective alpha7 nAChR agonist SSR180711 (5.0 mg/kg). However, the distribution of [11C]CHIBA-1001 was not altered by pretreatment with the selective alpha4beta2 nAChR agonist A85380 (1.0 mg/kg). Interestingly, the binding of [11C]CHIBA-1001 in the frontal cortex of the monkey brain was significantly decreased by subchronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (0.3 mg/kg, twice a day for 13 days); which is a non-human primate model of schizophrenia. CONCLUSIONS/SIGNIFICANCE: The present findings suggest that [11C]CHIBA-1001 could be a novel useful PET ligand for in vivo study of the receptor occupancy and pathophysiology of alpha7 nAChRs in the intact brain of patients with neuropsychiatric diseases such as schizophrenia and Alzheimer's disease

Symptomatic viral infection is associated with impaired response to treatment in children with acute asthma

Objective: To examine the influence of viral respiratory infection (VRI) on treatment response in acute asthma in children. Study design: A total of 218 children (mean age, 6.6 years) with acute asthma were recruited. Symptoms were recorded, an asthma severity score was determined, and whenever possible, a per-nasal aspirate was obtained for detection of viruses. Each child's response to inhaled ß 2-agonists was assessed after 6, 12, and 24 hours. Results: The 168 children with VRI symptoms received more treatment with inhaled ß 2-agonists after 6 hours (P = .010), 12 hours (P =.002), and 24 hours (P =.0005) compared with the 50 children without such symptoms. Asthma severity did not differ between the 2 groups. A per-nasal aspirate was obtained from 77% of the children. The most frequently identified virus was rhinovirus (61.4%). Among children with symptoms of a VRI, those with rhinovirus had an impaired response to ß 2-agonists at 6 hours (P =.032). Conclusion: Children with acute asthma and symptoms of VRI respond less effectively to ß 2-agonists after 6, 12, or 24 hours and thus may benefit from more intense therapy and monitoring. Copyright © 2012 Mosby Inc. All rights reserved

Leukotriene pathway polymorphisms are associated with altered cysteinyl leukotriene production in children with acute asthma

Cysteinyl leukotrienes (cysLTs) are pro-inflammatory mediators with increasing evidence for a role in childhood acute asthma. This study examined the influence of polymorphisms in cysLT pathway genes on urinary leukotriene E4 (uLTE4) levels and clinical status in acute asthmatic children. Children aged 2-16 years were recruited during an asthma attack (n=205). Where possible, asthma severity scores were assigned, ALOX5AP G-336A, ALOX5 G-1708A, LTC4S A-444C and G-1072A, GPX4 C718T, and CYSTLTR1 T927C genotypes were determined and uLTE4 was measured in acute and convalescent samples. uLTE4 levels were higher acutely compared with convalescence (acute GM: 115.7 pg/mg creatinine; 95% CI 88.6-151.1, convalescence GM: 66.4 pg/mg creatinine; 95% CI 51.5-85.6; n=50 paired samples, p=0.003) and paired sample analysis showed genotype-specific effects with significantly increased uLTE4 for LTC4S-444AA (acute GM: 127.9 pg/mg creatinine; 95% CI 91.8-178.3, convalescence GM: 68.2 pg/mg creatinine; 95% CI 50.5-92.0; n=32, p=0.002), LTC4S-1072 GG (acute GM: 126.7 pg/mg creatinine; 95% CI 95.4-168.3, convalescence GM: 78.9 pg/mg creatinine; 95% CI 59.7-104.1; n=39, p=0.019) and CYSLTR1 927 TT/T_ (acute GM: 96.8 pg/mg creatinine; 95% CI 73.8-126.9, convalescence GM: 62.4 pg/mg creatinine; 95% CI 46.8-83.3; n=28, p=0.036) but not AC/CC, GA/AA, or TC/CC/C_, respectively. When we compared the allele frequencies of the CYSLTR1 SNP between asthmatics and non-asthmatics, the 927C allele was found to be a risk allele for asthma (OR=2.13, 95% CI: 1.06-4.26, p=0.033). Genotypes were not associated with acute or convalescent uLTE4 levels alone and neither the SNPs nor uLTE4 correlated with acute asthma severity. Leukotriene pathway gene polymorphisms may influence the magnitude of cysLT production during an attack, yet their influence alone may not be substantial enough to alter the severity of exacerbations. © 2009 Elsevier Ltd. All rights reserved

ß2-adrenoceptor polymorphisms predict response to ß2-agonists in children with acute asthma

The aim of this study was to determine the influence of single nucleotide polymorphisms in the ß2-adrenoceptor gene, on the response to inhaled ß2-agonists in children with acute asthma. We hypothesised that children with polymorphisms that generate enhanced receptor downregulation in vitro, Gly16 and Gln27, would have a slower response to ß2-agonist therapy during acute asthma. One hundred and forty-eight children with acute asthma were recruited and genotyped for ß2Arg16Gly and ß2Gln27Glu. For Gln27Glu, individuals Gln27Gln took longest to stretch out to 1, 2 and 4 hourly ß2-agonists, followed by heterozygotes who were intermediate and Glu27Glu who responded most rapidly (1hourly: 2.6hr vs. 2.0 vs. 1.4, p = 0.02; 2 hourly: 10.6hr vs. 10.7 vs. 6.8, p = 0.07; 4 hourly: 29.8hr vs. 28.5 vs. 24.3, p = 0.30). The ability to prospectively identify children who respond less effectively to ß 2-agonists during an acute asthma attack has the potential to allow the generation of genotype-specific treatment pathways. Copyright © 2008 Informa Healthcare USA, Inc

Electrophysiological examination of the effects of sustained flibanserin administration on serotonin receptors in rat brain

1. 5-HT(1A) receptor agonists have proven to be effective antidepressant medications, however they suffer from a significant therapeutic lag before depressive symptoms abate. Flibanserin is a 5-HT(1A) receptor agonist and 5-HT(2A) receptor antagonist developed to possibly induce a more rapid onset of antidepressant action through its preferential postsynaptic 5-HT(1A) receptor agonism. 2. Flibanserin antagonized the effect of microiontophoretically-applied DOI in the medial prefrontal cortex (mPFC) following 2 days of administration, indicating antagonism of postsynaptic 5-HT(2A) receptors. This reduction in the effect of locally-applied DOI was no longer present following 7-day flibanserin administration. 3. Two-day flibanserin administration only marginally reduced the firing activity of dorsal raphe (DRN) 5-HT neurons. Following 7 days of administration, 5-HT neuronal firing activity had returned to normal and the somatodendritic 5-HT(1A) autoreceptors were desensitized. 4. The responsiveness of postsynaptic 5-HT(1A) receptors located on CA(3) hippocampus pyramidal neurons and mPFC neurons, examined using microiontophoretically-applied 5-HT and gepirone, was unchanged following a 7-day flibanserin treatment. 5. As demonstrated by the ability of the 5-HT(1A) receptor antagonist WAY 100635 to selectively increase the firing of hippocampal neurons in 2- and 7-day treated rats, flibanserin enhanced the tonic activation of postsynaptic 5-HT(1A) receptors in this brain region. 6. The results suggest that flibanserin could be a therapeutically useful compound putatively endowed with a more rapid onset of antidepressant action