Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis.

Developmental defects affecting the heart and aortic arch arteries are a significant phenotype observed in individuals with 22q11 deletion syndrome and are caused by a microdeletion on chromosome 22q11. TBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key gene, when mutated, for the arch artery defects. Pax9 is expressed in the pharyngeal endoderm and is downregulated in Tbx1 mutant mice. We show here that Pax9-deficient mice are born with complex cardiovascular malformations that affect the outflow tract and aortic arch arteries with failure of the 3rd and 4th pharyngeal arch arteries to form correctly. Transcriptome analysis indicated that Pax9 and Tbx1 may function together, and mice double heterozygous for Tbx1/Pax9 presented with a significantly increased incidence of interrupted aortic arch when compared with Tbx1 heterozygous mice. Using a novel Pax9Cre allele, we demonstrated that the site of this Tbx1-Pax9 genetic interaction is the pharyngeal endoderm, therefore revealing that a Tbx1-Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for crucial tissue interactions during normal morphogenesis of the pharyngeal arch artery system.

Attempted ignition of petrol vapour by lit cigarettes and lit cannabis resin joints.

A recent murder enquiry prompted experimentation to confirm and visually demonstrate that lit cigarettes are not a viable source of ignition of petrol vapour. In addition, tests comprising the attempted ignition of petrol vapour using hot and smouldering cannabis resin were also undertaken. A series of experiments was also designed to recreate circumstances specific to the crime under investigation by undertaking cigarette/joint ignition tests involving a mannequin clothed in a cotton garment onto which petrol was applied. The ultimate aim of the experiments was to produce a visual aid for use during court proceedings. Thirty nine (39) ignition attempts that involved exposing lit commercial cigarettes, hand-rolled cigarettes and cannabis resin joints to petrol vapour were undertaken; ignition was not achieved in any of the scenarios. In addition, a single attempt to ignite petrol vapour emanating from a pool of liquid fuel was effected with a smouldering piece of cannabis resin; no ignition occurred. In all cases the petrol was clearly present within the limits of flammability since ignition was subsequently effected using a naked flame.

Mechanism for the acute effects of organophosphate pesticides on the adult 5-HT system.

The neurotransmitter serotonin (5-HT) is involved in mood disorder aetiology and it has been reported that (organophosphate) OP exposure affects 5-HT turnover. The aim of this study was to elucidate the mechanism underlying OP effects on the adult 5-HT system. First, acute in vivo administration of the OP diazinon (0, 1.3, 13 or 39 mg/kg i.p.) to male Hooded Lister rats inhibited the activity of the cholinergic enzyme acetylcholinesterase in blood and in the hippocampus, dorsal raphe nucleus (DRN), striatum and prefrontal cortex. Diazinon-induced cholinesterase inhibition was greatest in the DRN, the brain's major source of 5-HT neurones. Second, acute in vivo diazinon exposure (0 or 39 mg/kg i.p.) increased the basal firing rate of DRN neurones measured ex vivo in brain slices. The excitatory responses of DRN neurones to α1-adrenoceptor or AMPA/kainate receptor activation were not affected by in vivo diazinon exposure but the inhibitory response to 5-HT was attenuated, indicating 5-HT1A autoreceptor down-regulation. Finally, direct application of the diazinon metabolite diazinon oxon to naive rat brain slices increased the firing rate of DRN 5-HT neurones, as did chlorpyrifos-oxon, indicating the effect was not unique to diazinon. The oxon-induced augmentation of firing was blocked by the nicotinic acetylcholine receptor antagonist mecamylamine and the AMPA/kainate glutamate receptor antagonist DNQX. Together these data indicate that 1) acute OP exposure inhibits DRN cholinesterase, leading to acetylcholine accumulation, 2) the acetylcholine activates nicotinic receptors on 5-HT neurones and also on glutamatergic neurones, thus releasing glutamate and activating 5-HT neuronal AMPA/kainate receptors 3) the increase in 5-HT neuronal activity, and resulting 5-HT release, may lead to 5-HT1A autoreceptor down-regulation. This mechanism may be involved in the reported increase in risk of developing anxiety and depression following occupational OP exposure.

The role of graded category structure in imaginative thought.

Participants generated lists of exemplars from the categories of animals, tools, and fruit, and their lists were used to determine the relative accessibility of individual exemplars. Measures of accessibility included output dominance (the number of participants who listed an exemplar), rank (how early instances were listed), and two scores that reflect their combination-output precedence and dominance/rank. Other participants drew and described novel exemplars of those categories that might exist on an imaginary planet and reported on the factors that influenced their creations. References to Earth animals, tools, or fruit were used to determine imagination frequency (the number of participants who mentioned relying on particular Earth exemplars). Items high in accessibility were also high in imagination frequency, implying that those items that come to mind most readily are the ones most likely to serve as starting points for the development of novel ideas. This result held even when task constraints weighed against the use of such items (Experiment 2) and when participants were encouraged to be as creative as possible (Experiment 4), suggesting that it is difficult to avoid the influence of highly accessible category exemplars. Other measures of category structure, including the rated typicality, familiarity, and frequency of exemplars, did not predict imagination frequency as well. The results are discussed in terms of expanding concept boundaries and the inadvertent application of knowledge that is readily accessible.