Imaging protective mast cells in living mice during severe contact hypersensitivity

Contact hypersensitivity (CHS) is a common skin disease induced by epicutaneous sensitization to haptens. Conflicting results have been obtained regarding pathogenic versus protective roles of mast cells (MCs) in CHS, and this has been attributed in part to the limitations of certain models for studying MC functions in vivo. Here we describe a fluorescent imaging approach that enables in vivo selective labeling and tracking of MC secretory granules by real-time intravital 2-photon microscopy in living mice, and permits the identification of such MCs as a potential source of cytokines in different disease models. We show using this method that dermal MCs release their granules progressively into the surrounding microenvironment, but also represent an initial source of the antiinflammatory cytokine IL-10, during the early phase of severe CHS reactions. Finally, using 3 different types of MC-deficient mice, as well as mice in which IL-10 is ablated specifically in MCs, we show that IL-10 production by MCs can significantly limit the inflammation and tissue pathology observed in severe CHS reactions.Laurent L. Reber, Riccardo Sibilano, Philipp Starkl, Axel Roers, Michele A. Grimbaldeston, Mindy Tsai, Nicolas Gaudenzio, and Stephen J. Gall

IgG subclasses determine pathways of anaphylaxis in mice

Background: Animal models have demonstrated that allergen-specific IgG confers sensitivity to systemic anaphylaxis that relies on IgG Fc receptors (Fc?Rs). Mouse IgG2a and IgG2b bind activating Fc?RI, Fc?RIII, and Fc?RIV and inhibitory Fc?RIIB; mouse IgG1 binds only Fc?RIII and Fc?RIIB. Although these interactions are of strikingly different affinities, these 3 IgG subclasses have been shown to enable induction of systemic anaphylaxis.Objective: We sought to determine which pathways control the induction of IgG1-, IgG2a-, and IgG2b-dependent passive systemic anaphylaxis.Methods: Mice were sensitized with IgG1, IgG2a, or IgG2b anti-trinitrophenyl mAbs and challenged with trinitrophenyl-BSA intravenously to induce systemic anaphylaxis that was monitored by using rectal temperature. Anaphylaxis was evaluated in mice deficient for Fc?Rs injected with mediator antagonists or in which basophils, monocytes/macrophages, or neutrophils had been depleted. Fc?R expression was evaluated on these cells before and after anaphylaxis.Results: Activating Fc?RIII is the receptor primarily responsible for all 3 models of anaphylaxis, and subsequent downregulation of this receptor was observed. These models differentially relied on histamine release and the contribution of mast cells, basophils, macrophages, and neutrophils. Strikingly, basophil contribution and histamine predominance in mice with IgG1- and IgG2b-induced anaphylaxis correlated with the ability of inhibitory Fc?RIIB to negatively regulate these models of anaphylaxis.Conclusion: We propose that the differential expression of inhibitory Fc?RIIB on myeloid cells and its differential binding of IgG subclasses controls the contributions of mast cells, basophils, neutrophils, and macrophages to IgG subclass–dependent anaphylaxis. Collectively, our results unravel novel complexities in the involvement and regulation of cell populations in IgG-dependent reactions in vivo

A dissociated glucocorticoid receptor modulator reduces airway hyperresponsiveness and inflammation in a mouse model of asthma

The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activationvia direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively modulating the GR by only triggering its transrepression function. We have studied in this paper the activity of Compound A (CpdA), a dissociated GR modulator favoring GR monomer formation, in a predominantly Th2-driven asthma model. CpdA acted similarly to the glucocorticoid dexamethasone (DEX) in counteracting OVA-induced airway hyperresponsiveness, recruitment of eosinophils, dendritic cells, neutrophils, B and T cells, and macrophages in bronchoalveolar lavage fluid, lung Th2, Tc2, Th17, Tc17, and mast cell infiltration, collagen deposition, and goblet cell metaplasia. Both CpdA and DEX inhibited Th2 cytokine production in bronchoalveolar lavage as well as nuclear translocation of NF-κB and its subsequent recruitment onto the IκBα promoter in the lung. By contrast, DEX but not CpdA induces expression of the GR-dependent model gene MAPK phosphatase 1 in the lung, confirming the dissociative action of CpdA. Mechanistically, we demonstrate that CpdA inhibited IL-4-induced STAT6 translocation and that GR is essential for CpdA to mediate chemokine repression. In conclusion, we clearly show in this study the anti-inflammatory effect of CpdA in a Th2-driven asthma model in the absence of transactivation, suggesting a potential therapeutic benefit of this strategy. Copyrigh

Dr Elizabeth Alexander: first female radio astronomer

During March–April 1945, solar radio emission was detected at 200 MHz by operators of a Royal New Zealand Air Force radar unit located on Norfolk Island. Initially dubbed the ‘Norfolk Island Effect’, this anomalous radiation was investigated throughout 1945 by British-born Elizabeth Alexander, head of the Operational Research Section of the Radio Development Laboratory in New Zealand. Alexander prepared a number of reports on this work, and in early 1946 she published a short paper in the newly-launched journal, Radio & Electronics. A geologist by training, Elizabeth Alexander happened to be in the right place at the right time, and unwittingly became the first woman in the world to work in the field that would later become known as radio astronomy. Her research also led to further solar radio astronomy projects in New Zealand in the immediate post-war year, and in part was responsible for the launch of the radio astronomy program at the Division of Radiophysics, CSIRO, in Sydney

Children's implicit knowledge of harmony in Western music

Three experiments examined children's knowledge of harmony in Western music. The children heard a series of chords followed by a final, target chord. In Experiment 1, French 6- and 11-year-olds judged whether the target was sung with the vowel /i/ or /u/. In Experiment 2, Australian 8- and 11-year-olds judged whether the target was played on a piano or a trumpet. In Experiment 3, Canadian 8- and 11-year-olds judged whether the target sounded good (i.e. consonant) or bad (dissonant). The target was either the most stable chord in the established musical key (i.e. the tonic, based on do, the first note of the scale) or a less stable chord. Performance was faster (Experiments 1, 2 and 3) and more accurate (Experiment 3) when the target was the tonic chord. The findings confirm that children have implicit knowledge of syntactic functions that typify Western harmony

Radiophysics field stations and the early development of radio astronomy

During the period 1946–1961 Australia was one of the world’s leading nations in radio astronomy and played a key role in its development. Much of the research was carried out at a number of different field stations and associated remote sites situated in or near Sydney which were maintained by the Commonwealth Scientific and Industrial Research Organisation’s Division of Radiophysics. The best-known of these were Dover Heights, Dapto, Fleurs, Hornsby Valley and Potts Hill. At these and other field stations a succession of innovative radio telescopes was erected, and these were used by a band of young scientists—mainly men with engineering qualifications—to address a wide range of research issues, often with outstanding success