Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function

The growth and function of organs such as pancreatic islets adapt to meet physiological challenges and maintain metabolic balance, but the mechanisms controlling these facultative responses are unclear. Diabetes in patients treated with calcineurin inhibitors such as cyclosporin A indicates that calcineurin/nuclear factor of activated T-cells (NFAT) signalling might control adaptive islet responses, but the roles of this pathway in beta-cells in vivo are not understood. Here we show that mice with a beta-cell-specific deletion of the calcineurin phosphatase regulatory subunit, calcineurin b1 (Cnb1), develop age-dependent diabetes characterized by decreased beta-cell proliferation and mass, reduced pancreatic insulin content and hypoinsulinaemia. Moreover, beta-cells lacking Cnb1 have a reduced expression of established regulators of beta-cell proliferation. Conditional expression of active NFATc1 in Cnb1-deficient beta-cells rescues these defects and prevents diabetes. In normal adult beta-cells, conditional NFAT activation promotes the expression of cell-cycle regulators and increases beta-cell proliferation and mass, resulting in hyperinsulinaemia. Conditional NFAT activation also induces the expression of genes critical for beta-cell endocrine function, including all six genes mutated in hereditary forms of monogenic type 2 diabetes. Thus, calcineurin/NFAT signalling regulates multiple factors that control growth and hallmark beta-cell functions, revealing unique models for the pathogenesis and therapy of diabetes.     

Magnetite defines a vertebrate magnetoreceptor

The key behavioural, physiological and anatomical components of a magnetite-based magnetic sense have been demonstrated in rainbow trout (Oncorhynchus mykiss). Candidate receptor cells located within a discrete sub-layer of the olfactory lamellae contained iron-rich crystals that were similar in size and shape to magnetite crystals extracted from salmon. Here we show that these crystals, which mapped to individual receptors using confocal and atomic force microscopy, are magnetic, as they are uniquely associated with dipoles detected by magnetic force microscopy. Analysis of their magnetic properties identifies the crystals as single-domain magnetite. In addition, three-dimensional reconstruction of the candidate receptors using confocal and atomic force microscopy imaging confirm that several magnetic crystals are arranged in a chain of about 1 microm within the receptor, and that the receptor is a multi-lobed single cell. These results are consistent with a magnetite-based detection mechanism, as 1-microm chains of single-domain magnetite crystals are highly suitable for the behavioural and physiological responses to magnetic intensity previously reported in the trout.     

Calcineurin sets the bandwidth for discrimination of signals during thymocyte development

At critical times in development, cells are able to convert graded signals into discrete developmental outcomes; however, the mechanisms involved are poorly understood. During thymocyte development, cell fate is determined by signals originating from the alphabeta T-cell receptor. Low-affinity/avidity interactions between the T-cell receptor and peptide-MHC complexes direct differentiation to the single-positive stage (positive selection), whereas high-affinity/avidity interactions induce death by apoptosis (negative selection). Here we show that mice deficient in both calcineurin and nuclear factor of activated T cells (NFAT)c2/c3 lack a population of preselection thymocytes with enhanced ability to activate the mitogen-activated protein kinase (Raf-MEK-ERK) pathway, and fail to undergo positive selection. This defect can be partially rescued with constitutively active Raf, indicating that calcineurin controls MAPK signalling. Analysis of mice deficient in both Bim (which is required for negative selection) and calcineurin revealed that calcineurin-induced ERK (extracellular signal-regulated kinase) sensitization is required for differentiation in response to 'weak' positive selecting signals but not in response to 'strong' negative selecting signals (which normally induce apoptosis). These results indicate that early calcineurin/NFAT signalling produces a developmental period of ERK hypersensitivity, allowing very weak signals to induce positive selection. This mechanism might be generally useful in the discrimination of graded signals that induce different cell fates.     

New South American leafhoppers in the genus Docalidia , with a key to 37 species (Cicadellidae: Coelidiinae, Teruliini)

Ten new species of Docalidia are described and illustrated. These are pennyi, gracilitas, zanoli, triquetra, paracrista, convexa, setacea, and caterva from Brazil and vesica and vella from Peru. A key to males of 37 species described since the last revision of the genus is included. The number of known species is now 116, making Docalidia the largest teruliine genus.     

Microhabitat affinities of Gambel oak seedlings

Previous work suggested that Gambel oak seedlings are rare in the northern parts of its range in Utah where summer rainfall is relatively low but should be abundant in southern parts of the range where summer rainfall is usually high. Gambel oak grades from a relatively minor component of a ponderosa pine/mixed conifer assemblage in the south to a virtually monotypic formation in the north, where it exists as long-lived clones.   Quadrat analysis in Arizona and New Mexico, within the oak zone, revealed a seedling density ranging from 120 to 1320 per hectare. We found a significant tendency of seedlings to be located on the NE (cool, shady) side of sheltering objects in the environment. Mature ponderosa pine ranged in density from ca 40 to 500 stems per hectare, whereas mature Gambel oak ranged from ca 10 to 20 genets per hectare with ca 1 to 7 ramets per clone. These results support our previous conclusion that Gambel oak in northern Utah probably became established as a minor component of a mixed pine/oak woodland at a time in mid-Holocene when summer rainfall was much higher than today.     

Stromal fibroblasts in cancer initiation and progression

It is widely accepted that the development of carcinoma--the most common form of human cancer--is due to the accumulation of somatic mutations in epithelial cells. The behaviour of carcinomas is also influenced by the tumour microenvironment, which includes extracellular matrix, blood vasculature, inflammatory cells and fibroblasts. Recent studies reveal that fibroblasts have a more profound influence on the development and progression of carcinomas than was previously appreciated. These new findings have important therapeutic implications.