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.     

A module map showing conditional activity of expression modules in cancer

DNA microarrays are widely used to study changes in gene expression in tumors, but such studies are typically system-specific and do not address the commonalities and variations between different types of tumor. Here we present an integrated analysis of 1,975 published microarrays spanning 22 tumor types. We describe expression profiles in different tumors in terms of the behavior of modules, sets of genes that act in concert to carry out a specific function. Using a simple unified analysis, we extract modules and characterize gene-expression profiles in tumors as a combination of activated and deactivated modules. Activation of some modules is specific to particular types of tumor; for example, a growth-inhibitory module is specifically repressed in acute lymphoblastic leukemias and may underlie the deregulated proliferation in these cancers. Other modules are shared across a diverse set of clinical conditions, suggestive of common tumor progression mechanisms. For example, the bone osteoblastic module spans a variety of tumor types and includes both secreted growth factors and their receptors. Our findings suggest that there is a single mechanism for both primary tumor proliferation and metastasis to bone. Our analysis presents multiple research directions for diagnostic, prognostic and therapeutic studies.     

Early history of Earth's crust-mantle system inferred from hafnium isotopes in chondrites

The 176Lu to 176Hf decay series has been widely used to understand the nature of Earth's early crust-mantle system. The interpretation, however, of Lu-Hf isotope data requires accurate knowledge of the radioactive decay constant of 176Lu (lambda176Lu), as well as bulk-Earth reference parameters. A recent calibration of the lambda176Lu value calls for the presence of highly unradiogenic hafnium in terrestrial zircons with ages greater than 3.9 Gyr, implying widespread continental crust extraction from an isotopically enriched mantle source more than 4.3 Gyr ago, but does not provide evidence for a complementary depleted mantle reservoir. Here we report Lu-Hf isotope measurements of different Solar System objects including chondrites and basaltic eucrites. The chondrites define a Lu-Hf isochron with an initial 176Hf/177Hf ratio of 0.279628 +/- 0.000047, corresponding to lambda176Lu = 1.983 +/- 0.033 x 10-11 yr-1 using an age of 4.56 Gyr for the chondrite-forming event. This lambda176Lu value indicates that Earth's oldest minerals were derived from melts of a mantle source with a time-integrated history of depletion rather than enrichment. The depletion event must have occurred no later than 320 Myr after planetary accretion, consistent with timing inferred from extinct radionuclides.     

Accumulation of 2-μm latex particles in mouse Peyer's patches during chronic latex feeding

Summary 2-m latex particles accumulated in macrophages in intestinal Peyer's patches of mice given latex suspensions as drinking fluid for 2 months. The number of particles accumulating was a direct (but nonlinear) function of the number ingested. Some of the latex particles were still present in Peyer's patches 6 weeks after the cessation of latex feeding.Acknowledgments. Research supported by the U. S. Energy Research and Development Administration. We thank Mr W. Marin, Division of Photography and Graphic Arts, Brookhaven National Laboratory, for figure 2.The research described in this report involved animals maintained in animal care facilities fully accredited by the American Association for Accreditation of Laboratory Animal Care.     

Regulation of cap-dependent translation by eIF4E inhibitory proteins

Eukaryotic messenger RNAs contain a modified guanosine, termed a cap, at their 5' ends. Translation of mRNAs requires the binding of an initiation factor, eIF4E, to the cap structure. Here, we describe a family of proteins that through a shared sequence regulate cap-dependent translation. The biological importance of this translational regulation is immense, and affects such processes as cell growth, development, oncogenic transformation and perhaps even axon pathfinding and memory consolidation.     

Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN

Human vision starts with the activation of rod photoreceptors in dim light and short (S)-, medium (M)-, and long (L)- wavelength-sensitive cone photoreceptors in daylight. Recently a parallel, non-rod, non-cone photoreceptive pathway, arising from a population of retinal ganglion cells, was discovered in nocturnal rodents. These ganglion cells express the putative photopigment melanopsin and by signalling gross changes in light intensity serve the subconscious, 'non-image-forming' functions of circadian photoentrainment and pupil constriction. Here we show an anatomically distinct population of 'giant', melanopsin-expressing ganglion cells in the primate retina that, in addition to being intrinsically photosensitive, are strongly activated by rods and cones, and display a rare, S-Off, (L + M)-On type of colour-opponent receptive field. The intrinsic, rod and (L + M) cone-derived light responses combine in these giant cells to signal irradiance over the full dynamic range of human vision. In accordance with cone-based colour opponency, the giant cells project to the lateral geniculate nucleus, the thalamic relay to primary visual cortex. Thus, in the diurnal trichromatic primate, 'non-image-forming' and conventional 'image-forming' retinal pathways are merged, and the melanopsin-based signal might contribute to conscious visual perception.     

Early planetesimal melting from an age of 4.5662 Gyr for differentiated meteorites

Long- and short-lived radioactive isotopes and their daughter products in meteorites are chronometers that can test models for Solar System formation. Differentiated meteorites come from parent bodies that were once molten and separated into metal cores and silicate mantles. Mineral ages for these meteorites, however, are typically younger than age constraints for planetesimal differentiation. Such young ages indicate that the energy required to melt their parent bodies could not have come from the most likely heat source-radioactive decay of short-lived nuclides ((26)Al and (60)Fe) injected from a nearby supernova-because these would have largely decayed by the time of melting. Here we report an age of 4.5662 +/- 0.0001 billion years (based on Pb-Pb dating) for basaltic angrites, which is only 1 Myr younger than the currently accepted minimum age of the Solar System and corresponds to a time when (26)Al and (60)Fe decay could have triggered planetesimal melting. Small (26)Mg excesses in bulk angrite samples confirm that (26)Al decay contributed to the melting of their parent body. These results indicate that the accretion of differentiated planetesimals pre-dated that of undifferentiated planetesimals, and reveals the minimum Solar System age to be 4.5695 +/- 0.0002 billion years.     

An integrated view of the chemistry and mineralogy of martian soils

The mineralogical and elemental compositions of the martian soil are indicators of chemical and physical weathering processes. Using data from the Mars Exploration Rovers, we show that bright dust deposits on opposite sides of the planet are part of a global unit and not dominated by the composition of local rocks. Dark soil deposits at both sites have similar basaltic mineralogies, and could reflect either a global component or the general similarity in the compositions of the rocks from which they were derived. Increased levels of bromine are consistent with mobilization of soluble salts by thin films of liquid water, but the presence of olivine in analysed soil samples indicates that the extent of aqueous alteration of soils has been limited. Nickel abundances are enhanced at the immediate surface and indicate that the upper few millimetres of soil could contain up to one per cent meteoritic material.