Structure of the insulin receptor ectodomain reveals a folded-over conformation

The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding.     

Mammalian cochlear supporting cells can divide and trans-differentiate into hair cells

Sensory hair cells of the mammalian organ of Corti in the inner ear do not regenerate when lost as a consequence of injury, disease, or age-related deafness. This contrasts with other vertebrates such as birds, where the death of hair cells causes surrounding supporting cells to re-enter the cell cycle and give rise to both new hair cells and supporting cells. It is not clear whether the lack of mammalian hair cell regeneration is due to an intrinsic inability of supporting cells to divide and differentiate or to an absence or blockade of regenerative signals. Here we show that post-mitotic supporting cells purified from the postnatal mouse cochlea retain the ability to divide and trans-differentiate into new hair cells in culture. Furthermore, we show that age-dependent changes in supporting cell proliferative capacity are due in part to changes in the ability to downregulate the cyclin-dependent kinase inhibitor p27(Kip1) (also known as Cdkn1b). These results indicate that postnatal mammalian supporting cells are potential targets for therapeutic manipulation.     

Relativistic Effects in the Global Positioning System

l'INTRo~TloNThepurposeofthisworkistoexplainhowrelativisticeffectsareaccountedforintheGlobalPositioningSystem(GPS).AlthoughclockvelocitiesaresmallandgravitationalfieldsareweakneartheEarth,theygiverisetosignificantrelativisticeffects.Theseeffectsincludesecond--orderDopplerfrequencyshiftsofclocksduetotheirrelativevelocities,gravitationalfrequencyshifts,andtheSagnaceffectduetotheEarth'srotation.Ifsucheffectsarenotaccountedforproperly,theGPSsimplywouldnotworkatallwell.Thesuccessandself--con…     

Long-term interactions of climate, productivity, species richness, and growth form in relictual sagebrush steppe plant communities

Vegetation trends due to climatic changes are difficult to separate from disturbances caused by varying land uses. To separate climatic influences from livestock grazing and fire disturbances within sagebrush steppe, we compared vegetation structure and productivity during 2 periods (10-year sequences of data from the late 1950s to the late 1960s and 3 years in the early 1990s) at 12 stands within 3 relict areas in or near the Great Rift of southern Idaho. Yearto- year fluctuations in annual net aboveground phytomass accumulation (ANAPA) were considerable in response to varying climate during both periods. More importantly, an apparently significant increase in ANAPA was observed during the latter study period. However, this apparent increase may have been due to the unusually wet conditions of 1993. Throughout both study periods, ANAPA was even more positively correlated with species richness than with precipitation, although both influences were statistically significant. Aggregation of these data by plant growth forms showed that shrubs, particularly sagebrushes, have progressively increased their proportion relative to herbaceous understory. This directional (successional) change in the proportional contributions of growth forms to ANAPA was probably due more to long-term absence of fire at these isolated locations than to any detectable climate change or lack of grazing. This finding reduces our confidence in the use of such areas as reference sites for monitoring or as living examples for restoration efforts, but it does increase our understanding of vegetation dynamics within sagebrush steppe. ACRONYMS. ANAPA—annual net aboveground phytomass accumulations, ANOVA—analysis of variance, ANPP—aboveground net primary production, COV—coefficient of variation, CY—crop year, CYP—crop-year precipitation, ES—ecological site, MANOVA—multivariate analysis of variance, MAT—mean annual temperature, NRCS—Natural Resources Conservation Service, PDSI—Palmer Drought Severity Index, RUE—rainfall use efficiency.     

Ground nesting and aggressive behavior by the Swainson's Hawk ( Buteo swainsoni )

A successful ground nesting by Swainson’s Hawks, Buteo swainsoni, is reported for central Utah. Unusual aggressive nest defense behavior is described for this ground nesting pair.