α6ß4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of α3ß1 integrin

Growth factor-induced cell migration and proliferation are essential for epithelial wound repair. Cell migration during wound repair also depends upon expression of laminin-5, a ligand for α6ß4 integrin. We investigated the role of α6ß4 integrin in laminin-5-dependent keratinocyte migration by re-expressing normal or attachment-defective ß4 integrin in ß4 integrin null keratinocytes. We found that expression of ß4 integrin in either a ligand bound or ligand unbound state was necessary and sufficient for EGF-induced cell migration. In a ligand bound state, ß4 integrin supported EGF-induced cell migration though sustained activation of Rac1. In the absence of α6ß4 integrin ligation, Rac1 activation became tempered and EGF chemotaxis proceeded through an alternate mechanism that depended upon α3ß1 integrin and was characterized by cell scattering. α3ß1 integrin also relocalated from cell-cell contacts to sites of basal clustering where it displayed increased conformational activation. The aberrant distribution and activation of α3ß1 integrin in attachment-defective ß4 cells could be reversed by the activation of Rac1. Conversely, in WT ß4 cells the normal cell-cell localization of α3ß1 integrin became aberrant after the inhibition of Rac1. These studies indicate that the extracellular domain of ß4 integrin, through its ability to bind ligand, functions to integrate the divergent effects of growth factors on the cytoskeleton and adhesion receptors so that coordinated keratinocyte migration can be achieved

Galaxy populations in massive galaxy clusters to z = 1.1 : colour distribution, concentration, halo occupation number and red sequence fraction

We study the galaxy populations in 74 Sunyaev–Zeldovich effect selected clusters from the South Pole Telescope survey, which have been imaged in the science verification phase of the Dark Energy Survey. The sample extends up to z ∼ 1.1 with 4 × 1014M ≤ M200 ≤ 3 × 1015M . Using the band containing the 4000 Å break and its redward neighbour, we study the colour–magnitude distributions of cluster galaxies to ∼m∗ + 2, finding that: (1)The intrinsic rest frame g − r colour width of the red sequence (RS) population is ∼0.03 out to z ∼ 0.85 with a preference for an increase to ∼0.07 at z = 1, and (2) the prominence of the RS declines beyond z ∼ 0.6. The spatial distribution of cluster galaxies is well described by the NFW profile out to 4R200 with a concentration of cg = 3.59+0.20 −0.18, 5.37+0.27 −0.24 and 1.38+0.21 −0.19 for the full, the RS and the blue non-RS populations, respectively, but with ∼40 per cent to 55 per cent cluster to cluster variation and no statistically significant redshift or mass trends. The number of galaxies within the virial region N200 exhibits a mass trend indicating that the number of galaxies per unit total mass is lower in the most massive clusters, and shows no significant redshift trend. The RS fraction within R200 is (68 ± 3) per cent at z = 0.46, varies from ∼55 per cent at z = 1 to ∼80 per cent at z = 0.1 and exhibits intrinsic variation among clusters of ∼14 per cent. We discuss a model that suggests that the observed redshift trend in RS fraction favours a transformation time-scale for infalling field galaxies to become RS galaxies of 2–3 Gyr

Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: A worldwide collaborative project

PURPOSE:: To achieve clinical validation of cutoff values for newborn screening by tandem mass spectrometry through a worldwide collaborative effort. METHODS:: Cumulative percentiles of amino acids and acylcarnitines in dried blood spots of approximately 25-30 million normal newborns and 10,742 deidentified true positive cases are compared to assign clinical significance, which is achieved when the median of a disorder range is, and usually markedly outside, either the 99th or the 1st percentile of the normal population. The cutoff target ranges of analytes and ratios are then defined as the interval between selected percentiles of the two populations. When overlaps occur, adjustments are made to maximize sensitivity and specificity taking all available factors into consideration. RESULTS:: As of December 1, 2010, 130 sites in 45 countries have uploaded a total of 25,114 percentile data points, 565,232 analyte results of true positive cases with 64 conditions, and 5,341 cutoff values. The average rate of submission of true positive cases between December 1, 2008, and December 1, 2010, was 5.1 cases/day. This cumulative evidence generated 91 high and 23 low cutoff target ranges. The overall proportion of cutoff values within the respective target range was 42% (2,269/5,341). CONCLUSION:: An unprecedented level of cooperation and collaboration has allowed the objective definition of cutoff target ranges for 114 markers to be applied to newborn screening of rare metabolic disorders. © 2011 Lippincott Williams & Wilkins