Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor.

Signaling through growth factor receptors controls such diverse cell functions as proliferation, migration, and differentiation. A critical question has been how the activation of these receptors is regulated. Most, if not all, of the known ligands for these receptors are soluble factors. However, as matrix components are highly tissue-specific and change during development and pathology, it has been suggested that select growth factor receptors might be stimulated by binding to matrix components. Herein, we describe a new class of ligand for the epidermal growth factor (EGF) receptor (EGFR) found within the EGF-like repeats of tenascin-C, an antiadhesive matrix component present during organogenesis, development, and wound repair. Select EGF-like repeats of tenascin-C elicited mitogenesis and EGFR autophosphorylation in an EGFR-dependent manner. Micromolar concentrations of EGF-like repeats induced EGFR autophosphorylation and activated extracellular signal-regulated, mitogen-activated protein kinase to levels comparable to those induced by subsaturating levels of known EGFR ligands. EGFR-dependent adhesion was noted when the ligands were tethered to inert beads, simulating the physiologically relevant presentation of tenascin-C as hexabrachion, and suggesting an increase in avidity similar to that seen for integrin ligands upon surface binding. Specific binding to EGFR was further established by immunofluorescence detection of EGF-like repeats bound to cells and cross-linking of EGFR with the repeats. Both of these interactions were abolished upon competition by EGF and enhanced by dimerization of the EGF-like repeat. Such low affinity behavior would be expected for a matrix-tethered ligand; i.e., a ligand which acts from the matrix, presented continuously to cell surface EGF receptors, because it can neither diffuse away nor be internalized and degraded. These data identify a new class of insoluble growth factor ligands and a novel mode of activation for growth factor receptors

"Stay at Home and Live with Integrity": Advice to German Emigrants to the United States from the Journeymen’s Father

In recent decades, American historians have asserted that a broad chasm existed between the rhetoric of equality in Jacksonian America and the actual economic reality that existed. Several years ago, Edward Pessen observed that the so-called Era of the Common Man brought no startling social or economic improvements for the common sort of people. More recently, authors like Alan Dawley, Paul E. Johnson, and Sean Wilentz have argued that not only was there no improvement in the conditions for working men, but the universe of options for skilled journeymen was undergoing a radical contraction, which endangered their integrity as an independent productive class.* Furthermore, eroding economic conditions seem to have led to a decline in the commitment to democratic ideology. Michael Holt posits that economic dislocation of the artisan class as a result of the industrial revolution and increased pressure for jobs created by rising immigration led many Americans to support programs which were designed to reduce immigration, or at least to reduce the political influence of incoming immigrants. This support resulted in the rise of such antidemocratic organizations as the nativist societies which eventually formed the American Know-Nothing party.

Stay at Home and Live with Integrity : Advice to German Emigrants to the United States from the Journeymen’s Father

In recent decades, American historians have asserted that a broad chasm existed between the rhetoric of equality in Jacksonian America and the actual economic reality that existed. Several years ago, Edward Pessen observed that the so-called Era of the Common Man brought no startling social or economic improvements for the common sort of people. More recently, authors like Alan Dawley, Paul E. Johnson, and Sean Wilentz have argued that not only was there no improvement in the conditions for working men, but the universe of options for skilled journeymen was undergoing a radical contraction, which endangered their integrity as an independent productive class.* Furthermore, eroding economic conditions seem to have led to a decline in the commitment to democratic ideology. Michael Holt posits that economic dislocation of the artisan class as a result of the industrial revolution and increased pressure for jobs created by rising immigration led many Americans to support programs which were designed to reduce immigration, or at least to reduce the political influence of incoming immigrants. This support resulted in the rise of such antidemocratic organizations as the nativist societies which eventually formed the American Know-Nothing party.

Mach-Zehnder Interferometry in a Strongly Driven Superconducting Qubit

We demonstrate Mach-Zehnder-type interferometry in a superconducting flux qubit. The qubit is a tunable artificial atom, whose ground and excited states exhibit an avoided crossing. Strongly driving the qubit with harmonic excitation sweeps it through the avoided crossing two times per period. As the induced Landau-Zener transitions act as coherent beamsplitters, the accumulated phase between transitions, which varies with microwave amplitude, results in quantum interference fringes for n=1...20 photon transitions. The generalization of optical Mach-Zehnder interferometry, performed in qubit phase space, provides an alternative means to manipulate and characterize the qubit in the strongly-driven regime.Comment: 14 pages, 6 figure

Axial Multicentric Osteosarcoma in an English Cocker Spaniel

No abstract available

A New Definition of Exoplanet Habitability: Introducing the Photosynthetic Habitable Zone

It may be possible to detect biosignatures of photosynthesis in an exoplanet's atmosphere. However, such a detection would likely require a dedicated study, occupying a large amount of telescope time. It is therefore prudent, while searching for signs of life that we may recognise, to pick the best target possible. In this work, we present a new region, the ``photosynthetic habitable zone'' \textemdash the distance from a star where both liquid water and oxygenic photosynthesis can occur. It is therefore the region where detectable biosignatures of oxygenic photosynthesis are most likely to occur. Our analysis indicates that in the most ideal conditions for life and no atmospheric effects, the photosynthetic habitable zone is almost as broad as the habitable zone. On the other hand, if conditions for life are anything less than excellent and atmospheric effects are even moderate, the photosynthetic habitable zone is concentrated at larger separations around more massive stars. Such cases are also not tidally locked to their host star, which could result in planetary rotation periods similar to the Earth's. We identify five planets, Kepler-452 b, Kepler-1638 b, Kepler-1544 b and Kepler-62 e and Kepler-62 f, that are consistently in the photosynthetic habitable zone for a variety of conditions, and we predict their day lengths to be between 9 and 11 hours. We conclude that the parameter space in which we should search for signs of life is much narrower than the standard habitable zone.Comment: 12 pages, 3 figures, accepted to ApJ

Measurement-induced localization of relative degrees of freedom

Published versio

Dbl3 drives Cdc42 signaling at the apical margin to regulate junction position and apical differentiation

Epithelial cells develop morphologically characteristic apical domains that are bordered by tight junctions, the apical–lateral border. Cdc42 and its effector complex Par6–atypical protein kinase c (aPKC) regulate multiple steps during epithelial differentiation, but the mechanisms that mediate process-specific activation of Cdc42 to drive apical morphogenesis and activate the transition from junction formation to apical differentiation are poorly understood. Using a small interfering RNA screen, we identify Dbl3 as a guanine nucleotide exchange factor that is recruited by ezrin to the apical membrane, that is enriched at a marginal zone apical to tight junctions, and that drives spatially restricted Cdc42 activation, promoting apical differentiation. Dbl3 depletion did not affect junction formation but did affect epithelial morphogenesis and brush border formation. Conversely, expression of active Dbl3 drove process-specific activation of the Par6–aPKC pathway, stimulating the transition from junction formation to apical differentiation and domain expansion, as well as the positioning of tight junctions. Thus, Dbl3 drives Cdc42 signaling at the apical margin to regulate morphogenesis, apical–lateral border positioning, and apical differentiation

Targeting the Ets Binding Site of the HER2/neu Promoter with Pyrrole-Imidazole Polyamides

Three DNA binding polyamides (1-3) were synthesized that bind with high affinity (Ka = 8.7·10^9 M^-1 to 1.4·10^10 M^-1) to two 7-base pair sequences overlapping the Ets DNA binding site (EBS; GAGGAA) within the regulatory region of the HER2/neu proximal promoter. As measured by electrophoretic mobility shift assay, polyamides binding to flanking elements upstream (1) or downstream (2 and 3) of the EBS were one to two orders of magnitude more effective than the natural product distamycin at inhibiting formation of complexes between the purified EBS protein, epithelial restricted with serine box (ESX), and the HER2/neu promoter probe. One polyamide, 2, completely blocked Ets-DNA complex formation at 10 nM ligand concentration, whereas formation of activator protein-2-DNA complexes was unaffected at the activator protein-2 binding site immediately upstream of the HER2/neu EBS, even at 100 nM ligand concentration. At equilibrium, polyamide 1 was equally effective at inhibiting Ets/DNA binding when added before or after in vitro formation of protein-promoter complexes, demonstrating its utility to disrupt endogenous Ets-mediated HER2/neu preinitiation complexes. Polyamide 2, the most potent inhibitor of Ets-DNA complex formation by electrophoretic mobility shift assay, was also the most effective inhibitor of HER2/neu promoter-driven transcription measured in a cell-free system using nuclear extract from an ESX- and HER2/neu-overexpressing human breast cancer cell line, SKBR-3