Measurement of the Strong Coupling alpha s from Four-Jet Observables in e+e- Annihilation

Data from e+e- annihilation into hadrons at centre-of-mass energies between 91 GeV and 209 GeV collected with the OPAL detector at LEP, are used to study the four-jet rate as a function of the Durham algorithm resolution parameter ycut. The four-jet rate is compared to next-to-leading order calculations that include the resummation of large logarithms. The strong coupling measured from the four-jet rate is alphas(Mz0)= 0.1182+-0.0003(stat.)+-0.0015(exp.)+-0.0011(had.)+-0.0012(scale)+-0.0013(mass) in agreement with the world average. Next-to-leading order fits to the D-parameter and thrust minor event-shape observables are also performed for the first time. We find consistent results, but with significantly larger theoretical uncertainties.Comment: 25 pages, 15 figures, Submitted to Euro. Phys. J.

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Targeted Disruption of β-Arrestin 2-Mediated Signaling Pathways by Aptamer Chimeras Leads to Inhibition of Leukemic Cell Growth

<div><p></p><p>β-arrestins, ubiquitous cellular scaffolding proteins that act as signaling mediators of numerous critical cellular pathways, are attractive therapeutic targets because they promote tumorigenesis in several tumor models. However, targeting scaffolding proteins with traditional small molecule drugs has been challenging. Inhibition of β-arrestin 2 with a novel aptamer impedes multiple oncogenic signaling pathways simultaneously. Additionally, delivery of the β-arrestin 2-targeting aptamer into leukemia cells through coupling to a recently described cancer cell-specific delivery aptamer, inhibits multiple β-arrestin-mediated signaling pathways known to be required for chronic myelogenous leukemia (CML) disease progression, and impairs tumorigenic growth in CML patient samples. The ability to target scaffolding proteins such as β-arrestin 2 with RNA aptamers may prove beneficial as a therapeutic strategy.</p><p>Highlights</p><p></p><p></p><p>An RNA aptamer inhibits β-arrestin 2 activity.</p><p></p><p></p><p>Inhibiting β-arrestin 2 impedes multiple tumorigenic pathways simultaneously.</p><p></p><p></p><p>The therapeutic aptamer is delivered to cancer cells using a cell-specific DNA aptamer.</p><p></p><p></p><p>Targeting β-arrestin 2 inhibits tumor progression in CML models and patient samples.</p><p></p><p></p></div

Construction and delivery of an internalizing β-arrestin 2 aptamer chimera.

<p>(A) Comparative western analysis was performed on the nucleolin protein levels of different cellular fractions in two different cell types. K562 cells, a CML cell-line, had approximately 30x more membrane-associated nucleolin than lymphoblastoid cells, which are non-cancerous human B cells. Representative blot image shown. (B) The nucleolin aptamer, which requires membrane-associated nucleolin for cell binding and internalization, bound and internalized into K562 cells as analyzed by flow cytometry. (C) Aptamer chimeras were generated with the nucleolin aptamer and the β-arr2A3 aptamer. The nucleolin aptamer acted as a cell-specific delivery agent, and was joined to the β-arr2A3 aptamer by complementary base pair annealing. (D) Biotinylated β-arr2A3 was hybridized to nucleolin aptamer and then allowed to internalize into cells for 24 hours. Cells were then lysed and subjected to biotin pull-downs by way of streptavidin beads. Coimmunoprecipitated β-arrestin 2 was visualized by western blot. (E) Quantification of β-arrestin 2 signals from (D), representative results of 3 independent experiments are shown. (F) Nucleolin-β-arr2 was applied to K562 cells and allowed to internalize for 6 hours. Cells were lysed, and lysates were immunoprecipitated using an anti-β-arrestin 2 antibody. Reactions were then subjected to northern blot analysis and were probed for the presence of the β-arr2A3 aptamer. (### = Control IgG antibody).</p