Chemical structure-guided design of dynapyrazoles, potent cell-permeable dynein inhibitors with a unique mode of action

Cytoplasmic dyneins are motor proteins in the AAA+ superfamily that transport cellular cargos toward microtubule minus-ends. Recently, ciliobrevins were reported as selective cell-permeable inhibitors of cytoplasmic dyneins. As is often true for first-in-class inhibitors, the use of ciliobrevins has in part been limited by low potency. Moreover, suboptimal chemical properties, such as the potential to isomerize, have hindered efforts to improve ciliobrevins. Here, we characterized the structure of ciliobrevins and designed conformationally constrained isosteres. These studies identified dynapyrazoles, inhibitors more potent than ciliobrevins. At single-digit micromolar concentrations dynapyrazoles block intraflagellar transport in the cilium and lysosome motility in the cytoplasm, processes that depend on cytoplasmic dyneins. Further, we find that while ciliobrevins inhibit both dynein's microtubule-stimulated and basal ATPase activity, dynapyrazoles strongly block only microtubule-stimulated activity. Together, our studies suggest that chemical-structure-based analyses can lead to inhibitors with improved properties and distinct modes of inhibition

Unsteady Vortex Behaviour of a Rotating 65° Delta Wing Using Pressure Sensitive Paint (PSP)

Visualization and measurements of aerodynamic effects on a delta-wing model were conducted using an optical pressure measurement system, based on the pressure-sensitive paint (PSP) technique. A special 65° delta wing, the so called DLR-PSP model, was tested in the transonic wind tunnel DNW-TWG in Göttingen. A rolling apparatus was built up to enable roll rates up to 10 Hz. The experiments were carried out at angles-of-attack up to alpha = 17° at Ma = 0.8. For this rotating model an unsteady PSP technique was successfully applied

Instationäre PSP-Messungen durchgeführt am DLR-PSP Modell im DNW-TWG

Der bisherige Einsatz von drucksensitiven Farben PSP=(Pressure Sensitive Paint) hat gezeigt, dass die flächenhafte, quantitative Druckinformation zum Verständnis aerodynamischer Prozesse von erheblicher Bedeutung ist. Sie liefert nicht nur eine umfangreiche Druckverteilung in Form von Absolutwerten, sondern lässt sich auch zur Bestimmung von Kräften und Momenten ganzer Windkanalmodelle, aber auch einzelner Modellbauteile wie Ruder, Klappen usw. heranziehen, sofern die gesamte Modelloberfläche mittels PSP erfasst ist. Diese, auf optischem Wege erfasste, flächenhafte Druckverteilung mittels PSP liefert somit auch eine wesentliche Grundlage zur theoretischen Modellierung von Strömungen um Körper (CFD). Aufgrund der bisher präsentierten Messergebnisse wächst die Nachfrage des PSP-Einsatzes für instationäre Strömungsprozesse, insbesondere bei transsonischen Geschwindigkeiten, in zunehmenden Maße. Dieses gilt nicht nur für den Bereich der Aeroelastik, sondern auch für Anwendungen an Turbomaschinen und Hubschrauberrotoren

Sample characterization of Danubian cemeteries : the examples of Vedrovice (Moravia) and Nitra-Horne Krskany (Slovakia)

International audienc

Surface Temperature Effects on Boundary-Layer Transition at Various Subsonic Mach Numbers and Streamwise Pressure Gradients

The effect on transition of a non-adiabatic surface was systematically studied in the present experimental work in combination with the influence of variations in Mach number and pressure gradient. The investigations were carried out in a (quasi-) two-dimensional flow at four different subsonic Mach numbers and chord Reynolds numbers up to 13 million. Various streamwise pressure gradients and wall temperature ratios were examined. The experiments were conducted in the low-turbulence Cryogenic Ludwieg-Tube Göttingen on a two-dimensional flat-plate configuration designed for an essentially uniform pressure gradient on the model upper surface. The model was instrumented with a temperature-sensitive paint to measure globally and non-intrusively the surface temperature and thus the boundary-layer transition. A marked influence of a variation in the wall temperature ratio on transition was observed for all considered Mach numbers, being this effect more pronounced at lower Mach numbers. The measured transition locations were also correlated with the results of linear local stability analysis. Smaller disturbance amplification factors were found at transition for larger Mach numbers and, in most of the examined cases, for smaller wall temperature ratios and stronger flow acceleration