Point projection radiography of electromagnetically accelerated flyer plates with an external X-pinch driver.

A platform for flyer plate benchmarking experiments has been developed, with an external X-pinch driver for point projection radiography. The experiments were performed using CEPAGE, a low inductance pulsed power machine at First Light Fusion (2 MA, 1.4 µs), with a new vacuum transmission line and flyer load hardware designed specifically to give a line of sight for radiography. A broadband 10-20 keV x-ray source was produced by a portable X-pinch driver (140 kA, 350 ns) [Strucka et al., Matter Radiat. Extremes 7, 016901 (2021)] and was used to image the flyer. Radiography compliments the pre-existing diagnostic suite, which consists of current probes, velocimetry, and side-on optical probing of the impact shock transmitted into a transparent sample. The platform allows for significant insights into the 2D and 3D nature of the flyer launch, such as deformation and instability formation. It was used to diagnose a 10 × 9 × 1 mm3 aluminum flyer, which reached a peak velocity of 4.2 km s-1 before impact with a poly(methylmethacrylate) sample. The experimental configuration, on-shot source characterization, and the results from two flyer plate experiments on CEPAGE are discussed.

Sequential regulation of keratinocyte differentiation by 1,25(OH)2D3, VDR, and its coregulators.

Keratinocyte differentiation requires the sequential regulation of gene expression. We have explored the role of 1,25(OH)(2)D(3) and its receptor (VDR) in this process. VDR sequentially binds to coactivator complexes such as Vitamin D receptor interacting protein (DRIP) and steroid receptor coactivator (SRC) during differentiation. Different genes respond differently to the VDR/coactivator complexes as determined by knockdown studies. The binding of DRIP205 and SRC to VDR is ligand (i.e. 1,25(OH)(2)D(3)) dependent. LXXLL motifs in these coactivators are critical for this binding; however, the affinity for VDR of the different LXXLL motifs in these coactivators varies. Hairless is an inhibitor of 1,25(OH)(2)D(3) dependent gene transcription. A phiXXphiphi motif in hairless is crucial for hairless binding to VDR, and its binding is ligand independent. 1,25(OH)(2)D(3) displaces hairless and recruits the coactivators to VDREs. Hsp90 and p23 are chaperone proteins recruited to the DRIP/VDR complex, where they block the binding of the complex to VDREs and block 1,25(OH)(2)D(3) stimulated transcription. Thus four mechanisms explain the ability of 1,25(OH)(2)D(3) to sequentially regulate gene transcription during differentiation: changes in coregulator levels, their differential binding to VDR, differential gene responsiveness to the VDR/coregulator complexes, and chaperone proteins facilitating the cycling of VDR/coregulator complexes on and off the VDREs.

Linear pharmacokinetic behavior of ropinirole during multiple dosing in patients with Parkinson's disease.

The objectives of this study were to measure the pharmacokinetics of ropinirole at steady state when the drug is used as an adjunct to L-dopa and evaluate the long-term tolerability of ropinirole in this indication. Twenty-four patients who were taking L-dopa for Parkinson's disease and experiencing a lack of symptomatic control were recruited. Patients received open-label adjunctive treatment with ropinirole for up to 2 years. The starting dose was 0.5 mg bid, which could be titrated to a maximum of 6.0 mg tid. Ropinirole demonstrated approximately dose-linear pharmacokinetics at steady state; corresponding values were higher during tid than bid dosing. A reduction in mean L-dopa dose was maintained throughout the trial. The combination of L-dopa and ropinirole was generally well tolerated, with only 1 patient withdrawing from treatment because of adverse events. Thus, ropinirole shows approximately linear steady-state pharmacokinetics and a good safety profile when administered with L-dopa.