An RNA molecule that specifically inhibits G-protein-coupled receptor kinase 2 in vitro

G-protein-coupled receptors are desensitized by a two-step process. In a first step, G-protein-coupled receptor kinases (GRKs) phosphorylate agonist-activated receptors that subsequently bind to a second class of proteins, the arrestins. GRKs can be classified into three subfamilies, which have been implicated in various diseases. The physiological role(s) of GRKs have been difficult to study as selective inhibitors are not available. We have used SELEX (systematic evolution of ligands by exponential enrichment) to develop RNA aptamers that potently and selectively inhibit GRK2. This process has yielded an aptamer, C13, which bound to GRK2 with a high affinity and inhibited GRK2-catalyzed rhodopsin phosphorylation with an IC50 of 4.1 nM. Phosphorylation of rhodopsin catalyzed by GRK5 was also inhibited, albeit with 20-fold lower potency (IC50 of 79 nM). Furthermore, C13 reveals significant specificity, since almost no inhibitory activity was detectable testing it against a panel of 14 other kinases. The aptamer is two orders of magnitude more potent than the best GRK2 inhibitors described previously and shows high selectivity for the GRK family of protein kinases.

A square-planar nickel(II) monoradical complex with a bis(salicylidene)diamine ligand

The new square-planar Ni-II-N2O2 complex [Ni(L-Me)] (1(Me)), where L-Me, stands for the dianionic phenolato form of N,N'bis(3,5-di-tert-butyl-salicylidene)-4,5-dimethyl-1,2-phenyl- enediamine ((LH2)-L-Me), has been synthesised and fully characterised. X-ray crystallography was also used for the characterisation. The electrochemical one-electron oxidation of 1(Me) produces the thermally stable (within the temperature range 10-295 K) cationic species (1(Me))(+). The UV/Vis and X-band EPR experimental data, supported by DFT calculations, indicate that (1(Me))(+), is best described as a Ni-II monoradical complex and, thus, does NOT exist in a Ni-III ground state, in contrast to its demethylated counterpart [Ni(L-H)](+) (1(H))(+) below 170 K.

Ensuring operational compliance and ethical responsibility in the regulation of ART: the HFEA, past, present, and future

Under the Public Bodies Bill 2010, the HFEA, cornerstone in the regulation of assisted reproduction technologies (ART) for the last twenty years, is due to be abolished. This implies that there is no longer a need for a dedicated regulator for ART and that the existing roles of the Authority as both operational compliance monitor, and instance of ethical evaluation, may be absorbed by existing healthcare regulators. This article presents a timely analysis of these disparate functions of the HFEA, charting reforms adopted in 2008 and assessing the impact of the current proposals. Taking assisted conception treatment as the focus activity, it will be shown that the last few years have seen a concentration on the HFEA as a technical regulator based upon the principles of Better Regulation, with little analysis of how the ethical responsibility of the Authority fits into this framework. The current proposal to abolish the HFEA continues to fail to address this crucial question. Notwithstanding the fact that the scope of the Authority's ethical role may be questioned, its abolition requires that the Government consider what alternatives exists - or need to be put in place - to provide both responsive operational regulation and a forum for ethical reflection and decision-making in an area which continues to pose regulatory challenges