Endocrine and behavioural responses to acute central CRF challenge are antagonized in the periphery and CNS, respectively, in C57BL/6 mice

Corticotropin releasing factor (CRF) is a major mediator of central and peripheral responses to environmental stressors, and antagonism of its receptors (CRF-R1, -R2) is an active area of pharmacotherapeutic research for stress-related disorders. Stress responses include CRF activation of the hypothalamus-pituitary-adrenal axis and behavioural inhibition. Valid in vivo models for the study of these neuro-endocrine and -behavioural CRF pathways and their central-peripheral antagonism are important. The aims of this study in C57BL/6 mice were to describe the acute effects of intracerebroventricular (ICV) CRF using plasma ACTH-CORT titres and locomotor activity as readouts, and to study the impact on these readouts of central versus peripheral pre-treatment with the CRF-R1/2 antagonist, astressin. The following experiments were performed: Effects of (i) serial blood sampling (SBS) per se, (ii) physical confinement+SBS, (iii) ICV saline infusion+SBS, on plasma titres of ACTH-CORT. (iv) Effects of ICV or IP CRF infusion on plasma ACTH-CORT. (v) Effects of ICV CRF on plasma CRF. (vi) Effects of ICV or IP astressin on ICV or IP CRF-stimulated plasma CORT. (vii) Effects of ICV or IP astressin on ICV CRF-induced locomotor inactivity. Main findings were: (i)-(ii) Serial blood sampling per se and physical confinement+SBS led to similar, mild increases in plasma ACTH-CORT. (iii) ICV saline infusion led to a marked increase in plasma ACTH, possibly due to assay crossreactivity with "washed out" pituitary peptides, and a mild increase in plasma CORT. (iv) ICV CRF (0.001-1μg) induced no further increase in plasma ACTH versus vehicle, and induced dose-dependent increased plasma CORT. 1μg ICV CRF also reduced locomotor activity. (v) ICV CRF-induced dose-dependent increased plasma CRF. (vi) ICV astressin failed to block ICV CRF-induced increased plasma CORT, whereas IP astressin did do so. (vii) ICV CRF-induced locomotor inactivity was blocked by ICV astressin, but not by IP astressin. Therefore, ICV CRF-induced a dose-dependent increase in plasma CORT via a peripheral pathway and a reduction in locomotion via a central pathway, indicated by the double dissociation in the ability of astressin to antagonize these effects relative to its route of administration, IP or ICV, respectively. The preparation described here could be readily used to provide initial indications on the central and peripheral activity of CRF-R antagonists, including pharmacokinetics following peripheral administration

First operation and mass separation with the CARIBU MR-TOF

The recent installation of a Multi-Reflection Time-of-Flight (MR-TOF) isobar separator at the CARIBU facility has the promising potential to significantly improve the mass separation and selection of short-lived neutron-rich beams. Ions cycled in the km-long isochronous trajectories between two electrostatic mirrors can be separated to high levels of mass-resolving power within a short time (tens of ms). The installation process is described and results from the first operation are discussed. Following an optimization of the mirror voltages a mass-resolving power of 6.8·104 was achieved and a separation of isobars was demonstrated. The higher purity beams provided by the MR-TOF and delivered to the Canadian Penning Trap (CPT) will provide access to further measurements of neutron-rich nuclei along the astrophysical r-process path

Corrigendum:A novel multiple-stage antimalarial agent that inhibits protein synthesis

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery