Improved safety margin for embryotoxicity in rats for the new endoperoxide artefenomel (OZ439) as compared to artesunate.

BACKGROUND: Combination medicines including an artemisinin are the mainstay of antimalarial therapy. Artemisinins are potent embryotoxicants in animal species due to their trioxane moiety. METHODS: As part of its development, the new synthetic trioxolane antimalarial artefenomel (OZ439) was tested in rat whole embryo culture and in rat embryo-fetal toxicity studies with dosing throughout organogenesis or with a single dose on Gestational Day (GD) 12. The single-dose studies included groups treated with artesunate to allow a direct comparison of the embryotoxicity of the two antimalarials and included toxicokinetics hematology and histological examination of embryos. In addition, the distribution of artefenomel-related material in plasma was determined after the administration of 14 C-artefenomel. RESULTS: Artefenomel and artesunate showed similar patterns of embryotoxicity including cardiovascular defects and resorption with a steep dose-response. They both also caused a depletion of circulating embryonic erythroblasts both in vitro and in vivo and decreases in maternal reticulocyte count. However, artefenomel was ∼250-fold less potent than the active metabolite of artesunate (dihydroartemisinin) as an embryotoxicant in vitro. The safety margin (based on AUC) for artefenomel administered on GD 12 was approximately 100-fold greater than that for artesunate. Also, unlike artesunate, artefenomel was not a selective developmental toxicant. CONCLUSIONS: The lesser embryotoxicity of artefenomel is likely linked to its original design which included two blocking side groups that had been introduced to lower the reactivity with ferrous iron. Our data support the hypothesis that artefenomel's improved safety margin is linked to a lower potential for inhibiting heme biosynthesis in embryonic erythroblasts.

In operando evidence of deoxygenation in ionic liquid gating of YBa2Cu3O7-X.

Field-effect experiments on cuprates using ionic liquids have enabled the exploration of their rich phase diagrams [Leng X, et al. (2011) Phys Rev Lett 107(2):027001]. Conventional understanding of the electrostatic doping is in terms of modifications of the charge density to screen the electric field generated at the double layer. However, it has been recently reported that the suppression of the metal to insulator transition induced in VO2 by ionic liquid gating is due to oxygen vacancy formation rather than to electrostatic doping [Jeong J, et al. (2013) Science 339(6126):1402-1405]. These results underscore the debate on the true nature, electrostatic vs. electrochemical, of the doping of cuprates with ionic liquids. Here, we address the doping mechanism of the high-temperature superconductor YBa2Cu3O7-X (YBCO) by simultaneous ionic liquid gating and X-ray absorption experiments. Pronounced spectral changes are observed at the Cu K-edge concomitant with the superconductor-to-insulator transition, evidencing modification of the Cu coordination resulting from the deoxygenation of the CuO chains, as confirmed by first-principles density functional theory (DFT) simulations. Beyond providing evidence of the importance of chemical doping in electric double-layer (EDL) gating experiments with superconducting cuprates, our work shows that interfacing correlated oxides with ionic liquids enables a delicate control of oxygen content, paving the way to novel electrochemical concepts in future oxide electronics.

Variation in Spot and Stripe Patterns in Original and Regenerated Zebrafish Caudal Fins.

Tissue regeneration requires not only the replacement of lost cells and tissues, but also the recreation of morphologies and patterns. Skin pigment pattern is a relatively simple system that can allow researchers to uncover the underlying mechanisms of pattern formation. To gain insight into how pigment patterns form, undergraduate students in the senior level course Developmental Biology designed an experiment that assayed pigment patterns in original and regenerated caudal fins of wild-type, striped, and mutant, spotted zebrafish. A majority of the WT fins regenerated with a similar striped pattern. In contrast, the pattern of spots even in the original fins of the mutants varied among individual fish. Similarly, the majority of the spots in the mutants did not regenerate with the same morphology, size, or spacing as the original fins. This was true even when only a small amount of fin was removed, leaving most of the fin to potentially reseed the pattern in the regenerating tissue. This suggests that the mechanism that creates the wild-type, striped pattern persists to recreate the pattern during regeneration. The mechanism that creates the spots in the mutants, however, must include an unknown element that introduces variability.

Phase diagram of electrostatically doped SrTiO3.

Electric double layer transistor configurations have been employed to electrostatically dope single crystals of insulating SrTiO(3). Here we report on the results of such doping over broad ranges of temperature and carrier concentration employing an ionic liquid as the gate dielectric. The surprising results are, with increasing carrier concentration, an apparent carrier-density dependent conductor-insulator transition, a regime of the anomalous Hall effect, suggesting magnetic ordering, and finally the appearance of superconductivity. The possible appearance of magnetic order near the boundary between the insulating and superconducting regimes is reminiscent of effects associated with quantum critical behavior in some complex compounds.