Generation of superoxide and singlet oxygen from α-tocopherolquinone and analogues.

Three potential routes to generation of reactive oxygen species from a tocopherolquinone have been identified. The quinone of the water-soluble vitamin E analogue Trolox C (Trol-Q) is reduced by hydrated electron and isopropanol a hydroxyalkyl radical, and the resulting semiquinone reacts with molecular oxygen to form superoxide with a second order rate constant of 1.3 x 108 dm3 mol-1 s-1, illustrating the potential for redox cycling. Illumination (UV-A, 355 nm) of the quinone of 2,2,5,7,8-pentamethyl-6-hydroxychromanol (PMHC-Q) leads to a reactive short-lived (ca 10-6 s) triplet state, able to oxidise tryptophan with a second order rate constant greater than 109 dm3 mol-1 s-1. The triplet states of these quinones sensitize singlet oxygen formation with quantum yields of about 0.8. Such potentially damaging reactions of a tocopherolquinone may in part account for the recent findings that high levels of dietary vitamin E supplementation lack any beneficial effect and may lead to slightly enhanced levels of overall mortality

Lead optimisation of dehydroemetine for repositioned use in malaria

Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC50: 47 nM ± 2.1 nM). Dehydroemetine, a synthetic analogue of emetine dihydrochloride has been reported to have less cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modelled on the published emetine binding site on cryo-EM structure 3J7A (Pf 80S ribosome in complex with emetine) and it was found that (-)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than (-)-S,S-dehydroisoemetine. (-)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison with (-)-S,S-dehydroisoemetine (IC50 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1′. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug resistant strains tested. Drug interaction studies showed (-)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride, and (-)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity on the mitochondrial membrane potential indicating a possible multi-modal mechanism of action. [Abstract copyright: Copyright © 2020 Panwar et al.

Evaluation of a primary care triumvirate leadership development programme

This paper evaluates a primary care triumvirate leadership programme from the perspectives of key stakeholders (General Practitioners, General Practice Nurses, Practice Managers, programme and practice colleagues); and to provide evidencedinformed recommendations for future primary care triumvirate healthcare leadership development. Kirkpatrick's Four/Five Levels of Evaluation Model was used as the evaluation approach. Data was collected by the use of face to face and telephone focus group interviews. Thematic analysis was used to generate themes relating to the four levels of Kirkpatrick's model. Findings show how adopting a primary care triumvirate leadership approach offers a promising platform for operationalising the contemporary collective and distributed approaches to leadership development. Future programmes could benefit further by adopting a multi-dimensional leadership development model. This would expose the primary care triumvirate leader to the evidence based Six 'E's' approach to leadership development (evaluate, examine, exposure, education, environment, experience)

Dark matter annihilation and decay in dwarf spheroidal galaxies: The classical and ultrafaint dSphs

Dwarf spheroidal (dSph) galaxies are prime targets for present and future gamma-ray telescopes hunting for indirect signals of particle dark matter. The interpretation of the data requires careful assessment of their dark matter content in order to derive robust constraints on candidate relic particles. Here, we use an optimised spherical Jeans analysis to reconstruct the `astrophysical factor' for both annihilating and decaying dark matter in 21 known dSphs. Improvements with respect to previous works are: (i) the use of more flexible luminosity and anisotropy profiles to minimise biases, (ii) the use of weak priors tailored on extensive sets of contamination-free mock data to improve the confidence intervals, (iii) systematic cross-checks of binned and unbinned analyses on mock and real data, and (iv) the use of mock data including stellar contamination to test the impact on reconstructed signals. Our analysis provides updated values for the dark matter content of 8 `classical' and 13 `ultrafaint' dSphs, with the quoted uncertainties directly linked to the sample size; the more flexible parametrisation we use results in changes compared to previous calculations. This translates into our ranking of potentially-brightest and most robust targets---viz., Ursa Minor, Draco, Sculptor---, and of the more promising, but uncertain targets---viz., Ursa Major 2, Coma---for annihilating dark matter. Our analysis of Segue 1 is extremely sensitive to whether we include or exclude a few marginal member stars, making this target one of the most uncertain. Our analysis illustrates challenges that will need to be addressed when inferring the dark matter content of new `ultrafaint' satellites that are beginning to be discovered in southern sky surveys.Comment: 19 pages, 14 figures, submitted to MNRAS. Supplementary material available on reques

Peptidomimetic inhibitors of N-myristoyltransferase from human malaria and leishmaniasis parasites

N-Myristoyltransferase (NMT) has been shown to be essential in Leishmania and subsequently validated as a drug target in Plasmodium. Herein, we discuss the use of antifungal NMT inhibitors as a basis for inhibitor development resulting in the first sub-micromolar peptidomimetic inhibitors of Plasmodium and Leishmania NMTs. High-resolution structures of these inhibitors with Plasmodium and Leishmania NMTs permit a comparative analysis of binding modes, and provide the first crystal structure evidence for a ternary NMT-Coenzyme A/myristoylated peptide product complex

Expanding the scope of the Babler-Daubin oxidation : 1,3-oxidative transposition of secondary allylic alcohols

We report the catalytic chromium-mediated oxidation of secondary allylic alcohols to give α,β-unsaturated aldehydes with exclusive (E)-stereoselectivity. This facile procedure employs catalytic PCC (5 mol%) and periodic acid (H5IO6) as a co-oxidant. This transformation occurs specifically with aromatic substituted allyl alcohols containing both electron withdrawing and electron donating substituents as well as a range of functional groups

No Detectable Fertility Benefit from a Single Additional Mating in Wild Stalk-Eyed Flies

Background: Multiple mating by female insects is widespread, and the explanation(s) for repeated mating by females has been the subject of much discussion. Females may profit from mating multiply through direct material benefits that increase their own reproductive output, or indirect genetic benefits that increase offspring fitness. One particular direct benefit that has attracted significant attention is that of fertility assurance, as females often need to mate multiply to achieve high fertility. This hypothesis has never been tested in a wild insect population.Methodology/Principal Findings: Female Malaysian stalk-eyed flies (Teleopsis dalmanni) mate repeatedly during their lifetime, and have been shown to be sperm limited under both laboratory and field conditions. Here we ask whether receiving an additional mating alleviates sperm limitation in wild females. In our experiment one group of females received a single additional mating, while a control group received an interrupted, and therefore unsuccessful, mating. Females that received an additional mating did not lay more fertilised eggs in total, nor did they lay proportionately more fertilised eggs. Female fertility declined significantly through time, demonstrating that females were sperm limited. However, receipt of an additional mating did not significantly alter the rate of this decline.Conclusions/Significance: Our data suggest that the fertility consequences of a single additional mating were small. We discuss this effect (or lack thereof), and suggest that it is likely to be attributed to small ejaculate size, a high proportion of failed copulations, and the presence of X-linked meiotic drive in this species

Peptidomimetic inhibitors of N-myristoyltransferase from human malaria and leishmaniasis parasites

N-Myristoyltransferase (NMT) has been shown to be essential in Leishmania and subsequently validated as a drug target in Plasmodium. Herein, we discuss the use of antifungal NMT inhibitors as a basis for inhibitor development resulting in the first sub-micromolar peptidomimetic inhibitors of Plasmodium and Leishmania NMTs. High-resolution structures of these inhibitors with Plasmodium and Leishmania NMTs permit a comparative analysis of binding modes, and provide the first crystal structure evidence for a ternary NMT-Coenzyme A/myristoylated peptide product complex

Structure-Based Design of Potent and Selective Leishmania N-Myristoyltransferase Inhibitors

Inhibitors of Leishmania N-myristoyltransferase (NMT), a potential target for the treatment of leishmaniasis, obtained from a high-throughput screen, were resynthesized to validate activity. Crystal structures bound to Leishmania major NMT were obtained, and the active diastereoisomer of one of the inhibitors was identified. On the basis of structural insights, enzyme inhibition was increased 40-fold through hybridization of two distinct binding modes, resulting in novel, highly potent Leishmania donovani NMT inhibitors with good selectivity over the human enzyme