A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.

Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.

Abundant Acceptor Emission from Nitrogen-Doped ZnO Films Prepared by Atomic Layer Deposition under Oxygen-Rich Conditions.

Nitrogen-doped and undoped ZnO films were grown by thermal atomic layer deposition (ALD) under oxygen-rich conditions. Low-temperature photoluminescence spectra reveal a dominant donor-related emission at 3.36 eV and characteristic acceptor-related emissions at 3.302 and 3.318 eV. Annealing at 800 °C in oxygen atmosphere leads to conversion of conductivity from n- to p-type, which is reflected in photoluminescence spectra. Annealing does not increase any acceptor-related emission in the undoped sample, while in the ZnO:N it leads to a considerable enhancement of the photoluminescence at 3.302 eV. The high resolution cathodoluminescence cross-section images show different spatial distribution of the donor-related and the acceptor-related emissions, which complementarily contribute to the overall luminescence of the annealed ZnO:N material. Similar area of both emissions indicates that the acceptor luminescence comes neither from the grain boundaries nor from stacking faults. Moreover, in ZnO:N the acceptor-emission regions are located along the columns of growth, which shows a perspective to achieve a ZnO:N material with homogeneous acceptor conductivity at least at the micrometer scale.

[Multiple and successive treatment failures in a patient infected by Plasmodium falciparum in Cambodia and treated by dihydroartemisinin-piperaquine]. / Echecs thérapeutiques multiples et successifs chez un patient infecté par Plasmodium falciparum au Cambodge et traité par dihydroartémisinine-pipéraquine.

Cases of treatment failures following administration of artemisinin-based combination therapies (ACT) remain rare in malaria endemic areas. In Cambodia, however, failures of these treatments are now commonly observed. Usually, these post-treatment recurrences occur only once and a second course of the same treatment is sufficient to cure patients.We describe here an atypical case of a Plasmodium falciparum-infected patient manifesting several malaria recrudescence episodes following dihydroartemisinin-piperaquine (Eurartesim®) treatment. This case report illustrates the current issue of resistance to the latest generation of antimalarial drugs in Southeast Asia and highlights the difficulty in efficaciously fighting malaria in this region if new therapy remains unimplemented.

Defective antiadherence activity of bladder extracts from patients with recurrent urinary tract infection.

A substantial body of animal work indicates that the initial first line defense against invading microorganisms in the urinary tract is the antiadherence activity of the surface mucin layer. Previous work has demonstrated that bacterial adherence to anion exchange resin can be used as a model for adherence to the mucin deficient rabbit bladder. This anion exchange resin adherence model can also be used as a rapid screen for potential antiadherence agents. In vitro saline extracts of bladder mucosa from various mammalian species including man have been shown to inhibit bacterial adherence to both anion exchange resin and the mucin deficient rabbit bladder. The present report investigates the ability of in vivo saline bladder washes from several groups of patients to inhibit bacterial adherence to anion exchange resin. This has an advantage over other methods of quantitation or visualization of mucin since it is the ability of the bladder extract to prevent bacterial adherence, and not merely the quantity of mucin, that determines the effectiveness of the mucin lining in preventing bacterial attachment. Bladder washes from patients with recurrent urinary tract infection were significantly less potent at inhibiting bacterial adherence than extracts from other groups of patients. This decreased functional antiadherence activity of bladder extracts may help explain the frequency of urinary tract infection in this group of patients.