Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages-erythrocytic, gametocyte, liver, and gamete activation stages-indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin-sensitive and artemisinin-resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum-infected mice

Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the Plasmodium falciparum proteasome (Pf20S) β5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against P. falciparum strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin. P. falciparum selected for resistance to an AsnEDA β5 inhibitor surprisingly harbored a point mutation in the noncatalytic β6 subunit. The β6 mutant was resistant to the species-selective Pf20S β5 inhibitor but remained sensitive to the species-nonselective β5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S β5 inhibitor was accompanied by increased sensitivity to a Pf20S β2 inhibitor. Finally, the β5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S β5 and β2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other

Magnetic domain structure and domain wall analysis of ferromagnetic MnAs nanodisks selectively-grown on Si (111) substrates for spintronic applications

We report on the experimental and analytic results on magnetic domain and domain wall structures of MnAs nanodisks on AlGaAs nanopillar buffers selectively grown on Si (111) substrates partially covered with dielectric SiO2 thin film mask patterns using selective-area metal-organic vapor phase epitaxy. The results on the size dependence of the magnetic domain structure in MnAs nanodisks investigated by magnetic force microscopy show that a single domain is predominant in the MnAs nanodisks with an area of approximately 3 × 104 nm2 or less. It is also indicated that in the nanodisks with an area of approximately 6 × 104 nm2 or more, multiple domains, in particular, two magnetic domain structures with a 180° domain wall, are predominant. In addition, in the case of nanodisks with multiple domains, not only Néel walls but also Bloch walls are possibly formed, according to the detailed analyses of the magnetic force microscope images obtained. These results suggest that the magnetic domains and domain walls can be tuned by the control of the MnAs nanodisk size making them interesting nanostructures for spintronic applications

Laser power and wavelength dependence of alumina reduction using YAG laser ablation considering inverse bremsstrahlung

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