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

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

Statistical effects in X-ray diffraction lattice strain measurements of ferritic steel using crystal plasticity

The influence of statistics on calculated lattice strains has been studied by comparing crystal plasticity finite element (CPFE) calculations with strains measured experimentally. Experimentally, when Bragg's law is obeyed, a plane normal must lie within a narrow orientation range (∼ 0.02° for synchrotron diffraction), or Bragg tolerance. However, CPFE models consider only a small number of grains compared to experiments, necessitating a justification of the statistically representative volume. It also becomes necessary to assess the threshold of Bragg tolerance allowable for the determined statistically representative volume. In this study, an 8 × 8 × 8 model was deemed as statistically representative such that only small benefits are obtained in terms of lattice strain calculations by adopting larger models such as 10 × 10 × 10. Based on the selected model, an allowable Bragg tolerance of approximately 5° was calculated. Also highlighted was the coupling between lattice strain, texture, hardening and applied boundary condition which are discriminators that will affect the choice of model size and Bragg tolerance threshold

Study of variable stars in the MOA data base: long-period red variables in the Large Magellanic Cloud

One hundred and forty six long-period red variable stars in the Large Magellanic Cloud (LMC) from the three year MOA project database were analysed. A careful periodic analysis was performed on these stars and a catalogue of their magnitudes, colours, periods and amplitudes is presented. We convert our blue and red magnitudes to $K$ band values using 19 oxygen-rich stars. A group of red short-period stars separated from the Mira sequence has been found on a (log P, K) diagram. They are located at the short period side of the Mira sequence consistent with the work of Wood and Sebo (1996). There are two interpretations for such stars; a difference in pulsation mode or a difference in chemical composition. We investigated the properties of these stars together with their colour, amplitude and periodicity. We conclude that they have small amplitudes and less regular variability. They are likely to be higher mode pulsators. A large scatter has been also found on the long period side of the (log P, K) diagram. This is possibly a systematic spread given that the blue band of our photometric system covers both standard B and V bands and affects carbon-rich stars.Comment: 19 pages, 19 figures, accepted for publication in MNRA

Natural polymorphisms in mycobacterium tuberculosis conferring resistance to delamanid in drug-naïve patients.

Mutations in the genes of the F420 signaling pathway, including dnn, fgd1, fbiA, fbiB, fbiC, and fbiD, of Mycobacterium tuberculosis (Mtb) complex can lead to delamanid resistance. We searched for such mutations among 129 Mtb strains from Asia, South-America, and Africa using whole-genome sequencing; 70 (54%) strains had at least one mutation in one of the genes. For ten strains with mutations, we determined the minimum inhibitory concentration (MIC) of delamanid. We found one strain from a delamanid-naïve patient carrying the natural polymorphism Tyr29del (ddn) that was associated with a critical MIC to delamanid

Experiences of using the Theoretical Domains Framework across diverse clinical environments: a qualitative study

Background: The Theoretical Domains Framework (TDF) is an integrative framework developed from a synthesis of psychological theories as a vehicle to help apply theoretical approaches to interventions aimed at behavior change. Purpose: This study explores experiences of TDF use by professionals from multiple disciplines across diverse clinical settings. Methods: Mixed methods were used to examine experiences, attitudes, and perspectives of health professionals in using the TDF in health care implementation projects. Individual interviews were conducted with ten health care professionals from six disciplines who used the TDF in implementation projects. Deductive content and thematic analysis were used. Results: Three main themes and associated subthemes were identified including: 1) reasons for use of the TDF (increased confidence, broader perspective, and theoretical underpinnings); 2) challenges using the TDF (time and resources, operationalization of the TDF) and; 3) future use of the TDF. Conclusion: The TDF provided a useful, flexible framework for a diverse group of health professionals working across different clinical settings for the assessment of barriers and targeting resources to influence behavior change for implementation projects. The development of practical tools and training or support is likely to aid the utility of TDF