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

Improving the Prospects for Detecting Extrasolar Planets in Gravitational Microlensing in 2002

Gravitational microlensing events of high magnification have been shown to be promising targets for detecting extrasolar planets. However, only a few events of high magnification have been found using conventional survey techniques. Here we demonstrate that high magnification events can be readily found in microlensing surveys using a strategy that combines high frequency sampling of target fields with online difference imaging analysis. We present 10 microlensing events with peak magnifications greater than 40 that were detected in real-time towards the Galactic Bulge during 2001 by MOA. We show that Earth mass planets can be detected in future events such as these through intensive follow-up observations around the event peaks. We report this result with urgency as a similar number of such events are expected in 2002.Comment: 11 pages, 3 embedded ps figures including 2 colour, revised version accepted by MNRA

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

This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.phpBACKGROUND: 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

Microlensing optical depth towards the Galactic bulge from MOA observations during 2000 with Difference Image Analysis

We analyze the data of the gravitational microlensing survey carried out by by the MOA group during 2000 towards the Galactic Bulge (GB). Our observations are designed to detect efficiently high magnification events with faint source stars and short timescale events, by increasing the the sampling rate up to 6 times per night and using Difference Image Analysis (DIA). We detect 28 microlensing candidates in 12 GB fields corresponding to 16 deg^2. We use Monte Carlo simulations to estimate our microlensing event detection efficiency, where we construct the I-band extinction map of our GB fields in order to find dereddened magnitudes. We find a systematic bias and large uncertainty in the measured value of the timescale $t_{\rm Eout}$ in our simulations. They are associated with blending and unresolved sources, and are allowed for in our measurements. We compute an optical depth tau = 2.59_{-0.64}^{+0.84} \times 10^{-6} towards the GB for events with timescales 0.3<t_E<200 days. We consider disk-disk lensing, and obtain an optical depth tau_{bulge} = 3.36_{-0.81}^{+1.11} \times 10^{-6}[0.77/(1-f_{disk})] for the bulge component assuming a 23% stellar contribution from disk stars. These observed optical depths are consistent with previous measurements by the MACHO and OGLE groups, and still higher than those predicted by existing Galactic models. We present the timescale distribution of the observed events, and find there are no significant short events of a few days, in spite of our high detection efficiency for short timescale events down to t_E = 0.3 days. We find that half of all our detected events have high magnification (>10). These events are useful for studies of extra-solar planets.Comment: 65 pages and 30 figures, accepted for publication in ApJ. A systematic bias and uncertainty in the optical depth measurement has been quantified by simulation

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

Contribution of bistability and noise to cell fate transitions determined by feedback opening

AbstractAlternative cell fates represent a form of non-genetic diversity, which can promote adaptation and functional specialization. It is difficult to predict the rate of the transition between two cell fates due to the strong effect of noise on feedback loops and missing parameters. We opened synthetic positive feedback loops experimentally to obtain open-loop functions. These functions allowed us to identify a deterministic model of bistability by bypassing noise and the requirement to resolve individual processes in the loop. Combining the open-loop function with kinetic measurements and reintroducing the measured noise, we were able to predict the transition rates for the feedback systems without parameter tuning. Noise in gene expression was the key determinant of the transition rates inside the bistable range. Transitions between two cell fates were also observed outside of the bistable range, evidenced by bimodality and hysteresis. In this case, a slow transient process was the rate-limiting step in the transitions. Thus, feedback opening is an effective approach to identify the determinants of cell fate transitions and to predict their rates