Pantothenamides Are Potent, On-Target Inhibitors of Plasmodium falciparum Growth When Serum Pantetheinase Is Inactivated

Growth of the virulent human malaria parasite Plasmodium falciparum is dependent on an extracellular supply of pantothenate (vitamin B(5)) and is susceptible to inhibition by pantothenate analogues that hinder pantothenate utilization. In this study, on the hunt for pantothenate analogues with increased potency relative to those reported previously, we screened a series of pantothenamides (amide analogues of pantothenate) against P. falciparum and show for the first time that analogues of this type possess antiplasmodial activity. Although the active pantothenamides in this series exhibit only modest potency under standard in vitro culture conditions, we show that the potency of pantothenamides is selectively enhanced when the parasite culture medium is pre-incubated at 37°C for a prolonged period. We present evidence that this finding is linked to the presence in Albumax II (a serum-substitute routinely used for in vitro cultivation of P. falciparum) of pantetheinase activity: the activity of an enzyme that hydrolyzes the pantothenate metabolite pantetheine, for which pantothenamides also serve as substrates. Pantetheinase activity, and thereby pantothenamide degradation, is reduced following incubation of Albumax II-containing culture medium for a prolonged period at 37°C, revealing the true, sub-micromolar potency of pantothenamides. Importantly we show that the potent antiplasmodial effect of pantothenamides is attenuated with pantothenate, consistent with the compounds inhibiting parasite proliferation specifically by inhibiting pantothenate and/or CoA utilization. Additionally, we show that the pantothenamides interact with P. falciparum pantothenate kinase, the first enzyme involved in converting pantothenate to coenzyme A. This is the first demonstration of on-target antiplasmodial pantothenate analogues with sub-micromolar potency, and highlights the potential of pantetheinase-resistant pantothenamides as antimalarial agents.Aspects of this work were supported by grants from the South African Malaria Initiative (SAMI) to ES and KJS and the American Lebanese Syrian Associated Charities (ALSAC), St. Jude Children’s Research Hospital, to REL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

A High Frequency (HF) Inductive Power Transfer Circuit for High Temperature Applications Using SiC Schottky Diodes

Wireless sensors placed in high temperature environments, such as aircraft engines, are desirable to reduce the mass and complexity of routing wires. While communication with the sensors is straight forward, providing power wirelessly is still a challenge. This paper introduces an inductive wireless power transfer circuit incorporating SiC Schottky diodes and its operation from room temperature (25 C) to 500 C

Planetary Protection Knowledge Gaps for Human Extraterrestrial Missions: Workshop Report

This report on Planetary Protection Knowledge Gaps for Human Extraterrestrial Missions summarizes the presentations, deliberations and findings of a workshop at NASA Ames Research Center, March 24-26, 2015, which was attended by more than 100 participants representing a diverse mix of science, engineering, technology, and policy areas. The main objective of the three-day workshop was to identify specific knowledge gaps that need to be addressed to make incremental progress towards the development of NASA Procedural Requirements (NPRs) for Planetary Protection during human missions to Mars

High Temperature Capacitive Pressure Sensor Employing a SiC Based Ring Oscillator

In an effort to develop harsh environment electronic and sensor technologies for aircraft engine safety and monitoring, we have used capacitive-based pressure sensors to shift the frequency of a SiC-electronics-based oscillator to produce a pressure-indicating signal that can be readily transmitted, e.g. wirelessly, to a receiver located in a more benign environment. Our efforts target 500 C, a temperature well above normal operating conditions of commercial circuits but within areas of interest in aerospace engines, deep mining applications and for future missions to the Venus atmosphere. This paper reports for the first time a ring oscillator circuit integrated with a capacitive pressure sensor, both operating at 500 C. This demonstration represents a significant step towards a wireless pressure sensor that can operate at 500 C and confirms the viability of 500 C electronic sensor systems

The Effects of Lottery Promotions, Credit Constraints, and the Stock Market on Daily New Jersey Lottery Sales

This paper estimates the price elasticity of demand for daily Pick 3 and Pick 4 lottery games using random price variation generated by the New Jersey Lottery’s evening Pick 3 Green Ball promotion and Pick 4 Red Ball promotion. These promotions lower the price of a lottery ticket for an evening daily numbers game by increasing prize payments during the promotion period. The own-price elasticity of demand for evening Pick 3 is -0.50, while the own-price elasticity of demand for evening Pick 4 is -0.57. This inelastic demand implies that the loss in margin outweighs the gain in sales during the promotion for the promoted lottery game. Midday Pick 3 and Pick 4 lottery sales increase because of the price promotions for their evening counterparts. The lottery promotions also moderately increase midday daily game sales and Pick 3 and Pick 4 sales temporarily after the promotions end. Our findings that sales are significantly higher on Fridays and at the start of a month are consistent with daily lottery players facing credit constraints

A Population-based survey of the prevalence and types of glaucoma in Nigeria: results from the Nigeria National Blindness and Visual Impairment Survey.

BACKGROUND: Glaucoma is the leading cause of irreversible blindness worldwide. There tends to be a lower reporting of glaucoma in Africa compared to other blinding conditions in global burden data. Research findings of glaucoma in Nigeria will significantly increase our understanding of glaucoma in Nigeria, in people of the West African diaspora and similar population groups. We determined the prevalence and types of glaucoma in Nigeria from the Nigeria National Blindness and Visual Impairment cross-sectional Survey of adults aged ≥40 years. METHODS: Multistage stratified cluster random sampling with probability-proportional-to-size procedures were used to select a nationally representative sample of 15,027 persons aged ≥40 years. Participants had logMAR visual acuity measurement, FDT visual function testing, autorefraction, A-scan biometry and optic disc assessment. Participants with visual acuity of worse than 6/12 or suspicious optic discs had detailed examination including Goldmann applanation tonometry, gonioscopy and fundus photography. Disc images were graded by Moorfields Eye Hospital Reading Centre. Glaucoma was defined using International Society of Geographical and Epidemiological Ophthalmology criteria; and classified into primary open-angle or primary angle-closure or secondary glaucoma. Diagnosis of glaucoma was based on ISGEO classification. The type of glaucoma was determined by gonioscopy. RESULTS: A total of 13,591 participants in 305 clusters were examined (response rate 90.4 %). Optic disc grading was available for 25,289 (93 %) eyes of 13,081 (96 %) participants. There were 682 participants with glaucoma; a prevalence of 5.02 % (95 % CI 4.60-5.47). Among those with definite primary glaucoma that had gonioscopy (n = 243), open-angle glaucoma was more common (86 %) than angle-closure glaucoma (14 %). 8 % of glaucoma was secondary with the commonest causes being couching (38 %), trauma (21 %) and uveitis (19 %). Only 5.6 % (38/682) of participants with glaucoma knew they had the condition. One in every 5 persons with glaucoma (136;20 %) was blind i.e., visual acuity worse than 3/60. CONCLUSION: Nigeria has a high prevalence of glaucoma which is largely open-angle glaucoma. A high proportion of those affected are blind. Secondary glaucoma was mostly as a consequence of procedures for cataract. Public health control strategies and high quality glaucoma care service will be required to reduce morbidity and blindness from glaucoma

Adalimumab in refractory cystoid macular edema associated with birdshot chorioretinopathy

Purpose To report the clinical outcomes of adalimumab therapy in cases of birdshot chorioretinitis (BCR) with cystoid macular edema (CME) refractory to conventional immunotherapy. Methods This is a retrospective case series of three BCR patients treated with adalimumab for refractory CME. The main outcome measure was central subfield thickness (CST) on optical coherence tomography. Any patients treated with local steroids and/or receiving systemic steroids higher than 40 mg prednisolone daily during adalimumab therapy were excluded. Results At baseline, all patients were receiving systemic corticosteroids and two second-line immunosuppressive agents. The mean duration of treatment with adalimumab was 31.2 months (range 17.2–52). The mean CST was 327 ± 112.7 μm (mean ± SD) at baseline and 256.2 ± 39.7 μm at 6 months and 235.5 ± 32.5 μm at 12 months. Adalimumab permitted cessation or reduction in the daily dose of oral prednisolone plus withdrawal of a second-line agent in all patients. Conclusions In these patients, adalimumab was effective in the treatment of refractory CME

New insights into measurement variability in glaucomatous visual fields from computer modelling.

To develop a model to simulate visual fields (VFs) in glaucoma patients, and to characterize variability of the Mean Deviation (MD) VF summary measurement using real VFs and simulations

Recent Results from Epitaxial Growth on Step Free 4H-SiC Mesas

This paper updates recent progress made in growth, characterization, and understanding of high quality homoepitaxial and heteroepitaxial films grown on step-free 4H-SiC mesas. First, we report initial achievement of step-free 4H-SiC surfaces with carbon-face surface polarity. Next, we will describe further observations of how step-free 4H-SiC thin lateral cantilever evolution is significantly impacted by crystal faceting behavior that imposes non-uniform film thickness on cantilever undersides. Finally, recent investigations of in-plane lattice constant mismatch strain relief mechanisms observed for heteroepitaxial growth of 3C-SiC as well as 2H-AlN/GaN heterofilms on step-free 4H-SiC mesas will be reviewed. In both cases, the complete elimination of atomic heterointerface steps on the mesa structure enables uniquely well-ordered misfit dislocation arrays to form near the heterointerfaces with remarkable lack of dislocations threading vertically into the heteroepilayers. In the case of 3C-SiC heterofilms, it has been proposed that dislocation half-loops nucleate at mesa edges and glide laterally along the step-free 3C/4H interfaces. In contrast, 3C-SiC and 2H-AlN/GaN heterofilms grown on 4H-SiC mesas with steps exhibit highly disordered interface misfit dislocation structure coupled with 100X greater density of dislocations threading through the thickness of the heteroepilayers. These results indicate that the presence of steps at the heteroepitaxial interface (i.e., on the initial heteroepitaxial nucleation surface) plays a highly important role in the defect structure, quality, and relaxation mechanisms of single-crystal heteroepitaxial films

Parental experiences of end of life care decision-making for children with life-limiting conditions in the paediatric intensive care unit: a qualitative interview study

Objectives To provide an in-depth insight into the experience and perceptions of bereaved parents who have experienced end of life care decision-making for children with life-limiting or life-threatening conditions in the paediatric intensive care unit (PICU). Design An in-depth qualitative interview study with a sample of parents of children with life-limiting or life-threatening conditions who had died in PICU within the previous 12 months. A thematic analysis was conducted on the interview transcripts. Setting A PICU in a large National Health Service (NHS) tertiary children’s hospital in the West Midlands, UK. Participants 17 parents of 11 children who had died in the PICU. Results Five interconnected themes were identified related to end of life care decision-making:(1) parents have significant knowledge and experiences that influence the decision-making process.(2) Trusted relationships with healthcare professionals are key to supporting parents making end of life decisions.(3) Verbal and non-verbal communication with healthcare professionals impacts on the family experience.(4) Engaging with end of life care decision-making can be emotionally overwhelming, but becomes possible if parents reach a ‘place of acceptance’.(5) Families perceive benefits to receiving end of life care for their child in a PICU. Conclusions and implications The death of a child is an intensely emotional experience for all involved. This study adds to the limited evidence base related to parental experiences of end of life care decision-making and provides findings that have international relevance, particularly related to place of care and introduction of end of life care discussions. The expertise and previous experience of parents is highly relevant and should be acknowledged. End of life care decision-making is a complex and nuanced process; the information needs and preferences of each family are individual and need to be understood by the professionals involved in their care