New developments in probing and targeting protein acylation in malaria, leishmaniasis and African sleeping sickness

Infections by protozoan parasites, such as Plasmodium falciparum or Leishmania donovani, have a significant health, social and economic impact and threaten billions of people living in tropical and sub-tropical regions of developing countries worldwide. The increasing range of parasite strains resistant to frontline therapeutics makes the identification of novel drug targets and the development of corresponding inhibitors vital. Post-translational modifications (PTMs) are important modulators of biology and inhibition of protein lipidation has emerged as a promising therapeutic strategy for treatment of parasitic diseases. In this review we summarize the latest insights into protein lipidation in protozoan parasites. We discuss how recent chemical proteomic approaches have delivered the first global overviews of protein lipidation in these organisms, contributing to our understanding of the role of this PTM in critical metabolic and cellular functions. Additionally, we highlight the development of new small molecule inhibitors to target parasite acyl transferases

Determining the effects of cattle grazing treatments on Yosemite toads (Anaxyrus [=Bufo] canorus) in montane meadows.

Amphibians are experiencing a precipitous global decline, and population stability on public lands with multiple uses is a key concern for managers. In the Sierra Nevada Mountains (California, USA), managers have specifically identified livestock grazing as an activity that may negatively affect Yosemite toads due to the potential overlap of grazing with toad habitat. Grazing exclusion from Yosemite toad breeding and rearing areas and/or entire meadows have been proposed as possible management actions to alleviate the possible impact of cattle on this species. The primary objective of this study was to determine if different fencing treatments affect Yosemite toad populations. We specifically examined the effect of three fencing treatments on Yosemite toad breeding pool occupancy, tadpoles, and young of the year (YOY). Our hypothesis was that over the course of treatment implementation (2006 through 2010), Yosemite toad breeding pool occupancy and early life stage densities would increase within two fencing treatments relative to actively grazed meadows due to beneficial changes to habitat quality in the absence of grazing. Our results did not support our hypothesis, and showed no benefit to Yosemite toad presence or early life stages in fenced or partially fenced meadows compared to standard USDA Forest Service grazing levels. We found substantial Yosemite toad variation by both meadow and year. This variation was influenced by meadow wetness, with water table depth significant in both the tadpole and YOY models

Global Profiling and Inhibition of Protein Lipidation in Vector and Host Stages of the Sleeping Sickness Parasite Trypanosoma brucei

The enzyme N-myristoyltransferase (NMT) catalyzes the essential fatty acylation of substrate proteins with myristic acid in eukaryotes and is a validated drug target in the parasite Trypanosoma brucei, the causative agent of African trypanosomiasis (sleeping sickness). N-Myristoylation typically mediates membrane localization of proteins and is essential to the function of many. However, only a handful of proteins are experimentally validated as N-myristoylated in T. brucei. Here, we perform metabolic labeling with an alkyne-tagged myristic acid analogue, enabling the capture of lipidated proteins in insect and host life stages of T. brucei. We further compare this with a longer chain palmitate analogue to explore the chain length-specific incorporation of fatty acids into proteins. Finally, we combine the alkynyl-myristate analogue with NMT inhibitors and quantitative chemical proteomics to globally define N-myristoylated proteins in the clinically relevant bloodstream form parasites. This analysis reveals five ARF family small GTPases, calpain-like proteins, phosphatases, and many uncharacterized proteins as substrates of NMT in the parasite, providing a global view of the scope of this important protein modification and further evidence for the crucial and pleiotropic role of NMT in the cell

Composites Materials and Manufacturing Technologies for Space Applications

Composite materials offer significant advantages in space applications. Weight reduction is imperative for deep space systems. However, the pathway to deployment of composites alternatives is problematic. Improvements in the materials and processes are needed, and extensive testing is required to validate the performance, qualify the materials and processes, and certify components. Addressing these challenges could lead to the confident adoption of composites in space applications and provide spin-off technical capabilities for the aerospace and other industries. To address the issues associated with composites applications in space systems, NASA sponsored a Technical Interchange Meeting (TIM) entitled, "Composites Materials and Manufacturing Technologies for Space Applications," the proceedings of which are summarized in this Conference Publication. The NASA Space Technology Mission Directorate and the Game Changing Program chartered the meeting. The meeting was hosted by the National Center for Advanced Manufacturing (NCAM)-a public/private partnership between NASA, the State of Louisiana, Louisiana State University, industry, and academia, in association with the American Composites Manufacturers Association. The Louisiana Center for Manufacturing Sciences served as the coordinator for the TIM

Diabetes by Air, Land, and Sea: Effect of Deployments on HbA1c and BMI

INTRODUCTION: Service members (SMs) in the United States (U.S.) Armed Forces have diabetes mellitus at a rate of 2-3%. Despite having a chronic medical condition, they have deployed to environments with limited medical support. Given the scarcity of data describing how they fare in these settings, we conducted a retrospective study analyzing the changes in glycated hemoglobin (HbA1c) and body mass index (BMI) before and after deployment. MATERIALS AND METHODS: SMs from the U.S. Army, Air Force, Navy, and Marine Corps with diabetes who deployed overseas were identified through the Military Health System (MHS) Management Analysis and Reporting Tool and the Defense Manpower Data Center. Laboratory and pharmaceutical data were obtained from the MHS Composite Health Care System and the Pharmacy Data Transaction Service, respectively. Paired t-tests were conducted to calculate changes in HbA1c and BMI before and after deployment. RESULTS: SMs with diabetes completed 11,325 deployments of greater than 90 days from 2005 to 2017. Of these, 474 (4.2%) SMs had both HbA1c and BMI measurements within 90 days prior to departure and within 90 days of return. Most (84.2%) required diabetes medications: metformin in 67.3%, sulfonylureas in 19.0%, dipeptidyl peptidase-4 inhibitors in 13.9%, and insulin in 5.5%. Most SMs deployed with an HbA1c \u3c 7.0% (67.1%), with a mean predeployment HbA1c of 6.8%. Twenty percent deployed with an HbA1c between 7.0 and 7.9%, 7.2% deployed with an HbA1c between 8.0 and 8.9%, and 5.7% deployed with an HbA1c of 9.0% or higher. In the overall population and within each military service, there was no significant change in HbA1c before and after deployment. However, those with predeployment HbA1c \u3c 7.0% experienced a rise in HbA1c from 6.2 to 6.5% (P \u3c 0.001), whereas those with predeployment HbA1c values ≥7.0% experienced a decline from 8.0 to 7.5% (P \u3c 0.001). Those who deployed between 91 and 135 days had a decline in HbA1c from 7.1 to 6.7% (P = 0.010), but no significant changes were demonstrated in those with longer deployment durations. BMI declined from 29.6 to 29.3 kg/m2 (P \u3c 0.001), with other significant changes seen among those in the Army, Navy, and deployment durations up to 315 days. CONCLUSIONS: Most SMs had an HbA1c \u3c 7.0%, suggesting that military providers appropriately selected well-managed SMs for deployment. HbA1c did not seem to deteriorate during deployment, but they also did not improve despite a reduction in BMI. Concerning trends included the deployment of some SMs with much higher HbA1c, utilization of medications with adverse safety profiles, and the lack of HbA1c and BMI evaluation proximal to deployment departures and returns. However, for SMs meeting adequate glycemic targets, we demonstrated that HbA1c remained stable, supporting the notion that some SMs may safely deploy with diabetes. Improvement in BMI may compensate for factors promoting hyperglycemia in a deployed setting, such as changes in diet and medication availability. Future research should analyze in a prospective fashion, where a more complete array of diabetes and readiness-related measures to comprehensively evaluate the safety of deploying SMs with diabetes

Recovering structure from many low-information 2-D images of randomly-oriented samples

Abstract. New sources and detectors are allowing scientists to look at matter with finer spatial and temporal resolutions. These experiments can produce data that are a series of severely Poisson limited snap-shots of randomly oriented samples. An extreme case of this is destructive imaging of single particles with an x-ray free-electron laser -many frames are needed for a reconstruction, but there is no a priori information associated with the frames about particle orientation. We use Cornell's Pixel Array Detectors (PADs) to examine the practical limits of an expectation maximization (EM) algorithm designed to deal with extremely low-fluence data, having just a few photons per frame. We demonstrate image reconstruction of a high-contrast sample using hundreds of thousands of randomly oriented frames with an average x-ray photon occupancy as low as 2.5 photons per frame. Practical aspects of reducing low-fluence data, such as thresholding and noise limits, will be discussed for high-and low-contrast samples; and data collected in the presence of significant background signal

Spin foams with timelike surfaces

Spin foams of 4d gravity were recently extended from complexes with purely spacelike surfaces to complexes that also contain timelike surfaces. In this article, we express the associated partition function in terms of vertex amplitudes and integrals over coherent states. The coherent states are characterized by unit 3--vectors which represent normals to surfaces and lie either in the 2--sphere or the 2d hyperboloids. In the case of timelike surfaces, a new type of coherent state is used and the associated completeness relation is derived. It is also shown that the quantum simplicity constraints can be deduced by three different methods: by weak imposition of the constraints, by restriction of coherent state bases and by the master constraint.Comment: 22 pages, no figures; v2: remarks on operator formalism added in discussion; correction: the spin 1/2 irrep of the discrete series does not appear in the Plancherel decompositio