Implementing Pasteur's vision for rabies elimination: the evidence base and the needed policy actions

It has been 129 years since Louis Pasteur's experimental protocol saved the life of a child mauled by a rabid dog, despite incomplete understanding of the etiology or mechanisms by which the miracle cure worked (1). The disease has since been well understood, and highly effective vaccines are available, yet Pasteur's vision for ridding the world of rabies has not been realized. Rabies remains a threat to half the world's population and kills more than 69,000 people each year, most of them children (2). We discuss the basis for this neglect and present evidence supporting the feasibility of eliminating canine-mediated rabies and the required policy actions

The action mechanism of daptomycin

The final publication is available at Elsevier via http://dx.doi.org/10.1016/j.bmc.2016.05.052 © 2016.Daptomycin is a lipopeptide antibiotic produced by the soil bacterium Streptomyces roseosporus that is clinically used to treat severe infections with Gram-positive bacteria. In this review, we discuss the mode of action of this important antibiotic. Although daptomycin is structurally related to amphomycin and similar lipopeptides that inhibit peptidoglycan biosynthesis, experimental studies have not produced clear evidence that daptomycin shares their action mechanism. Instead, the best characterized effect of daptomycin is the permeabilization and depolarization of the bacterial cell membrane. This activity, which can account for daptomycin's bactericidal effect, correlates with the level of phosphatidylglycerol (PG) in the membrane. Accordingly, reduced synthesis of PG or its increased conversion to lysyl-PG promotes bacterial resistance to daptomycin. While other resistance mechanisms suggest that daptomycin may indeed directly interfere with cell wall synthesis or cell division, such effects still await direct experimental confirmation. Daptomycin's complex structure and biosynthesis have hampered the analysis of its structure activity relationships. Novel methods of total synthesis, including a recent one that is carried out entirely on a solid phase, will enable a more thorough and systematic exploration of the sequence space

An Acyl-Linked Dimer of Daptomycin Is Strongly Inhibited by the Bacterial Cell Wall

This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publi-cation in ACS Infectious Diseases,© American Chemical Society after peer review. To access the final edited and published work see http://pubs.acs.org/doi/full/10.1021/acsinfecdis.7b00019.The lipopeptide antibiotic daptomycin is active against Gram-positive pathogens. It permeabilizes bacterial cell membranes, which involves the formation of membrane-associated oligomers. We here studied a dimer of daptomycin whose two subunits were linked through a bivalent aliphatic acyl chain. Unexpectedly, the dimer had very low activity on vegetative Staphylococcus aureus and Bacillus subtilis cells. However, activity resembled that of monomeric daptomycin on liposomes and on B. subtilis L-forms. These findings underscore the importance of the bacterial cell wall in daptomycin resistance.NSERC operating grants to M.P. (250265-2013) and S.T. (155283-2012)

Imidazole aldoximes effective in assisting butyrylcholinesterase catalysis of organophosphate detoxification.

Intoxication by organophosphate (OP) nerve agents and pesticides should be addressed by efficient, quickly deployable countermeasures such as antidotes reactivating acetylcholinesterase or scavenging the parent OP. We present here synthesis and initial in vitro characterization of 14 imidazole aldoximes and their structural refinement into three efficient reactivators of human butyrylcholinesterase (hBChE) inhibited covalently by nerve agent OPs, sarin, cyclosarin, VX, and the OP pesticide metabolite, paraoxon. Rapid reactivation of OP-hBChE conjugates by uncharged and nonprotonated tertiary imidazole aldoximes allows the design of a new OP countermeasure by conversion of hBChE from a stoichiometric to catalytic OP bioscavenger with the prospect of oral bioavailability and central nervous system penetration. The enhanced in vitro reactivation efficacy determined for tertiary imidazole aldoximes compared to that of their quaternary N-methyl imidazolium analogues is attributed to ion pairing of the cationic imidazolium with Asp 70, altering a reactive alignment of the aldoxime with the phosphorus in the OP-hBChE conjugate

An in vivo biosensor for neurotransmitter release and in situ receptor activity.

Tools from molecular biology, combined with in vivo optical imaging techniques, provide new mechanisms for noninvasively observing brain processes. Current approaches primarily probe cell-based variables, such as cytosolic calcium or membrane potential, but not cell-to-cell signaling. We devised cell-based neurotransmitter fluorescent engineered reporters (CNiFERs) to address this challenge and monitor in situ neurotransmitter receptor activation. CNiFERs are cultured cells that are engineered to express a chosen metabotropic receptor, use the G(q) protein-coupled receptor cascade to transform receptor activity into a rise in cytosolic [Ca(2+)] and report [Ca(2+)] with a genetically encoded fluorescent Ca(2+) sensor. The initial realization of CNiFERs detected acetylcholine release via activation of M1 muscarinic receptors. We used chronic implantation of M1-CNiFERs in frontal cortex of the adult rat to elucidate the muscarinic action of the atypical neuroleptics clozapine and olanzapine. We found that these drugs potently inhibited in situ muscarinic receptor activity

Maine in the 104th Congress: Life without Mitchell

For many Mainers, the significance of the last election had little to do with the Republican sweep throughout the nation, but had much to do with the retirement of Senator George Mitchell. This article summarizes Senator Mitchell\u27s most critical policy contributions and the results of his influence at the state and national levels. His absence from Congress presents the currentMainedelegation with a new set of challenges. These issues are explored, in part, from the broader perspective ofMaine\u27s history in Congress

Sediment Management for Southern California Mountians, Coastal Plains and Shoreline. Part D: Special Inland Studies

In southern California the natural environmental system involves the continual relocation of sedimentary materials. Particles are eroded from inland areas where there is sufficient relief and, precipitation. Then, with reductions in hydraulic gradient along the stream course and at the shoreline, the velocity of surface runoff is reduced and there is deposition. Generally, coarse sand, gravel and larger particles are deposited near the base of the eroding surfaces (mountains and hills) and the finer sediments are deposited on floodplains, in bays or lagoons, and at the shoreline as delta deposits. Very fine silt and clay particles, which make up a significant part of the eroded material, are carried offshore where they eventually deposit in deeper areas. Sand deposited at the shoreline is gradually moved along the coast by waves and currents, and provides nourishment for local beaches. However, eventually much of this littoral material is also lost to offshore areas. Human developments in the coastal region have substantially altered the natural sedimentary processes, through changes in land use, the harvesting of natural resources (logging, grazing, and sand and gravel mining); the construction and operation of water conservation facilities and flood control structures; and coastal developments. In almost all cases these developments have grown out of recognized needs and have well served their primary purpose. At the time possible deleterious effects on the local or regional sediment balance were generally unforeseen or were felt to be of secondary importance. In 1975 a large-scale study of inland and coastal sedimentation processes in southern California was initiated by the Environmental Quality Laboratory at the California Institute of Technology and the Center for Coastal Studies at Scripps Institution of Oceanography. This volume is one of a series of reports from this study. Using existing data bases, this series attempts to define quantitatively inland and coastal sedimentation processes and identify the effects man has had on these processes. To resolve some issues related to long-term sediment management, additional research and data will be needed. In the series there are four Caltech reports that provide supporting studies for the summary report (EQL Report No. 17). These reports include: EQL Report 17-A Regional Geological History EQL Report 17-B Inland Sediment Movements by Natural Processes EQL Report 17-C Coastal Sediment Delivery by Major Rivers in Southern California EQL Report 17-D -- Special Inland Studies Additional supporting reports on coastal studies (shoreline sedimentation processes, control structures, dredging, etc.) are being published by the Center for Coastal Studies at Scripps Institution of Oceanography, La Jolla, California

Molecular models for the core components of the flagellar type-III secretion complex

We show that by using a combination of computational methods, consistent three-dimensional molecular models can be proposed for the core proteins of the type-III secretion system. We employed a variety of approaches to reconcile disparate, and sometimes inconsistent, data sources into a coherent picture that for most of the proteins indicated a unique solution to the constraints. The range of difficulty spanned from the trivial (FliQ) to the difficult (FlhA and FliP). The uncertainties encountered with FlhA were largely the result of the greater number of helix packing possibilities allowed in a large protein, however, for FliP, there remains an uncertainty in how to reconcile the large displacement predicted between its two main helical hairpins and their ability to sit together happily across the bacterial membrane. As there is still no high resolution structural information on any of these proteins, we hope our predicted models may be of some use in aiding the interpretation of electron microscope images and in rationalising mutation data and experiments

Next Generation Diapers: Increasing Elastic Laminate Toughness

Disposable diapers are prone to accidental damage during use, since a caregiver may accidentally rip or puncture the elastic material. To reduce the incidence of material failure, the toughness of the apertured elastic trilaminate body paneling material needs to be improved without reducing the elasticity, breathability, and material cost. A “tougher” material was defined as a material with greater tensile strength and puncture resistance than standard, commercial product. The design team took a two-pronged approach to this problem. First, experiments were designed to quantify the effects of altering the die temperature, the resin blend, the cross directional stretch activation depth, and production line speed on toughness. A 2-level, full factorial analysis revealed that the process variables that had the largest effect were activation depth and die temperature. While altering the resin blend improved toughness, the trilaminate elasticity suffered. Decreasing both activation depth and die temperature resulted in a 19.7% greater puncture resistance than the original material, which was able to withstand 17.5% greater tensile load. However, only a minimal increase in its elongation at break, 5.7%, was achieved. Decreasing only activation depth provided a better balance of the desired characteristics: an 11.5% increase in puncture resistance, 16.1% increase in tensile load, and 14.6% increase in elongation. The experimental data collected was used to supplement a finite element analysis model of altered aperture orientation. This showed that rotating the oval aperture by 90° reduced the maximum stress by 62.3%. These findings will pave the way for further elastic laminate material improvements.https://scholarscompass.vcu.edu/capstone/1143/thumbnail.jp