Engineering topics

McNerney, M. Windy

Publications and source records attributed to McNerney, M. Windy.

5 records

DOE OSTI2021

Development of a CNS-permeable reactivator for nerve agent exposure: an iterative, multi-disciplinary approach

Nerve agents have experienced a resurgence in recent times with their use against civilian targets during the attacks in Syria (2012), the poisoning of Sergei and Yulia Skripal in the United Kingdom (2018) and Alexei Navalny in Russia (2020), strongly renewing the importance of antidote development against these lethal substances. The current standard treatment against their effects relies on the use of small molecule-based oximes that can efficiently restore acetylcholinesterase (AChE) activity. Despite their efficacy in reactivating AChE, the action of drugs like 2-pralidoxime (2-PAM) is primarily limited to the peripheral nervous system (PNS) and, thus, provides no significant protection to the central nervous system (CNS). This lack of action in the CNS stems from their ionic nature that, on one end makes them very powerful reactivators and on the other renders them ineffective at crossing the Blood Brain Barrier (BBB) to reach the CNS. In this report, we describe the use of an iterative approach composed of parallel chemical and in silico syntheses, computational modeling, and a battery of detailed in vitro and in vivo assays that resulted in the identification of a promising, novel CNS-permeable oxime reactivator. Additional experiments to determine acute and chronic toxicity are ongoing.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2017

The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB. To fully assess the potential of this compound as an effective treatment for nerve agent poisoning, a comprehensive evaluation of its pharmacokinetic (PK) and biodistribution profiles was performed using both intravenous and intramuscular exposure routes. The ultra-sensitive technique of accelerator mass spectrometry was used to quantify the compound’s PK profile, tissue distribution, and brain/plasma ratio at four dose concentrations in guinea pigs. PK analysis revealed a rapid distribution of the oxime with a plasma t1/2 of ~1 hr. Kidney and liver had the highest concentrations per gram of tissue followed by lung, spleen, heart and brain for all dose concentrations tested. The Cmax in the brain ranged between 0.03-0.18% of the administered dose, and the brain-to-plasma ratio ranged from 0.04 at the 10 mg/kg dose to 0.18 at the 200 mg/kg dose demonstrating dose dependent differences in brain and plasma concentrations. In vitro studies show that both passive diffusion and active transport contribute little to RS194B traversal of the BBB. These results indicate that biodistribution is widespread, but very low quantities accumulate in the guinea pig brain, indicating this compound may not be suitable as a centrally active reactivator.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

Predicting a Drug’s Membrane Permeability: A Computational Model Validated With in Vitro Permeability Assay Data

Membrane permeability is a key property to consider during the drug design process, and particularly vital when dealing with small molecules that have intracellular targets as their efficacy highly depends on their ability to cross the membrane. In this work, we describe the use of umbrella sampling Molecular Dynamics (MD) computational modeling to comprehensively assess the passive permeability profile of a range of compounds through a lipid bilayer. The model was initially calibrated through in vitro validation studies employing a Parallel Artificial Membrane Permeability Assay (PAMPA). The model was subsequently evaluated for its quantitative prediction of permeability profiles for a series of custom synthesized and closely related compounds. The results exhibited substantially improved agreement with the PAMPA data, relative to alternative existing methods. Our work introduces a computational model that underwent progressive molding and fine-tuning as a result of its synergistic collaboration with numerous in vitro PAMPA permeability assays. The presented computational model introduces itself as a useful, predictive tool for permeability prediction.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2014

Mind racing: The influence of exercise on long-term memory consolidation

Over time, regular exercise can lower the risk for age-related decline in cognition. However, the immediate effects of exercise on memory consolidation in younger adults have not been fully investigated. As such, in two experiments, the effects of exercise were assessed on three different memory tasks. These included paired-associate learning, procedural learning and text memory. Results indicate that performance on procedural learning and situation model memory was increased with exercise, regardless of if participants exercised before or after encoding. No benefit of exercise was found for paired-associate learning. These findings suggest that intense exercise may benefit certain types of memory consolidation.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2013

Working memory, situation models, and synesthesia

Research on language comprehension suggests a strong relationship between working memory span measures and language comprehension. However, there is also evidence that this relationship weakens at higher levels of comprehension, such as the situation model level. The current study explored this relationship by comparing 10 grapheme–color synesthetes who have additional color experiences when they read words that begin with different letters and 48 normal controls on a number of tests of complex working memory capacity and processing at the situation model level. On all tests of working memory capacity, the synesthetes outperformed the controls. Importantly, there was no carryover benefit for the synesthetes for processing at the situation model level. This reinforces the idea that although some aspects of language comprehension are related to working memory span scores, this applies less directly to situation model levels. As a result, this suggests that theories of working memory must take into account this limitation, and the working memory processes that are involved in situation model construction and processing must be derived.

59 BASIC BIOLOGICAL SCIENCES↗