Isomeric Carborane Neuromuscular Blocking Agents

We synthesized a family of neuromuscular blocking agents (NMB) based on decamethonium, but containing a carborane cluster in the methylene chain between the two quaternary ammonium groups. The carborane cluster isomers o-NMB, m-NMB, and p-NMB were tested in animals for neuromuscular block and compared with agents used clinically: rocuronium and decamethonium. All three isomers caused reversible muscle weakness in mice as determined by grip strength and inverted screen tests, with a potency rank of p-NMB > rocuronium > decamethonium > m-NMB > o-NMB. The mechanism of action of the compounds was determined by using the in vitro rat phrenic nerve hemi-diaphragm preparation and electrophysiologic measurements in cells. Neostigmine reversed hemi-diaphragm weakness caused by the three isomers and rocuronium, but not succinylcholine. In electrophysiologic recordings of currents through acetylcholine receptor channels, the carborane compounds did not activate channel activity but did inhibit channel activation by acetylcholine. These results demonstrate that the carborane neuromuscular blocking agents are non-depolarizers in contrast to the depolarizing action of the parent compound.     

Development and validation of a crisis self‐efficacy index

This study develops a crisis self‐efficacy index to provide a tool for crisis communication researchers and practitioners to understand behavioural aspects of crisis response better. Evaluations of public's crisis self‐efficacy using this index inform strategic message development to protect the public and minimize crisis damages by identifying the public/s most in need of self‐efficacy enhancing interventions. The index also provides practitioners a useful longitudinal index to evaluate progress in crisis preparedness programs and track changes in efficacy. A four‐stage survey index development process using structural equation modelling identifies four underlying constructs of crisis self‐efficacy: action, preventive, achievement and uncertainty management.     

Challenges and new methods for designing reliability experiments

Abstract

Engineers use reliability experiments to determine the factors that drive product reliability, build robust products, and predict reliability under use conditions. This article uses recent testing of a howitzer to illustrate the challenges in designing reliability experiments for complex, repairable systems. We review research in complex system reliability models, failure-time experiments, and experimental design principles. We highlight the need for reliability experiments that account for various intended uses and environments. We leverage lessons learned from current research and propose methods for designing an experiment for a complex, repairable system.     

Impact of defects on the decomposition of chemical warfare agent simulants in Zr-based metal organic frameworks

Metal organic frameworks (MOFs) containing zirconium secondary building units (SBUs) in UiO-67 and related MOFs, are highly active for neutralizing both the chemical warfare agents and simulants, such as dimethyl methylphosphonate (DMMP). However, two recent publications gave conflicting reports of DMMP reaction with UiO-67 under ultra high vacuum (UHV) conditions, with one reporting chemisorption and reaction (Wang et al., J Phys Chem C, 2017, 121, 11261–11272) and the other reporting only physisorption and reversible desorption (Ruffley et al., J Phys Chem C, 2019, 123, 19748–19758) from very similar temperature programmed desorption experiments. We show that the discrepancy between these experiments may be explained by different levels of missing linker defects in the UiO-67 samples. We present density functional theory calculations showing that SBU sites having two-adjacent missing linkers exhibit reaction barriers that are about 30 kJ/mol lower than SBU sites having a single missing linker. We also show that topology of the undercoordinated sites plays an important role in the reaction barrier under UHV conditions.     

Effects of feed composition,protein denaturation and storage of milk serum protein/lactose powders on lactosylation

During whey powder production, the feed is subjected to several heat treatments which can cause lactosylation of proteins. In this study, lactosylation of whey proteins was evaluated in spray-dried powders before and after storage by varying the native protein fraction as well as the serum protein/lactose ratio in the powders. The lactosylation of native α-lactalbumin and β-lactoglobulin in the powders before storage was not affected to a large extent by the protein denaturation or if the feed had been heat treated in a high or low lactose environment. After storage (relative humidity of 23.5%, 30 °C, 25 days), the kinetic of lactosylation tended to increase with increasing native protein fraction and bulk protein content in the powders. An explanation could be that proteins dissolved in the lactose glassy structure might have a lower reactivity, while proteins present in the protein glassy structure with dissolved lactose may display higher lactosylation reactivity.     

Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.