Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors—What Some May Have Forgotten or Would Rather Forget?

Hydroxamate‐based histone deacetylase inhibitors (HDACIs) have been approved as therapeutic agents by the US Food and Drug Administration for use in oncology applications. While the potential utility of such HDACIs in other areas of medicinal chemistry is tremendous, there are significant concerns that “pan‐HDAC inhibitors” may be too broadly acting and/or toxic for clinical use beyond oncology. In addition to the isozyme selectivity challenge, the potential mutagenicity of hydroxamate‐containing HDAC inhibitors represents a major hindrance in their application to other therapeutic areas. Herein we report on the mutagenicity of known hydroxamates, discuss the mechanisms responsible for their genotoxicity, and review some of the current alternatives to hydroxamates. We conclude that the hydroxamate group, while providing high‐potency HDACIs, is not necessarily the best zinc‐binding group for HDACI drug discovery.     

Size-dependent deposition of inhaled nanoparticles in the rat respiratory tract using a new nose-only exposure system

Concerns about the potential health effects of exposure to nanomaterials have led to a growing number of in vivo inhalation toxicity studies using nanoparticle aerosols. Estimates of aerosol deposition within the respiratory tract are important for these studies to enable: (a) the interpretation of the results, in particular, the evaluation of dose–response relationships; (b) comparison with the results of other related studies; and (c) the extrapolation of results from animal models to human. Unfortunately, only a limited number of studies have been undertaken to investigate respiratory tract deposition efficiencies for nano-sized aerosol particles. This is of particular importance as deposition efficiencies are predicted to vary significantly over the nano-size range for some elements of the respiratory tract. In this study, female Wistar-Kyoto rats were exposed in a new design nose-only inhalation exposure system to spark generated radioactive iridium-192 nanoparticle aerosols of four particle sizes chosen to cover the majority of the nano-size range (nominal sizes: 10, 15, 35, and 75 nm). The content of iridium-192 in the lung, head, gastrointestinal tract, and various other organs and tissues was measured. Aerosol deposition efficiencies in the whole respiratory tract and components (head airways, lung, alveolar region, and tracheobronchial region) were estimated and compared with the predictions of the Multiple Path Particle Dosimetry (MPPD) model (v2.11). The experimentally derived deposition efficiencies were broadly consistent with, but typically higher than, model predictions and the results of comparable studies in the literature.

Copyright © 2016 American Association for Aerosol Research     

Environmental Risks Associated with Beneficial End Uses of Mine Lakes in Southwestern Australia

Abstract  Lakes develop when pits from open cut mines are left to fill with groundwater. In recent years, mining companies, mining communities, and regulatory agencies have begun to consider potential beneficial end uses for mine lakes. Beneficial end uses are unlikely to be without environmental impacts, however, and a proper consideration of the total benefit to the community should consider them. This paper briefly reviews potential beneficial end uses and possible environmental impacts that might arise with them for mine lakes in the Collie Basin, a coal mining region in Western Australia. We identified eight distinct, but not necessarily incompatible, end uses from a search of the literature on mine lakes throughout the world: recreation and tourism, wildlife conservation, aquaculture, irrigation, livestock water, potable water, industrial water, and chemical extraction. Recreation, conservation, and possibly aquaculture use the mine lake directly, whereas the other end uses utilise extracted water. All end uses have the potential to have environmental effects, with the most common being an actual or perceived impact on human health and safety. A semi-quantitative risk assessment, using published literature sources, identified wildlife conservation as the end use with the least environmental risk, and irrigation as the end use with the greatest environmental risk. Such risks need to be balanced against economic and social benefits. There is an urgent need for a regulatory framework to address mine lake options.     

Reinforcing thermosets using crystalline desoxyanisoin structures

This article presents results on the potential of using crystalline flame retardants for thermoset reinforcement. The approach involves introducing reinforcement in thermosetting polymers through low molecular weight crystallizable additives. Thermally induced phase separation (TIPS) and crystallization of desoxyanisoin in diglycidylether of bisphenol‐A (DGEBA) epoxy monomer were investigated. Small angle light scattering and polarized optical microscopy were utilized to monitor phase separation and the crystallization of desoxyanisoin in DGEBA at different concentrations. Reaction induced phase separation (RIPS) with polyetheramine was carried out under isothermal and temperature gradient curing conditions. Altering the cure schedule resulted in a rich range of morphologies due to the competition between TIPS and RIPS. During isothermal cure, straight fiber‐like anisotropic crystals on a centimeter length scale developed. In contrast, thermal gradients frustrated the crystal growth and resulted in complex and rich morphologies. Desoxyanisoin provided marginal epoxy thermoset reinforcement at 10 vol %. However, the additive did not increase the thermoset flammability retardancy. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 39853.     

Manipulating the Level of Sensorimotor Stimulation during LI-rTMS Can Improve Visual Circuit Reorganisation in Adult Ephrin-A2A5-/- Mice

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has the potential to treat a variety of neurologic and psychiatric disorders. The extent of rTMS-induced neuroplasticity may be dependent on a subject’s brain state at the time of stimulation. Chronic low intensity rTMS (LI-rTMS) has previously been shown to induce beneficial structural and functional reorganisation within the abnormal visual circuits of ephrin-A2A5^-/- mice in ambient lighting. Here, we administered chronic LI-rTMS in adult ephrin-A2A5^-/- mice either in a dark environment or concurrently with voluntary locomotion. One day after the last stimulation session, optokinetic responses were assessed and fluorescent tracers were injected to map corticotectal and geniculocortical projections. We found that LI-rTMS in either treatment condition refined the geniculocortical map. Corticotectal projections were improved in locomotion+LI-rTMS subjects, but not in dark + LI-rTMS and sham groups. Visuomotor behaviour was not improved in any condition. Our results suggest that the beneficial reorganisation of abnormal visual circuits by rTMS can be significantly influenced by simultaneous, ambient visual input and is enhanced by concomitant physical exercise. Furthermore, the observed pathway-specific effects suggest that regional molecular changes and/or the relative proximity of terminals to the induced electric fields influence the outcomes of LI-rTMS on abnormal circuitry.     

Global synchronisation in Linda

The paper examines the ‘Distributed Summation’ problem, and its solution in Linda. A number of problems with the current set of primitives are examined, and a new primitive, collect, is proposed.     

A relationship between software coverage metrics and reliability

Software engineers have tacitly assumed that there exists a link between coverage and reliability. An argument is presented which leads to an inverse logarithmic relationship which depends upon the structure of the software and on a parameter called the strength of the coverage metric. The relationship is developed by considering reliability as a function of an idealized coverage metric and then interpreting the result for a range of actual coverage metrics.     

Effect of processing conditions on wood and glass fiber length attrition during twin screw composite compounding

In this study, we compare the effect of twin-screw extrusion processing on the attrition of wood fibers (WFs) with glass fiber. The effects of process variables and screw design on fiber length were investigated by performing a range of dead-stop experiments where the extruder was stopped, opened-up, and compound removed from the screw elements. Fibers, chemically extracted from the polypropylene matrix, were analyzed for length and width using a commercial fiber analyzer. It was found that WF length attrition and composite properties were less affected by screw design and twin-screw processing conditions (feed rate and screw speed) than glass fiber. Length weighted fiber length and X50 length (a measure used in particle size analysis) were equally correlated with process conditions and composite performance for both fiber types. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48551.