Hydrolysis of genotoxic methyl-substituted oxiranes : Experimental kinetic and semiempirical studies

The kinetics of acid-catalyzed hydrolysis of seven methylated aliphatic epoxides - R1R2C(O)CR3R4 (A: R1=R2=R3=R4=H; B: R1=R2=R3=H, R4=Me; C: R1=R2=H, R3=R4=Me; D: R1=R3=H, R2=R4=Me(trans); E: R1=R3=H, R2=R4=Me(cis); F: R1=R3=R4=Me, R2=H; G: R1=R2=R3=R4=Me) - has been studied at 36 ± 1.5°C. Compounds with two methyl groups at the same carbon atom of the oxirane ring exhibit highest rate constants (k(eff) in reciprocal molar concentration per second: 11.0 ± 1.3 for C, 10.7 ± 2.1 for F, and 8.7 ± 0.7 for G as opposed to 0.124 ± 0.003 for B, 0.305 ± 0.003 for D, and 0.635 ± 0.036 for E). Ethylene oxide (A) displays the lowest rate of hydrolysis (0.027 M-1 s-1). The results are consistent with literature data available for compounds A, B, and C. To model the reactivities we have employed quantum chemical calculations (MNDO, AM1, PM3, and MINDO/3) of the main reaction species. There is a correlation of the logarithm k(eff) with the total energy of epoxide ring opening. The best correlation coefficients (r) were obtained using the AM1 and MNDO methods (0.966 and 0.957, respectively). However, unlike MNDO, AM1 predicts approximately zero energy barriers for the oxirane ring opening of compounds B, C, E and G, which is not consistent with published kinetic data. Thus, the MNDO method provides a preferential means of modeling the acidic hydrolysis of the series of methylated oxiranes. The general ranking of mutagenicity in vitro, A > B > C, is in line with the concept that this sequence also gradually leaves the expoxide reactivity optimal for genotoxicity toward reactivities leading to higher biological detoxifications.

Genetic susceptibility to environmental toxicants : the interface between human and experimental studies in the development of new toxicological concepts

The growing knowledge of the genetic polymorphisms of enzymes metabolising xenobiotics in humans and their connections with individual susceptibility towards toxicants has created new and important interfaces between human epidemiology and experimental toxicology. The results of molecular epidemiological studies may provide new hypotheses and concepts, which call for experimental verification, and experimental concepts may obtain further proof by molecular epidemiological studies. If applied diligently, these possibilities may be combined to lead to new strategies of human-oriented toxicological research. This overview will present some outstanding examples for such strategies taken from the practically very important field of occupational toxicology. The main focus is placed on the effects of enzyme polymorphisms of the xenobiotic metabolism in association with the induction of bladder cancer and renal cell cancer after exposure to occupational chemicals. Also, smoking and induction of head and neck squamous cell cancer are considered.

Species differences in acrylonitrile metabolism and toxicity between experimental animals and humans based on observations in human accidental poisonings

The high acute toxicity of acrylonitrile may be a result of its intrinsic biological reactivity or of its metabolite cyanide. Intravenous N-acetylcysteine has been recommended for treatment of accidental intoxications in acrylonitrile workers, but such recommendations vary internationally. Acrylonitrile is metabolized in humans and experimental animals via two competing pathways; the glutathione-dependent pathway is considered to represent an avenue of detoxication whilst the oxidative pathway leads to a genotoxic epoxide, cyanoethylene oxide, and to elimination of cyanide. Cases of acute acrylonitrile overexposure or intoxication have occurred within persons having industrial contact with acrylonitrile; the route of exposure was by inhalation and/or by skin contact. The combined observations lead to the conclusion of a much higher impact of the oxidative metabolism of acrylonitrile in humans than in rodents. This is confirmed by differences in the clinical picture of acute life-threatening intoxications in both species, as well as by differential efficacies of antidotes. A combination of N-acetylcysteine with sodium thiosulfate seems an appropriate measure for antidote therapy of acute acrylonitrile intoxications. Clinical observations also highlight the practical importance of human individual susceptibility differences. Furthermore, differential adduct monitoring, assessing protein adducts with different rates of decay, enables the development of more elaborated biological monitoring strategies for the surveillance of workers with potential acrylonitrile contact.

Model choice problems using approximate Bayesian computation with applications to pathogen transmission data sets

Analytically or computationally intractable likelihood functions can arise in complex statistical inferential problems making them inaccessible to standard Bayesian inferential methods. Approximate Bayesian computation (ABC) methods address such inferential problems by replacing direct likelihood evaluations with repeated sampling from the model. ABC methods have been predominantly applied to parameter estimation problems and less to model choice problems due to the added difficulty of handling multiple model spaces. The ABC algorithm proposed here addresses model choice problems by extending Fearnhead and Prangle (2012, Journal of the Royal Statistical Society, Series B 74, 1–28) where the posterior mean of the model parameters estimated through regression formed the summary statistics used in the discrepancy measure. An additional stepwise multinomial logistic regression is performed on the model indicator variable in the regression step and the estimated model probabilities are incorporated into the set of summary statistics for model choice purposes. A reversible jump Markov chain Monte Carlo step is also included in the algorithm to increase model diversity for thorough exploration of the model space. This algorithm was applied to a validating example to demonstrate the robustness of the algorithm across a wide range of true model probabilities. Its subsequent use in three pathogen transmission examples of varying complexity illustrates the utility of the algorithm in inferring preference of particular transmission models for the pathogens.

Design and experimental testing of air slab caps which convert commercial electron diodes into dual purpose, correction-free diodes for small field dosimetry

Purpose Two diodes which do not require correction factors for small field relative output measurements are designed and validated using experimental methodology. This was achieved by adding an air layer above the active volume of the diode detectors, which canceled out the increase in response of the diodes in small fields relative to standard field sizes. Methods Due to the increased density of silicon and other components within a diode, additional electrons are created. In very small fields, a very small air gap acts as an effective filter of electrons with a high angle of incidence. The aim was to design a diode that balanced these perturbations to give a response similar to a water-only geometry. Three thicknesses of air were placed at the proximal end of a PTW 60017 electron diode (PTWe) using an adjustable “air cap”. A set of output ratios (ORfclin Det ) for square field sizes of side length down to 5 mm was measured using each air thickness and compared to ORfclin Det measured using an IBA stereotactic field diode (SFD). k fclin, f msr Qclin,Qmsr was transferred from the SFD to the PTWe diode and plotted as a function of air gap thickness for each field size. This enabled the optimal air gap thickness to be obtained by observing which thickness of air was required such that k fclin, f msr Qclin,Qmsr was equal to 1.00 at all field sizes. A similar procedure was used to find the optimal air thickness required to make a modified Sun Nuclear EDGE detector (EDGEe) which s “correction-free” in small field relative dosimetry. In addition, the feasibility of experimentally transferring k fclin, f msr Qclin,Qmsr values from the SFD to unknown diodes was tested by comparing the experimentally transferred k fclin, f msr Qclin,Qmsr values for unmodified PTWe and EDGEe diodes to Monte Carlo simulated values. Results 1.0 mm of air was required to make the PTWe diode correction-free. This modified diode (PTWeair) produced output factors equivalent to those in water at all field sizes (5–50 mm). The optimal air thickness required for the EDGEe diode was found to be 0.6 mm. The modified diode (EDGEeair) produced output factors equivalent to those in water, except at field sizes of 8 and 10 mm where it measured approximately 2% greater than the relative dose to water. The experimentally calculated k fclin, f msr Qclin,Qmsr for both the PTWe and the EDGEe diodes (without air) matched Monte Carlo simulated results, thus proving that it is feasible to transfer k fclin, f msr Qclin,Qmsr from one commercially available detector to another using experimental methods and the recommended experimental setup. Conclusions It is possible to create a diode which does not require corrections for small field output factor measurements. This has been performed and verified experimentally. The ability of a detector to be “correction-free” depends strongly on its design and composition. A nonwater-equivalent detector can only be “correction-free” if competing perturbations of the beam cancel out at all field sizes. This should not be confused with true water equivalency of a detector.

Porohyperelastic finite element model for the kangaroo humeral head cartilage based on experimental study and the consolidation theory

Solid-extracellular fluid interaction is believed to play an important role in the strain-rate dependent mechanical behaviors of shoulder articular cartilages. It is believed that the kangaroo shoulder joint is anatomically and biomechanically similar to human shoulder joint and it is easy to get in Australia. Therefore, the kangaroo humeral head cartilage was used as the suitable tissue for the study in this paper. Indentation tests from quasi-static (10-4/sec) to moderately high strain-rate (10-2/sec) on kangaroo humeral head cartilage tissues were conduced to investigate the strain-rate dependent behaviors. A finite element (FE) model was then developed, in which cartilage was conceptualized as a porous solid matrix filled with incompressible fluids. In this model, the solid matrix was modeled as an isotropic hyperelastic material and the percolating fluid follows Darcy’s law. Using inverse FE procedure, the constitutive parameters related to stiffness, compressibility of the solid matrix and permeability were obtained from the experimental results. The effect of solid-extracellular fluid interaction and drag force (the resistance to fluid movement) on strain-rate dependent behavior was investigated by comparing the influence of constant, strain dependent and strain-rate dependent permeability on FE model prediction. The newly developed porohyperelastic cartilage model with the inclusion of strain-rate dependent permeability was found to be able to predict the strain-rate dependent behaviors of cartilages.

Regulating supply-chains to address the occupational health and safety problems associated with precarious employment: The case of home-based clothing workers in Australia

Over the past 20 years the labour market, workforce and work organisation of most if not all industrialised countries have been significantly refashioned by the increased use of more flexible work arrangements, variously labelled as precarious employment or contingent work. There is now a substantial and growing body of international evidence that many of these arrangements are associated with a significant deterioration in occupational health and safety (OHS), using a range of measures such as injury rates, disease, hazard exposures and work-related stress. Moreover, there is an emerging body of evidence that these arrangements pose particular problems for conventional regulatory regimes. Recognition of these problems has aroused the concern of policy makers - especially in Europe, North America and Australia - and a number of responses have been adopted in terms of modifying legislation, producing new guidance material and codes of practice and revised enforcement practices. This article describes one such in itiative in Australia with regard to home-based clothing workers. The regulatory strategy developed in one Australian jurisdiction (and now being ‘exported’ into others) seeks to counter this process via contractual tracking mechanisms to follow the work, tie in liability and shift overarching legal responsibility to the top of the supply chain. The process also entails the integration of minimum standards relating to wages, hours and working conditions; OHS and access to workers’ compensation. While home-based clothing manufacture represents a very old type of ‘flexible’ work arrangement, it is one that regulators have found especially difficult to address. Further, the elaborate multi-tiered subcont racting and diffuse work locations found in this industry are also characteristic of newer forms of contingent work in other industries (such as some telework) and the regulatory challenges they pose (such as the tendency of elaborate supply chains to attenuate and fracture statutory responsibilities, at least in terms of the attitudes and behaviour of those involved).

Experimental investigations of improved dielectric condition monitoring methods on transformer oil-paper insulation system

Frequency Domain Spectroscopy (FDS) is successfully being used to assess the insulation condition of oil filled power transformers. However, it has to date only been implemented on de-energized transformers, which requires the transformers to be shut down for an extended period which can result in significant costs. To solve this issue, a method of implementing FDS under energized condition is proposed here. A chirp excitation waveform is used to replace the conventional sinusoidal waveform to reduce the measurement time in this method. Investigation of the dielectric response under the influence of a high voltage stress at power frequency is reported based on experimental results. To further understand the insulation ageing process, the geometric capacitance effect is removed to enhance the detection of the ageing signature. This enhancement enables the imaginary part of admittance to be used as a new indicator to assess the ageing status of the insulation.

Automated power semiconductor switching performance feature extraction from experimental double-pulse waveform data

Double-pulse tests are commonly used as a method for assessing the switching performance of power semiconductor switches in a clamped inductive switching application. Data generated from these tests are typically in the form of sampled waveform data captured using an oscilloscope. In cases where it is of interest to explore a multi-dimensional parameter space and corresponding result space it is necessary to reduce the data into key performance metrics via feature extraction. This paper presents techniques for the extraction of switching performance metrics from sampled double-pulse waveform data. The reported techniques are applied to experimental data from characterisation of a cascode gate drive circuit applied to power MOSFETs.

Significance of drying periods on nitrate removal in experimental biofilters

Nitrogen is an important nutrient that can impact the quality of aquatic environments when present in high concentration. Even though low concentration levels of ammonium-nitrogen have been observed in laboratory studies in bioretention basins, poor removal or even the production of nitrate-nitrogen within the filter is often recorded in such studies. Ten Perspex biofilter columns of 94 mm (internal diameter) were packed with a filter layer, transition layer and a gravel layer. While the filter layer was packed to a height of 800 mm, transition and gravel layers were packed to a composite height of 220 mm and operated with simulated stormwater in the laboratory. The filter layer contained 8% organic material by weight. A free board of 350 mm provided detention storage and head to facilitate infiltration. The columns were operated with different antecedent dry days (0 d to 21 d) and constant inflow concentration at a feed rate of 100 mL/min. Samples were collected from the outflow at different time intervals, between 2 min and 150 min from the start of outflow, and were tested for nitrate-nitrogen and total organic carbon. Washoff of organic carbon from the filter layer was observed to occur for 30 min of outflow. This indicated washoff of organic carbon from the filter itself. At the same time, a very low concentration of nitrate-nitrogen was recorded at the beginning of the outflow, indicating the effective removal of nitrate-nitrogen. We conclude that the removal of nitrate-nitrogen is insignificant during the wetting phase of a rainfall event and the process of denitrification is more pronounced during the drying phase of a rainfall event. Thus intermittent wetting and drying is crucial for the removal of nitrate-nitrogen in bioretention basins.

A distributed computing framework for all-to-all comparison problems

Distributed computation and storage have been widely used for processing of big data sets. For many big data problems, with the size of data growing rapidly, the distribution of computing tasks and related data can affect the performance of the computing system greatly. In this paper, a distributed computing framework is presented for high performance computing of All-to-All Comparison Problems. A data distribution strategy is embedded in the framework for reduced storage space and balanced computing load. Experiments are conducted to demonstrate the effectiveness of the developed approach. They have shown that about 88% of the ideal performance capacity have be achieved in multiple machines through using the approach presented in this paper.

Sexual selection in true fruit flies (Diptera: Tephritidae) : transcriptome and experimental evidences for phytochemicals increasing male competitive ability

In male tephritid fruit flies of the genus Bactrocera, feeding on secondary plant compounds (sensu lato male lures = methyl eugenol, raspberry ketone and zingerone) increases male mating success. Ingested male lures alter the male pheromonal blend, normally making it more attractive to females and this is considered the primary mechanism for the enhanced mating success. However, the male lures raspberry ketone and zingerone are known, across a diverse range of other organisms, to be involved in increasing energy metabolism. If this also occurs in Bactrocera, then this may represent an additional benefit to males as courtship is metabolically expensive and lure feeding may increase a fly's short-term energy. We tested this hypothesis by performing comparative RNA-seq analysis between zingerone-fed and unfed males of Bactrocera tryoni. We also carried out behavioural assays with zingerone- and cuelure-fed males to test whether they became more active. RNA-seq analysis revealed, in zingerone-fed flies, up-regulation of 3183 genes with homologues transcripts to those known to regulate intermale aggression, pheromone synthesis, mating and accessory gland proteins, along with significant enrichment of several energy metabolic pathways and gene ontology terms. Behavioural assays show significant increases in locomotor activity, weight reduction and successful mating after mounting; all direct/indirect measures of increased activity. These results suggest that feeding on lures leads to complex physiological changes, which result in more competitive males. These results do not negate the pheromone effect, but do strongly suggest that the phytochemical-induced sexual selection is governed by both female preference and male competitive mechanisms.

Experimental study of load-bearing cold-formed steel walls exposed to realistic design fires

This paper presents the details of full scale fire tests of LSF wall panels conducted using realistic fire time-temperature curves. Tests included eight LSF wall specimens of various configurations exposed to both parametric design and natural fire curves. Details of the fire test set-up, test procedure and the results including the measured time-temperature and deformation curves of LSF wall panels are presented along with wall stud failure modes and times. This paper also compares the structural and thermal behavioural characteristics of LSF wall studs with those based on the standard time-temperature curve. Finally, the stud failure times and temperatures are summarized for both standard and realistic design fire curves. This study provides the necessary test data to validate the numerical models of LSF wall panels and to undertake a detailed study into the structural and thermal performance of LSF wall panels exposed to realistic design fire curves.

Agency problems of corporate philanthropy

Evaluating agency theory and optimal contracting theory views of corporate philanthropy, we find that as corporate giving increases, shareholders reduce their valuation of firm cash holdings. Dividend increases following the 2003 Tax Reform Act are associated with reduced corporate giving. Using a natural experiment, we find that corporate giving is positively (negatively) associated with CEO charity preferences (CEO shareholdings and corporate governance quality). Evidence from CEO-affiliated charity donations, market reactions to insider-affiliated donations, its relation to CEO compensation, and firm contributions to director-affiliated charities indicates that corporate donations advance CEO interests and suggests misuses of corporate resources that reduce firm value.

Approaching wicked problems through design thinking

This paper explores possible ways in which design thinking can be used to understand the issues involved in wicked problems. Following brief reviews of both the design thinking and wicked problems literature, we offer a synthesis of these two areas. This paper distinguishes the connections of the various thinking styles inherent in design thinking methodologies and approaches to the phases of wicked problems. We create links between design thinking and cognitive mechanisms such as thinking styles, simple heuristics and schemas that can deepen understanding and effective decision making in the wicked problems in our complex environments.