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Organophosphorus (OP) pesticides are still widely applied but pose a severe toxicological threat if misused. For in vivo detoxification, the application of hydrolytic enzymes potentially offers a promising treatment. A well-studied example is the phosphotriesterase of Brevundimonas diminuta (BdPTE). Whereas wild-type BdPTE can hydrolyse pesticides like paraoxon, chlorpyrifos-oxon and mevinphos with high catalytic efficiencies, kcat/KM >2 × 107 M-1 min-1, degradation of malaoxon is unsatisfactory (kcat/KM ≈ 1 × 104 M-1 min-1). Here, we report the rational engineering of BdPTE mutants with improved properties and their efficient production in Escherichia coli. As result, the mutant BdPTE(VRNVVLARY) exhibits 37-fold faster malaoxon hydrolysis (kcat/KM = 4.6 × 105 M-1 min-1), together with enhanced expression yield, improved thermal stability and reduced susceptibility to oxidation. Therefore, this BdPTE mutant constitutes a powerful candidate to develop a biocatalytic antidote for the detoxification of this common pesticide metabolite as well as related OP compounds., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The lack of a human immunodeficiency virus (HIV) cure has heightened interest in immunotherapy. As such, type I interferons (IFNs), in particular, IFN alpha (IFN-α), have gained renewed attention. However, HIV pathogenesis is driven by sustained IFN-mediated immune activation, and the use of IFNs is rather controversial. The following questions therein remain: (i) which IFN-α subtype to use, (ii) at which regimen, and (iii) at what time point in HIV infection it might be beneficial. Here, we used IFN-α14 modified by PASylation for its long half-life in vivo to eventually treat HIV infection. We defined the IFN dosing regimen based on the maximum increase in interferon-stimulated gene (ISG) expression 6 h after its administration and a return to baseline of ubiquitin-specific protease 18 (USP18) prior to the next dose. Notably, USP18 is the major negative regulator of type I IFN signaling. HIV infection resulted in increased ISG expression levels in humanized mice. Intriguingly, high baseline ISG levels correlated with lower HIV load. No effect was observed on HIV replication when PASylated IFN-α14 was administered in the chronic phase. However, combined antiretroviral therapy (cART) restored responsiveness to IFN, and PASylated IFN-α14 administered during analytical cART interruption resulted in a transiently lower HIV burden than in the mock-treated mice. In conclusion, cART-mediated HIV suppression restored transient IFN responsiveness and provided a potential window for immunoenhancing therapies in the context of analytical cART interruption. IMPORTANCE cART is highly efficient in suppressing HIV replication in HIV-infected patients and has resulted in a dramatic reduction in morbidity and mortality in HIV-infected people, yet it does not cure HIV infection. In addition, cART has several disadvantages. Thus, the HIV research community is exploring novel ways to control HIV infection for longer periods without cART. Here, we explored novel, long-acting IFN-α14 for its efficacy to control HIV replication in HIV-infected humanized mice. We found that IFN-α14 had no effect on chronic HIV infection. However, when mice were treated first with cART, we observed a transiently restored responsiveness to INF and a transiently lower HIV burden after stopping cART. These data emphasize (i) the value of cART-mediated HIV suppression and immune reconstitution in creating a window of opportunity for exploring novel immunotherapies, (ii) the potential of IFNs for constraining HIV, and (iii) the value of humanized mice for exploring novel immunotherapies.

Fluctuation electron microscopy of bulk metallic glasses of CuZrAl(Ag) demonstrates that medium-range order is sensitive to minor compositional changes. By analyzing nanodiffraction patterns medium-range order is detected with crystal-like motifs based on the B2 CuZr structure and its distorted structures resembling the martensitic ones. This result demonstrates some structural homology between the metallic glass and its high temperature crystalline phase. The amount of medium-range order seems slightly affected with increasing Ag concentration (0, 2, 5 at.%) but the structural motifs of the medium-range ordered clusters become more diverse at the highest Ag concentration. The decrease of dominant clusters is consistent with the destabilization of the B2 structure measured by calorimetry and accounts for the increased glass-forming ability.

Stormwater is one of the last major untapped urban water resources that can be exploited as an alternative water source in Australia. The information in the current Australian Guidelines for Water Recycling relating to stormwater harvesting and reuse only emphasises on a limited number of stormwater quality parameters. In order to supply stormwater as a source for higher value end-uses, a more comprehensive assessment on the potential public health risks has to be undertaken. Owing to the stochastic variations in rainfall, catchment hydrology and also the types of non-point pollution sources that can provide contaminants relating to different anthropogenic activities and catchment land uses, the characterisation of public health risks in stormwater is complex, tedious and not always possible through the conventional detection and analytical methods. In this study, a holistic approach was undertaken to assess the potential public health risks in urban stormwater samples from a medium-density residential catchment. A combined chemical-toxicological assessment was used to characterise the potential health risks arising from chemical contaminants, while a combination of standard culture methods and quantitative polymerase chain reaction (qPCR) methods was used for detection and quantification of faecal indicator bacteria (FIB) and pathogens in urban stormwater. Results showed that the concentration of chemical contaminants and associated toxicity were relatively low when benchmarked against other alternative water sources such as recycled wastewater. However, the concentrations of heavy metals particularly cadmium and lead have exceeded the Australian guideline values, indicating potential public health risks. Also, high numbers of FIB were detected in urban stormwater samples obtained from wet weather events. In addition, qPCR detection of human-related pathogens suggested there are frequent sewage ingressions into the urban stormwater runoff during wet weather events. Further water quality monitoring study will be conducted at different contrasting urban catchments in order to undertake a more comprehensive public health risk assessment for urban stormwater.

A screening-level aquatic environmental risk assessment for macrocyclic fragrance materials using a "group approach" is presented using data for 30 macrocyclic fragrance ingredients. In this group approach, conservative estimates of environmental exposure and ecotoxicological effects thresholds for compounds within two subgroups (15 macrocyclic ketones and 15 macrocyclic lactones/lactides) were used to estimate the aquatic ecological risk potential for these subgroups. It is reasonable to separate these fragrance materials into the two subgroups based on the likely metabolic pathway required for biodegradation and on expected different ecotoxicological modes of action. The current volumes of use for the macrocyclic ketones in both Europe and North America ranges from <1 (low kg quantities) to no greater than 50 metric tonnes in either region and for macrocyclic lactones/lactides the volume of use range for both regions is <1 to no greater than 1000 metric tonnes in any one region. Based on these regional tonnages, biodegradability of these two subgroups of materials, and minimal in stream dilution (3:1), the conservatively predicted exposure concentrations for macrocyclic ketones would range from <0.01 to 0.05 μg/L in Europe and from <0.01 to 0.03 μg/L in North America. For macrocyclic lactones/lactides, the concentration within the mixing zone would range from <0.01 to 0.7 μg/L in Europe and from <0.01 to 1.0 μg/L in North America. The PNECs derived for the macrocyclic ketones is 0.22 μg/L and for macrocyclic lactones/lactides is 2.7 μg/L. The results of this screening-level aquatic ecological risk assessment indicate that at their current tonnage, often referred to as volumes of use, macrocyclic fragrance materials in Europe and North America, pose a negligible risk to aquatic biota; with no PEC/PNEC ratio exceeding 1 for any material in any subgroup., (Copyright © 2011 Elsevier Inc. All rights reserved.)

In the aquatic environment and in engineered water treatment systems, organic contaminants can undergo oxidative and photochemical transformations. For an overall risk assessment, the toxicity of the resulting transformation products has to be investigated. In this study, the toxicity of degradation products of diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) formed during its degradation by four (photo)oxidative processes (direct phototransformation, triplet-induced photosensitized oxidation, oxidation by hydroxyl radicals and ozone) was investigated in buffered aqueous solution. The toxicity was evaluated using the combined algae test with Pseudokirchneriella subcapitata that determines both, specific inhibition of photosynthesis and inhibition of the growth rate. The comparison between evolution of toxicity and degradation kinetics indicated that the toxicity during all studied processes was caused predominantly by diuron whereas the formation of degradation products did not contribute to the mixture toxicity. This implies that, if any more toxic transformation products than diuron were formed, their concentration was not sufficiently high to affect the mixture toxicity, which was dominated by the parent compound diuron. On this account, no further studies on identification of degradation products and their toxicity are needed. This study presents an example of a systematic and simple first tier method to assess the toxicity of degradation products., (2010 Elsevier B.V. All rights reserved.)