Background and purpose: Carboxylesterases (CEs) metabolize a wide range of xenobiotic substrates including heroin, cocaine, meperidine and the anticancer agent CPT‐11. In this study, we have ...purified to homogeneity human liver and intestinal CEs and compared their ability with hydrolyse heroin, cocaine and CPT‐11.
Experimental approach: The hydrolysis of heroin and cocaine by recombinant human CEs was evaluated and the kinetic parameters determined. In addition, microsomal samples prepared from these tissues were subjected to chromatographic separation, and substrate hydrolysis and amounts of different CEs were determined.
Key results: In contrast to previous reports, cocaine was not hydrolysed by the human liver CE, hCE1 (CES1), either as highly active recombinant protein or as CEs isolated from human liver or intestinal extracts. These results correlated well with computer‐assisted molecular modelling studies that suggested that hydrolysis of cocaine by hCE1 (CES1), would be unlikely to occur. However, cocaine, heroin and CPT‐11 were all substrates for the intestinal CE, hiCE (CES2), as determined using both the recombinant protein and the tissue fractions. Again, these data were in agreement with the modelling results.
Conclusions and implications: These results indicate that the human liver CE is unlikely to play a role in the metabolism of cocaine and that hydrolysis of this substrate by this class of enzymes is via the human intestinal protein hiCE (CES2). In addition, because no enzyme inhibition is observed at high cocaine concentrations, potentially this route of hydrolysis is important in individuals who overdose on this agent.
Research and innovation is key to delivering UK Government's civil nuclear energy policy, in particular to accelerate reduction in the hazard, timescale and cost of legacy decommissioning and ...geological disposal of radioactive wastes. To address this challenge, a national centre of excellence, the HADES Facility, has been established to support research and innovation in High Activity Decommissioning Engineering & Science, as part of the wider network of UK National Nuclear User Facilities. Herein, we describe the development of this user facility, the current status of its capability, and functional equipment specifications. The unique capabilities of the HADES Facility, in the UK academic landscape, are emphasised, including: handling of weighable quantities of 99Tc and transuranics; quantitative electron probe microanalysis of radioactive materials; hot isostatic pressing of radioactive materials; and laboratory-based X-ray absorption and emission spectroscopy. An example case study of the application of the HADES capability is described, involving thermal treatment of a real radioactive ion exchange resin waste to produce a conceptual vitrified waste form.
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•Digital Urban Environment Fingerprinting platform for global health risks proposed.•DUEF pillars: Environmental & Socioeconomic fingerprints, Stats/modelling, Information ...systems.•Critical evaluation of the current knowledge base and recommendations for further developments.
With the advent of the SARS-CoV-2 pandemic, Wastewater-Based Epidemiology (WBE) has been applied to track community infection in cities worldwide and has proven succesful as an early warning system for identification of hotspots and changingprevalence of infections (both symptomatic and asymptomatic) at a city or sub-city level. Wastewater is only one of environmental compartments that requires consideration. In this manuscript, we have critically evaluated the knowledge-base and preparedness for building early warning systems in a rapidly urbanising world, with particular attention to Africa, which experiences rapid population growth and urbanisation. We have proposed a Digital Urban Environment Fingerprinting Platform (DUEF) – a new approach in hazard forecasting and early-warning systems for global health risks and an extension to the existing concept of smart cities. The urban environment (especially wastewater) contains a complex mixture of substances including toxic chemicals, infectious biological agents and human excretion products. DUEF assumes that these specific endo- and exogenous residues, anonymously pooled by communities’ wastewater, are indicative of community-wide exposure and the resulting effects. DUEF postulates that the measurement of the substances continuously and anonymously pooled by the receiving environment (sewage, surface water, soils and air), can provide near real-time dynamic information about the quantity and type of physical, biological or chemical stressors to which the surveyed systems are exposed, and can create a risk profile on the potential effects of these exposures. Successful development and utilisation of a DUEF globally requires a tiered approach including: Stage I: network building, capacity building, stakeholder engagement as well as a conceptual model, followed by Stage II: DUEF development, Stage III: implementation, and Stage IV: management and utilization. We have identified four key pillars required for the establishment of a DUEF framework: (1) Environmental fingerprints, (2) Socioeconomic fingerprints, (3) Statistics and modelling and (4) Information systems. This manuscript critically evaluates the current knowledge base within each pillar and provides recommendations for further developments with an aim of laying grounds for successful development of global DUEF platforms.
Carboxylesterases (CE) are ubiquitous enzymes responsible for the metabolism of xenobiotics. Because the structural and amino acid homology among esterases of different classes, the identification of ...selective inhibitors of these proteins has proved problematic. Using Telik's target-related affinity profiling (TRAP) technology, we have identified a class of compounds based on benzil (1,2-diphenylethane-1,2-dione) that are potent CE inhibitors, with K i values in the low nanomolar range. Benzil and 30 analogues demonstrated selective inhibition of CEs, with no inhibitory activity toward human acetylcholinesterase or butyrylcholinesterase. Analysis of structurally related compounds indicated that the ethane-1,2-dione moiety was essential for enzyme inhibition and that potency was dependent on the presence of, and substitution within, the benzene ring. 3D-QSAR analyses of these benzil analogues for three different mammalian CEs demonstrated excellent correlations of observed versus predicted K i (r 2 > 0.91), with cross-validation coefficients (q 2) of 0.9. Overall, these results suggest that selective inhibitors of CEs with potential for use in clinical applications can be designed.
Hot Isostatic Pressing (HIPing) is a batch process thermal treatment technology where wastes are heated and compressed within a sealed stainless steel canister; typically resulting in durable, high ...density ceramics or glasses with minimal loss of volatile elements, and accountability of active inventories. The University of Sheffield has a small-scale research HIP with capability to process simulant wasteforms containing radioactive materials, to help underpin larger-scale industrial applications of this technology. It was under this remit that a series of trials were undertaken, to produce small simulant radioactive wasteforms incorporating problematic UK waste streams such as Magnox sludges and clinoptilolite ion-exchange material. Each trial was successfully batched, sealed, and HIPed at 1250 °C, resulting in solidified products entirely contained within the steel HIP canisters. The ability to safely produce active wasteforms within the same facility validates the active furnace isolation chamber (AFIC) system. Overall the success of these trials demonstrate the ability of smaller research HIP facilities to build up the scientific and technical case for further implementation of HIP technology as a viable waste treatment option.
Co-mixed simulant wasteforms consisting of calcined Magnox sludge simulant and clinoptilolite, with additions of a glass forming frit and CeO2 or U3O8 were processed using Hot Isostatic Pressing ...(HIP). This enabled the production of high waste loaded materials, with the successful incorporation of both simulant and active material. These formed heterogeneous glass-ceramic products, with decomposition of raw materials and some vitreous phase formation. The aqueous durability of these materials was assessed over a 28-day period using a modified PCT test, and favourably compared to the durability of an international glass. Overall this verifies the potential for HIP technology to be used in wasteform production, with potential large reductions in waste volume, especially if co-mixed wastes are considered.
In September, 1994, an outbreak of severe respiratory disease affected 18 horses, their trainer, and a stablehand in Queensland, Australia. Fourteen horses and one human being died. A novel virus was ...isolated from those affected and named equine morbillivirus (EMV). We report a case of encephalitis caused by this virus.
A 35-year-old man from Queensland had a brief aseptic meningitic illness in August, 1994, shortly after caring for two horses that died from EMV infection and then assisting at their necropsies. He then suffered severe encephalitis 13 months later, characterised by uncontrolled focal and generalised epileptic activity. Rising titres of neutralising antibodies to EMV in the patient's serum at the time of the second illness suggested an anamnestic response. Distinctive cortical changes were shown on magnetic resonance neuroimaging and histopathological examination of the brain at necropsy. Immunohistochemistry and electronmicroscopy of brain tissue revealed pathology characteristic of the earlier cases of EMV infection. PCR on cerebrospinal fluid taken during the second illness, brain tissue, and serum retained from the original illness resulted in an amplified product identical to that previously described from EMV.
The results of serology, PCR, electronmicroscopy, and immunohistochemistry strongly suggest that EMV was the cause of this patient's encephalitis, and that exposure to the virus occurred 3 months before the fatal illness.
The manufacture of a simulant UK Advanced Gas Cooled Reactor (AGR) spent nuclear fuel (SIMFuel) was achieved by Hot Isostatic Pressing (HIP). Characterisation of HIP AGR SIMFuels, tailored to burn ...ups of 25 GWd/t U and 43 GWd/t U (after 100 years cooling) demonstrated fission product partitioning, phase assemblage, microstructure and porosity in good agreement with spent nuclear fuels and SIMFuels, and AGR fuels in particular. A pivotal advantage of the application of the HIP manufacturing method is the retention of volatile fission products within the resultant SIMFuel as the result of using a hermetically-sealed container. This new approach to SIMFuel manufacture should enable the production of more accurate spent nuclear fuel surrogates to support research on spent fuel management, recycle, and disposal, and the thermal treatment of fuel residues and debris.
X-ray absorption spectroscopy was applied to understand the speciation of elements relevant to the immobilisation and disposal of radioactive plutonium bearing wastes, utilizing Ce as a Pu surrogate. ...Ce L3 XANES (X-ray Absorption Near Edge Structure) characterisation of a crystallised glass material produced by cold crucible plasma vitrification, at demonstration scale, evidenced incorporation as Ce3+ within the glass phase, providing an important validation of laboratory scale studies. U and Ce L3 XANES investigation of brannerite ceramics, U0.9Ce0.1Ti2O6, synthesized under oxidizing, neutral and reducing conditions, established the charge compensation mechanism as incorporation of Ce3+ through formation of U5+ and/or U6+ In each of these examples, X-ray Absorption Spectroscopy has provided a pivotal understanding of element speciation in relation to the mechanism of incorporation within the host wasteform intended for geological disposal.
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