Sustainability Indicators for Open-Cycle Thorium-Fuelled Nuclear Energy

The potential for countries which currently have a nominal nuclear energy infrastructure to adopt thorium-uranium-fuelled nuclear energy systems, using a once-through “open” nuclear fuel cycle, has been presented by the International Atomic Energy Agency. This paper highlights Generation III and III+ nuclear energy technologies that could potentially adopt an open thorium-uranium fuel cycle and qualitatively highlights the main differences between the open thorium-uranium and open uranium fuel cycles. Furthermore, 28 indicators (and corresponding metrics) have been identified that could elucidate the advantages and disadvantages of nuclear energy systems which utilise thorium-uranium fuels in an open cycle. Such systems will be compared to an AREVA EPR operating with a once-through uranium fuel cycle. The indicators determined in this work have been drawn by grouping 270 indicators from eight previous studies of indicators associated with holistic and specific appraisals of the various life-cycle stages associated with the nuclear fuel cycle. The 28 indicators cover technoeconomic, environmental, waste, social, and proliferation-resistance themes and can be determined quantitatively, either by explicit determination or from an appropriate sensitivity analysis

Life-cycle impacts from novel thorium-uranium-fuelled nuclear energy systems

Electricity generated from nuclear power plants is generally associated with low emis- sions per kWh generated, an aspect that feeds into the wider debate surrounding nuclear power. This paper seeks to investigate how life-cycle emissions would be affected by includ- ing thorium in the nuclear fuel cycle, and in particular its inclusion in technologies that could prospectively operate open Th–U-based nuclear fuel cycles. Three potential Th–U- based systems operating with open nuclear fuel cycles are considered: AREVA’s European Pressurised Reactor; India’s Advanced Heavy Water Reactor; and General Atomics’ Gas- Turbine Modular Helium Reactor. These technologies are compared to a reference U-fuelled European Pressurised Reactor. A life-cycle analysis is performed that considers the con- struction, operation, and decommissioning of each of the reactor technologies and all of the other associated facilities in the open nuclear fuel cycle. This includes the development of life-cycle analysis models to describe the extraction of thorium from monazitic beach sands and for the production of heavy water. The results of the life-cycle impact analysis highlight that the reference U-fuelled system has the lowest overall emissions per kWh generated, pre- dominantly due to having the second-lowest uranium ore requirement per kWh generated. The results highlight that the requirement for mined or recovered uranium (and thorium) ore is the greatest overall contributor to emissions, with the possible exception of nuclear energy systems that require heavy water. In terms of like-for-like comparison of mining and recovery techniques, thorium from monazitic beach sands has lower overall emissions than uranium that is either conventionally mined or recovered from in-situ leaching. Although monazitic beach sands (and equivalent placer deposits) only form 30% of the overall known thorium ore deposits, it is expected that such deposits would generally be utilised first if thorium becomes a viable nuclear fuel. Overall, for these four nuclear energy technologies, the range of CO2(eq) emissions per kWh generated (6.60–13.2 gCO2(eq)/kWh) appears to be low in comparison to the majority of electricity-generating technologies.This work is supported by the Engineering and Physical Sciences Research Council, EPSRC(UK), under grant no. EP/I018425/1.This is the final published version of the article. It was originally published in Energy Conversion and Management (Ashley SF, Fenner RA, Nuttall WJ, Parks GT, Energy Conversion and Management, 2015, 101, 136–150, doi:10.1016/j.enconman.2015.04.041). The final version is available at http://dx.doi.org/10.1016/j.enconman.2015.04.04

Species-selective killing of bacteria by antimicrobial peptide-PNAs

This is an open-access article distributed under the terms of the Creative Commons Attribution License, CC BY 4.0 which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Broad-spectrum antimicrobials kill indiscriminately, a property that can lead to negative clinical consequences and an increase in the incidence of resistance. Species-specific antimicrobials that could selectively kill pathogenic bacteria without targeting other species in the microbiome could limit these problems. The pathogen genome presents an excellent target for the development of such antimicrobials. In this study we report the design and evaluation of species-selective peptide nucleic acid (PNA) antibacterials. Selective growth inhibition of B. subtilis, E. coli, K. pnuemoniae and S. enterica serovar Typhimurium in axenic or mixed culture could be achieved with PNAs that exploit species differences in the translation initiation region of essential genes. An S. Typhimurium-specific PNA targeting ftsZ resulted in elongated cells that were not observed in E. coli, providing phenotypic evidence of the selectivity of PNA-based antimicrobials. Analysis of the genomes of E. coli and S. Typhimurium gave a conservative estimate of >150 PNA targets that could potentially discriminate between these two closely related species. This work provides a basis for the development of a new class of antimicrobial with a tuneable spectrum of activity.Peer reviewedFinal Published versio

Additive Anti-Tumor Effects of Lovastatin and Everolimus In Vitro through Simultaneous Inhibition of Signaling Pathways

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedThis work was supported by a research grant from the Ludwig-Maximilians University of Munich (Förderprogramm für Forschung und Lehre [FöFoLe], grant number 865/829)

Autocatalytic Activation of the Furin Zymogen Requires Removal of the Emerging Enzyme's N-Terminus from the Active Site

Before furin can act on protein substrates, it must go through an ordered process of activation. Similar to many other proteinases, furin is synthesized as a zymogen (profurin) which becomes active only after the autocatalytic removal of its auto-inhibitory prodomain. We hypothesized that to activate profurin its prodomain had to be removed and, in addition, the emerging enzyme's N-terminus had to be ejected from the catalytic cleft.We constructed and analyzed the profurin mutants in which the egress of the emerging enzyme's N-terminus from the catalytic cleft was restricted. Mutants were autocatalytically processed at only the primary cleavage site Arg-Thr-Lys-Arg(107) downward arrowAsp(108), but not at both the primary and the secondary (Arg-Gly-Val-Thr-Lys-Arg(75) downward arrowSer(76)) cleavage sites, yielding, as a result, the full-length prodomain and mature furins commencing from the N-terminal Asp108. These correctly processed furin mutants, however, remained self-inhibited by the constrained N-terminal sequence which continuously occupied the S' sub-sites of the catalytic cleft and interfered with the functional activity. Further, using the in vitro cleavage of the purified prodomain and the analyses of colon carcinoma LoVo cells with the reconstituted expression of the wild-type and mutant furins, we demonstrated that a three-step autocatalytic processing including the cleavage of the prodomain at the previously unidentified Arg-Leu-Gln-Arg(89) downward arrowGlu(90) site, is required for the efficient activation of furin.Collectively, our results show the restrictive role of the enzyme's N-terminal region in the autocatalytic activation mechanisms. In a conceptual form, our data apply not only to profurin alone but also to a range of self-activated proteinases

Leishmanicidal Metabolites from Cochliobolus sp., an Endophytic Fungus Isolated from Piptadenia adiantoides (Fabaceae)

Protozoan parasites belonging to genera Leishmania and Trypanosoma are the etiological agents of severe neglected tropical diseases (NTDs) that cause enormous social and economic impact in many countries of tropical and sub-tropical areas of the world. In our screening program for new drug leads from natural sources, we found that the crude extract of the endophytic fungus Cochliobolus sp. (UFMGCB-555) could kill 90% of the amastigote-like forms of Leishmania amazonensis and inhibit by 100% Ellman's reagent reduction in the trypanothione reductase (TryR) assay, when tested at 20 µg mL−1. UFMGCB-555 was isolated from the plant Piptadenia adiantoides J.F. Macbr (Fabaceae) and identified based on the sequence of the internally transcribed spacer (ITS) regions of its ribosomal DNA. The chromatographic fractionation of the extract was guided by the TryR assay and resulted in the isolation of cochlioquinone A and isocochlioquinone A. Both compounds were active in the assay with L. amazonensis, disclosing EC50 values (effective concentrations required to kill 50% of the parasite) of 1.7 µM (95% confidence interval = 1.6 to 1.9 µM) and 4.1 µM (95% confidence interval = 3.6 to 4.7 µM), respectively. These compounds were not active against three human cancer cell lines (MCF-7, TK-10, and UACC-62), indicating some degree of selectivity towards the parasites. These results suggest that cochlioquinones are attractive lead compounds that deserve further investigation aiming at developing new drugs to treat leishmaniasis. The findings also reinforce the role of endophytic fungi as an important source of compounds with potential to enter the pipeline for drug development against NTDs

Alpha-Toxin Induces Programmed Cell Death of Human T cells, B cells, and Monocytes during USA300 Infection

This investigation examines the influence of alpha-toxin (Hla) during USA300 infection of human leukocytes. Survival of an USA300 isogenic deletion mutant of hla (USA300Δhla) in human blood was comparable to the parental wild-type strain and polymorphonuclear leukocyte (PMN) plasma membrane permeability caused by USA300 did not require Hla. Flow cytometry analysis of peripheral blood mononuclear cells (PBMCs) following infection by USA300, USA300Δhla, and USA300Δhla transformed with a plasmid over-expressing Hla (USA300Δhla Comp) demonstrated this toxin plays a significant role inducing plasma membrane permeability of CD14+, CD3+, and CD19+ PBMCs. Rapid plasma membrane permeability independent of Hla was observed for PMNs, CD14+ and CD19+ PBMCs following intoxication with USA300 supernatant while the majority of CD3+ PBMC plasma membrane permeability induced by USA300 required Hla. Addition of recombinant Hla to USA300Δhla supernatant rescued CD3+ and CD19+ PBMC plasma membrane permeability generated by USA300 supernatant. An observed delay in plasma membrane permeability caused by Hla in conjunction with Annexin V binding and ApoBrdU Tunel assays examining PBMCs intoxicated with recombinant Hla or infected with USA300, USA300Δhla, USA300Δhla Comp, and USA300ΔsaeR/S suggest Hla induces programmed cell death of monocytes, B cells, and T cells that results in plasma membrane permeability. Together these findings underscore the importance of Hla during S. aureus infection of human tissue and specifically demonstrate Hla activity during USA300 infection triggers programmed cell death of human monocytes, T cells and B cells that leads to plasma membrane permeability