Sustainable inverse-vulcanised sulfur polymers (vol 8, pg 27892, 2018)

Correction for ‘Sustainable inverse-vulcanised sulfur polymers’ by Douglas J. Parker et al., RSC Adv., 2018, 8, 27892–27899

2D-infrared spectroscopy of proteins in water : using the solvent thermal response as an internal standard

Ultrafast two-dimensional infrared (2D-IR) spectra can now be obtained in a matter of seconds, opening up the possibility of high-throughput screening applications of relevance to the biomedical and pharmaceutical sectors. Determining quantitative information from 2D-IR spectra recorded on different samples and different instruments is however made difficult by variations in beam alignment, laser intensity, and sample conditions. Recently, we demonstrated that 2D-IR spectroscopy of the protein amide I band can be performed in aqueous (H2O) rather than deuterated (D2O) solvents, and we now report a method that uses the magnitude of the associated thermal response of H2O as an internal normalization standard for 2D-IR spectra. Using the water response, which is temporally separated from the protein signal, to normalize the spectra allows significant reduction of the impact of measurement-to-measurement fluctuations on the data. We demonstrate that this normalization method enables creation of calibration curves for measurement of absolute protein concentrations and facilitates reproducible difference spectroscopy methodologies. These advances make significant progress toward the robust data handling strategies that will be essential for the realization of automated spectral analysis tools for large scale 2D-IR screening studies of protein-containing solutions and biofluids

Structure and spectroscopy of CuH prepared via borohydride reduction

Copper(I) hydride (cuprous hydride, CuH) was the first binary metal hydride to be discovered (in 1844) and is singular in that it is synthesized in solution, at ambient temperature. There are several synthetic paths to CuH, one of which involves reduction of an aqueous solution of CuSO(4)·5H(2)O by borohydride ions. The product from this procedure has not been extensively characterized. Using a combination of diffraction methods (X-ray and neutron) and inelastic neutron scattering spectroscopy, we show that the CuH from the borohydride route has the same bulk structure as CuH produced by other routes. Our work shows that the product consists of a core of CuH with a shell of water and that this may be largely replaced by ethanol. This offers the possibility of modifying the properties of CuH produced by aqueous routes

Invasion ecology of wild pigs (Sus scrofa) in Florida, USA: the role of humans in the expansion and colonization of an invasive wild ungulate

Wild pigs (Sus scrofa) are the most widely distributed invasive wild ungulate in the United States, yet the factors that influence wild pig dispersal and colonization at the regional level are poorly understood. Our objective was to use a population genetic approach to describe patterns of dispersal and colonization among populations to gain a greater understanding of the invasion process contributing to the expansion of this species. We used 52 microsatellite loci to produce individual genotypes for 482 swine sampled at 39 locations between 2014 and 2016. Our data revealed the existence of genetically distinct subpopulations (FST = 0.1170, p\0.05). We found evidence of both fine-scale subdivision among the sampling locations, as well as evidence of long term genetic isolation. Several locations exhibited significant admixture (interbreeding) suggesting frequent mixing of individuals among locations; up to 14% of animals were immigrants from other populations. This pattern of admixture suggested successive rounds of human-assisted translocation and subsequent expansion across Florida. We also found evidence of genetically distinct populations that were isolated from nearby populations, suggesting recent introduction by humans. In addition, proximity to wild pig holding facilities was associated with higher migration rates and admixture, likely due to the escape or release of animals. Taken together, these results suggest that human-assisted movement plays a major role in the ecology and rapid population growth of wild pigs in Florida

Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III

Abstract Background Mucopolysaccharidosis type III is a progressive, neurodegenerative lysosomal storage disorder for which there is currently no effective therapy. Though numerous potential therapies are in development, there are several challenges to conducting clinical research in this area. We seek to make recommendations on the approach to clinical research in MPS III, including the selection of outcome measures and trial endpoints, in order to improve the quality and impact of research in this area. Results An international workshop involving academic researchers, clinical experts and industry groups was held in June 2015, with presentations and discussions on disease pathophysiology, biomarkers, potential therapies and clinical outcome measures. A set of recommendations was subsequently prepared by a working group and reviewed by all delegates. We present a series of 11 recommendations regarding the conduct of clinical research, outcome measures and management of natural history data in Mucopolysaccharidosis type III. Conclusions Improving the quality of clinical research in Mucopolysaccharidosis type III will require an open, collaborative and systematic approach between academic researchers, clinicians and industry. Natural history data should be published as soon as possible and ideally collated in a central repository. There should be agreement on outcome measures and instruments for evaluation of clinical outcomes to maximise the effectiveness of current and future clinical research

Unlocking the Diversity of Pyrroloiminoquinones Produced by Latrunculid Sponge Species

Sponges of the Latrunculiidae family produce bioactive pyrroloiminoquinone alkaloids including makaluvamines, discorhabdins, and tsitsikammamines. The aim of this study was to use LC-ESI-MS/MS-driven molecular networking to characterize the pyrroloiminoquinone secondary metabolites produced by six latrunculid species. These are Tsitsikamma favus, Tsitsikamma pedunculata, Cyclacanthia bellae, and Latrunculia apicalis as well as the recently discovered species, Tsitsikamma nguni and Tsitsikamma michaeli. Organic extracts of 43 sponges were analyzed, revealing distinct species-specific chemical profiles. More than 200 known and unknown putative pyrroloiminoquinones and related compounds were detected, including unprecedented makaluvamine-discorhabdin adducts and hydroxylated discorhabdin I derivatives. The chemical profiles of the new species T. nguni closely resembled those of the known T. favus (chemotype I), but with a higher abundance of tsitsikammamines vs. discorhabdins. T. michaeli sponges displayed two distinct chemical profiles, either producing mostly the same discorhabdins as T. favus (chemotype I) or non- or monobrominated, hydroxylated discorhabdins. C. bellae and L. apicalis produced similar pyrroloiminoquinone chemistry to one another, characterized by sulfur-containing discorhabdins and related adducts and oligomers. This study highlights the variability of pyrroloiminoquinone production by latrunculid species, identifies novel isolation targets, and offers fundamental insights into the collision-induced dissociation of pyrroloiminoquinones

Measuring proteins in H2O using 2D-IR spectroscopy; pre-processing steps and applications towards a protein library

The ability of two-dimensional infrared (2D-IR) spectroscopy to measure the amide I band of proteins in H2O rather than D2O-based solvents by evading the interfering water signals has enabled in-vivo studies of proteins under physiological conditions and in biofluids. Future exploitation of 2D-IR in analytical settings, from diagnostics to protein screening, will however require comparisons between multiple datasets, necessitating control of data collection protocols to minimise measurement-to-measurement inconsistencies. Inspired by analytical spectroscopy applications in other disciplines, we describe a workflow for pre-processing 2D-IR data that aims to simplify spectral cross-comparisons. Our approach exploits the thermal water signal that is collected simultaneously with, but is temporally separated from the amide I response to guide custom baseline correction and spectral normalisation strategies before combining them with Principal Component noise reduction tools. Case studies show that application of elements of the pre-processing workflow to previously-published data enables improvements in quantification accuracy and detection limits. We subsequently apply the complete workflow in a new pilot study, testing the ability of a prototype library of 2D-IR spectra to quantify the four major protein constituents of blood serum in a single, label-free measurement.  These advances show progress towards the robust data handling strategies that will be necessary for future applications of 2D-IR for pharmaceutical or biomedical applications

Optimising the cost of roadkill surveys based on an analysis of carcass persistence

Reliable estimates of wildlife mortality due to wildlife-vehicle collisions are key to understanding its impact on wildlife populations and developing strategies to prevent or reduce collisions. Standardised approaches for monitoring roadkill are needed to derive robust and unbiased estimates of mortality that are comparable across different study systems and ecological contexts. When designing surveys, there is a trade-off between survey frequency (and hence logistical effort and financial cost) and carcass detection. In this regard, carcass persistence (the period a carcass remains detectable before being removed by decomposition or scavengers) is important; the longer a carcass persists, the greater the likelihood it will be detected with lower survey effort by conducting more infrequent surveys. Using multi-taxon carcass data collected over a month of repeated driven surveys, combined with five covariates (species functional group, body weight, carcass position on road, carcass condition [either flattened or not after impact], and rainfall prior to each survey), we explored the drivers of carcass persistence with the overall aim of providing information to optimise the design of carcass surveys along linear infrastructure. Our methodological approach included a survival analysis to determine carcass persistence, linear regressions to test the effect of covariates, a subsampling analysis (using field data and a simulation exercise) to assess how the proportion of carcasses detected changes according to survey frequency, and an analysis to compare the costs of surveys based on study duration, transect length and survey frequency. Mean overall carcass persistence was 2.7 days and was significantly correlated with position on road and within-functional group body weight. There was no evidence for a significant effect of rainfall, while the effect of carcass condition was weakly non-significant. The proportion of carcasses detected decreased sharply when survey intervals were longer than three days. However, we showed that survey costs can be reduced by up to 80% by conducting non-daily surveys. Expanding on the call for a standardised methodology for roadkill surveys, we propose that carcass persistence be explicitly considered during survey design. By carefully considering the objectives of the survey and characteristics of the focal taxa, researchers can substantially reduce logistical costs. In addition, we developed an R Shiny web app that can be used by practitioners to compare survey costs across a variety of survey characteristics. This web app will allow practitioners to easily assess the trade-off between carcass detection and logistical effort.De Beers Group of Companies, Oppenheimer Generations, and Mopane Bush Lodge. This research was initiated by the Endangered Wildlife Trust, with funding from Bridgestone South Africa.https://www.elsevier.com/locate/jenvman2022-05-08hj2022Mammal Research Institut

Novel Protein Disulfide Isomerase Inhibitor with Anticancer Activity in Multiple Myeloma

Multiple myeloma cells secrete more disulfide bond–rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell–based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow–sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in active-site CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma

Dual Mechanism of Interleukin-3 Receptor Blockade by an Anti-Cancer Antibody

SummaryInterleukin-3 (IL-3) is an activated T cell product that bridges innate and adaptive immunity and contributes to several immunopathologies. Here, we report the crystal structure of the IL-3 receptor α chain (IL3Rα) in complex with the anti-leukemia antibody CSL362 that reveals the N-terminal domain (NTD), a domain also present in the granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-5, and IL-13 receptors, adopting unique “open” and classical “closed” conformations. Although extensive mutational analyses of the NTD epitope of CSL362 show minor overlap with the IL-3 binding site, CSL362 only inhibits IL-3 binding to the closed conformation, indicating alternative mechanisms for blocking IL-3 signaling. Significantly, whereas “open-like” IL3Rα mutants can simultaneously bind IL-3 and CSL362, CSL362 still prevents the assembly of a higher-order IL-3 receptor-signaling complex. The discovery of open forms of cytokine receptors provides the framework for development of potent antibodies that can achieve a “double hit” cytokine receptor blockade