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Journal articleBarkan-Öztürk H, Verdross P, Bismarck A, 2024,
Macroporous lignin adsorbents: A bio-sourced tool kit to defuse the Cr(VI) threat in wastewater
, Journal of Environmental Chemical Engineering, Vol: 12Amino-functionalised (triethylenetetramine) macroporous lignin monoliths were produced by curing an emulsion template containing untreated kraft black liquor with oxirane-crosslinkers. These lignin-based adsorbents were tested for the removal of Cr(VI) from water and synthetic waste water. A one-pot rout for their production is presented and their chemical and physical nature was investigated. Produced monoliths were tested in static and continuous adsorption experiments and chromium removal from water and synthetic wastewater was quantified via UV–vis spectroscopy. The nitrogen content of functionalised lignin monoliths reached up to 5.1 wt%, leading to adsorption capacities of up to 897 mg/g at pH = 2, as compared to non-functionalised lignin monoliths with a maximum adsorption capacity of 117 mg/g. The adsorption capacity of lignin monoliths produced is amongst the highest of bio-based materials presented in the literature.
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Journal articleBlank M, Wilson RC, Wan Y, et al., 2024,
Exploring real-world vancomycin target attainment in neonatal intensive care in the context of Staphylococcal infections: a retrospective observational cohort study
, Journal of Infection, Vol: 89, ISSN: 0163-4453 -
Journal articleByrne B, Cioccolo S, 2024,
The Mycobacterium lipid transporter MmpL3 is dimeric in detergent solution, SMALPs and reconstituted nanodiscs
, RSC Chemical Biology, ISSN: 2633-0679The mycobacterial membrane protein large 3 (MmpL3) transports key precursor lipids to the outer membrane of Mycobacterium species. Multiple structures of MmpL3 from both M. tuberculosis and M. smegmatis in various conformational states indicate that the protein is both structurally and functionally monomeric. However, most other resistance, nodulation and cell division (RND) transporters structurally characterised to date are either dimeric or trimeric. Here we present an in depth biophysical and computational analysis revealing that MmpL3 from M. smegmatis exists as a dimer in a variety of membrane mimetic systems (SMALPs, detergent-based solution and nanodiscs). Sucrose gradient separation of MmpL3 populations from M. smegmatis, reconstituted into nanodiscs, identified monomeric and dimeric populations of the protein using laser induced liquid bead ion desorption (LILBID), a native mass spectrometry technique. Preliminary cryo-EM analysis confirmed that MmpL3 forms physiological dimers. Untargeted lipidomics experiments on membrane protein co-purified lipids revealed PE and PG lipid classes were predominant. Molecular dynamics simulations, in the presence of physiologically-relevant lipid compositions revealed the likely dimer interface.
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Journal articleWan Y, Myall AC, Boonyasiri A, et al., 2024,
Integrated Analysis of Patient Networks and Plasmid Genomes to Investigate a Regional, Multispecies Outbreak of Carbapenemase-Producing Enterobacterales Carrying Both blaIMP and mcr-9 Genes.
, J Infect Dis, Vol: 230, Pages: e159-e170BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) are challenging in healthcare, with resistance to multiple classes of antibiotics. This study describes the emergence of imipenemase (IMP)-encoding CPE among diverse Enterobacterales species between 2016 and 2019 across a London regional network. METHODS: We performed a network analysis of patient pathways, using electronic health records, to identify contacts between IMP-encoding CPE-positive patients. Genomes of IMP-encoding CPE isolates were overlaid with patient contacts to imply potential transmission events. RESULTS: Genomic analysis of 84 Enterobacterales isolates revealed diverse species (predominantly Klebsiella spp, Enterobacter spp, and Escherichia coli); 86% (72 of 84) harbored an IncHI2 plasmid carrying blaIMP and colistin resistance gene mcr-9 (68 of 72). Phylogenetic analysis of IncHI2 plasmids identified 3 lineages showing significant association with patient contacts and movements between 4 hospital sites and across medical specialties, which was missed in initial investigations. CONCLUSIONS: Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of blaIMPCPE, which remained unidentified during standard investigations. With DNA sequencing and multimodal data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Plasmid-level outbreak analysis reveals that resistance spread may be wider than suspected, allowing more interventions to stop transmission within hospital networks.SummaryThis was an investigation, using integrated pathway networks and genomics methods, of the emergence of imipenemase-encoding carbapenemase-producing Enterobacterales among diverse Enterobacterales species between 2016 and 2019 in patients across a London regional hospital network, which was missed on routine investigations.
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Journal articleThenappan A, Maher TM, Yazbeck L, et al., 2024,
Competing Causes of Death in Idiopathic Pulmonary Fibrosis.
, Am J Respir Crit Care Med -
Journal articlePennisi I, Cavuto ML, Miglietta L, et al., 2024,
Rapid, portable, and electricity-free sample extraction method for enhanced molecular diagnostics in resource-limited settings
, Analytical Chemistry, Vol: 96, Pages: 11181-11188, ISSN: 0003-2700The COVID-19 pandemic has highlighted the need for rapid and reliable diagnostics that are accessible in resource-limited settings. To address this pressing issue, we have developed a rapid, portable, and electricity-free method for extracting nucleic acids from respiratory swabs (i.e. nasal, nasopharyngeal and buccal swabs), successfully demonstrating its effectiveness for the detection of SARS-CoV-2 in residual clinical specimens. Unlike traditional approaches, our solution eliminates the need for micropipettes or electrical equipment, making it user-friendly and requiring little to no training. Our method builds upon the principles of magnetic bead extraction and revolves around a low-cost plastic magnetic lid, called SmartLid, in combination with a simple disposable kit containing all required reagents conveniently prealiquoted. Here, we clinically validated the SmartLid sample preparation method in comparison to the gold standard QIAamp Viral RNA Mini Kit from QIAGEN, using 406 clinical isolates, including 161 SARS-CoV-2 positives, using the SARS-CoV-2 RT-qPCR assays developed by the US Centers for Disease Control and Prevention (CDC). The SmartLid method showed an overall sensitivity of 95.03% (95% CI: 90.44-97.83%) and a specificity of 99.59% (95% CI: 97.76-99.99%), with a positive agreement of 97.79% (95% CI: 95.84-98.98%) when compared to QIAGEN's column-based extraction method. There are clear benefits to using the SmartLid sample preparation kit: it enables swift extraction of viral nucleic acids, taking less than 5 min, without sacrificing significant accuracy when compared to more expensive and time-consuming alternatives currently available on the market. Moreover, its simplicity makes it particularly well-suited for the point-of-care where rapid results and portability are crucial. By providing an efficient and accessible means of nucleic acid extraction, our approach aims to introduce a step-change in diagnostic capabilities for resource-limited sett
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Journal articleDavies J, Mossop M, Jonathan I-H, et al., 2024,
Chronicity counts: the impact of P. aeruginosa, S. aureus, and co-infection in cystic fibrosis
, American Journal of Respiratory and Critical Care Medicine, Vol: 210, Pages: 240-242, ISSN: 1073-449X -
Journal articleKatsoulis O, Toussaint M, Jackson M, et al., 2024,
Neutrophil extracellular traps promote immunopathogenesis of virus-induced COPD exacerbations
, Nature Communications, Vol: 15, ISSN: 2041-1723Respiratory viruses are a major trigger of exacerbations in chronic obstructive pulmonary disease (COPD). Airway neutrophilia is a hallmark feature of stable and exacerbated COPD but roles played by neutrophil extracellular traps (NETS) in driving disease pathogenesis are unclear. Here, using human studies of experimentally-induced and naturally-occurring exacerbations we identify that rhinovirus infection induces airway NET formation which is amplified in COPD and correlates with magnitude of inflammation and clinical exacerbation severity. We show that inhibiting NETosis protects mice from immunopathology in a model of virus-exacerbated COPD. NETs drive inflammation during exacerbations through release of double stranded DNA (dsDNA) and administration of DNAse in mice has similar protective effects. Thus, NETosis, through release of dsDNA, has a functional role in the pathogenesis of COPD exacerbations. These studies open up the potential for therapeutic targeting of NETs or dsDNA as a strategy for treating virus-exacerbated COPD.
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Journal articleLong MB, Chotirmall SH, Shteinberg M, et al., 2024,
Rethinking bronchiectasis as an inflammatory disease.
, Lancet Respir MedBronchiectasis is understood to be the result of a complex interaction between infection, impaired mucociliary clearance, inflammation, and lung damage. Current therapeutic approaches to bronchiectasis are heavily focused on management of infection along with enhancing mucus clearance. Long-term antibiotics have had limited success in clinical trials, suggesting a need to re-evaluate the concept of bronchiectasis as an infective disorder. We invoke the example of asthma, for which treatment paradigms shifted away from targeting smooth muscle constriction, towards permanently suppressing airway inflammation, reducing risk and ultimately inducing remission with precision anti-inflammatory treatments. In this Review, we argue that bronchiectasis is primarily a chronic inflammatory disease, requiring early identification of at-risk individuals, and we introduce a novel concept of disease activity with important implications for clinical practice and future research. A new generation of novel anti-inflammatory treatments are under development and repurposing of anti-inflammatory agents from other diseases could revolutionise patient care.
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Journal articlePark Y-K, Sellés Vidal L, Bell D, et al., 2024,
Efficient synthesis of limonene production in Yarrowia lipolytica by combinatorial engineering strategies
, Biotechnology for Biofuels and Bioproducts, Vol: 17, ISSN: 2731-3654BackgroundLimonene has a variety of applications in the foods, cosmetics, pharmaceuticals, biomaterials, and biofuels industries. In order to meet the growing demand for sustainable production of limonene at industry scale, it is essential to find an alternative production system to traditional plant extraction. A promising and eco-friendly alternative is the use of microbes as cell factories for the synthesis of limonene.ResultsIn this study, the oleaginous yeast Yarrowia lipolytica has been engineered to produce D- and L-limonene. Four target genes, L- or D-LS (limonene synthase), HMG (HMG-CoA reductase), ERG20 (geranyl diphosphate synthase), and NDPS1 (neryl diphosphate) were expressed individually or fused together to find the optimal combination for higher limonene production. The strain expressing HMGR and the fusion protein ERG20-LS was the best limonene producer and, therefore, selected for further improvement. By increasing the expression of target genes and optimizing initial OD, 29.4 mg/L of L-limonene and 24.8 mg/L of D-limonene were obtained. We also studied whether peroxisomal compartmentalization of the synthesis pathway was beneficial for limonene production. The introduction of D-LS and ERG20 within the peroxisome improved limonene titers over cytosolic expression. Then, the entire MVA pathway was targeted to the peroxisome to improve precursor supply, which increased D-limonene production to 47.8 mg/L. Finally, through the optimization of fermentation conditions, D-limonene production titer reached 69.3 mg/L.ConclusionsIn this work, Y. lipolytica was successfully engineered to produce limonene. Our results showed that higher production of limonene was achieved when the synthesis pathway was targeted to the peroxisome, which indicates that this organelle can favor the bioproduction of terpenes in yeasts. This study opens new avenues for the efficient synthesis of valuable monoterpenes in Y. lipolytica.
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