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Journal articleMalcı K, Li IS, Kisseroudis N, et al., 2024,
Modulating Microbial Materials - Engineering Bacterial Cellulose with Synthetic Biology.
, ACS Synth BiolThe fusion of synthetic biology and materials science offers exciting opportunities to produce sustainable materials that can perform programmed biological functions such as sensing and responding or enhance material properties through biological means. Bacterial cellulose (BC) is a unique material for this challenge due to its high-performance material properties and ease of production from culturable microbes. Research in the past decade has focused on expanding the benefits and applications of BC through many approaches. Here, we explore how the current landscape of BC-based biomaterials is being shaped by progress in synthetic biology. As well as discussing how it can aid production of more BC and BC with tailored material properties, we place special emphasis on the potential of using BC for engineered living materials (ELMs); materials of a biological nature designed to carry out specific tasks. We also explore the role of 3D bioprinting being used for BC-based ELMs and highlight specific opportunities that this can bring. As synthetic biology continues to advance, it will drive further innovation in BC-based materials and ELMs, enabling many new applications that can help address problems in the modern world, in both biomedicine and many other application fields.
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Journal articleFisher MC, Burnett F, Chandler C, et al., 2024,
A one health roadmap towards understanding and mitigating emerging Fungal Antimicrobial Resistance: fAMR
, npj Antimicrobials and Resistance, Vol: 2, ISSN: 2731-8745The emergence of fungal antimicrobial resistance—fAMR—is having a growing impact on human and animal health, and food security. This roadmap charts inter-related actions that will enhance our ability to mitigate the risk of fAMR. As humanity’s reliance on antifungal chemicals escalates, our understanding of their one-health consequences needs to scale accordingly if we are to protect our ability to manage the global spectrum of fungal disease sustainably.
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Journal articleNarayana JK, Mac Aogáin M, Hansbro PM, et al., 2024,
The bronchiectasis microbiome: current understanding and treatment implications.
, Curr Opin Pulm MedPURPOSE OF REVIEW: Advances in DNA sequencing and analysis of the respiratory microbiome highlight its close association with bronchiectasis phenotypes, revealing fresh opportunities for diagnosis, stratification, and personalized clinical intervention. An under-recognized condition, bronchiectasis is increasingly the subject of recent large-scale, multicentre, and longitudinal clinical studies including detailed analysis of the microbiome. In this review, we summarize recent progress in our understanding of the bronchiectasis microbiome within the context of its potential use in treatment decisions. RECENT FINDINGS: Diverse microbiome profiles exist in bronchiectasis, in line with the established disease heterogeneity including treatment response. Classical microbiology has established Pseudomonas aeruginosa and Haemophilus influenza as two microbial markers of disease, while holistic microbiome analysis has uncovered important associations with less common bacterial taxa including commensal an/or pathobiont species, including the emerging role of the fungal mycobiome, virome, and interactome. Integration of airway microbiomes with other high-dimensional biological and clinical datasets holds significant promise to determining treatable traits and mechanisms of disease related to the microbiome. SUMMARY: The bronchiectasis microbiome is an emerging and key area of study with significant implications for understanding bronchiectasis, influencing treatment decisions and ultimately improving patient outcomes.
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Journal articleLong MB, Chotirmall SH, Shteinberg M, et al., 2024,
Rethinking bronchiectasis as an inflammatory disease.
, Lancet Respir Med, Vol: 12, Pages: 901-914Bronchiectasis 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 articleMadhuprakash J, Toghani A, Contreras MP, et al., 2024,
A disease resistance protein triggers oligomerization of its NLR helper into a hexameric resistosome to mediate innate immunity
, Science Advances, Vol: 10, ISSN: 2375-2548NRCs are essential helper NLR (nucleotide-binding domain and leucine-rich repeat) proteins that execute immune responses triggered by sensor NLRs. The resting state of NbNRC2 was recently shown to be a homodimer, but the sensor-activated state remains unclear. Using cryo-EM, we determined the structure of sensor-activated NbNRC2, which forms a hexameric inflammasome-like resistosome. Mutagenesis of the oligomerization interface abolished immune signaling, confirming the functional significance of the NbNRC2 resistosome. Comparative structural analyses between the resting state homodimer and sensor-activated homohexamer revealed substantial rearrangements, providing insights into NLR activation mechanisms. Furthermore, structural comparisons between NbNRC2 hexamer and previously reported CC-NLR pentameric assemblies revealed features allowing an additional protomer integration. Using the NbNRC2 hexamer structure, we assessed the recently released AlphaFold 3 for predicting activated CC-NLR oligomers, revealing high-confidence modeling of NbNRC2 and other CC-NLR amino-terminal α1 helices, a region proven difficult to resolve structurally. Overall, our work sheds light on NLR activation mechanisms and expands understanding of NLR structural diversity.
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Journal articleChotirmall SH, Chang AB, Chalmers JD, 2024,
Infection vs Inflammation: The Bronchiectasis "Tug Of War".
, Chest, Vol: 166, Pages: 928-930 -
Journal articleWee LE, Tan JYJ, Chiew CJ, et al., 2024,
Response.
, Chest, Vol: 166, Pages: e167-e168 -
Journal articlePates K, Shang Z, Jabbar R, et al., 2024,
The effects of COVID-19 on antifungal prescribing in the UK – lessons to learn
, Journal of Fungi, Vol: 10, ISSN: 2309-608XFungal infections are increasingly prevalent; however, antifungal stewardship attracts little funding or attention. Previous studies have shown that knowledge of guidelines and scientific evidence regarding antifungals is poor, leading to prescribing based on personal experiences and the inherent biases this entails. We carried out a retrospective study of inpatient antifungal usage at two major hospitals. We assessed the longitudinal trends in antifungal usage and the effect of COVID-19 on antifungal prescription, alongside levels of empirical and diagnostically targeted antifungal usage. Our results showed that the longitudinal patterns of total systemic antifungal usage within the trusts were similar to national prescribing trends; however, the composition of antifungals varied considerably, even when looking exclusively at the more homogenous group of COVID-19 patients. We showed a high level of empirical antifungal use in COVID-19 patients, with neither trust adhering to international recommendations and instead appearing to follow prior prescribing habits. This study highlights the significant challenges to optimise antifungal use with prescribing behaviour largely dictated by habit, a lack of adherence to guidelines, and high rates of empirical non-diagnostic-based prescribing. Further research and resources are required to understand the impact of antifungal stewardship on improving antifungal prescribing behaviours in this setting and the effects on outcome.
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Journal articleDomingo-Sabugo C, Willis-Owen SA, Mandal A, et al., 2024,
Genomic analysis defines distinct pancreatic and neuronal subtypes of lung carcinoid.
, J Pathol, Vol: 264, Pages: 332-343Lung carcinoids (L-CDs) are rare, poorly characterised neuroendocrine tumours (NETs). L-CDs are more common in women and are not the consequence of cigarette smoking. They are classified histologically as typical carcinoids (TCs) or atypical carcinoids (ACs). ACs confer a worse survival. Histological classification is imperfect, and there is increasing interest in molecular markers. We therefore investigated global transcriptomic and epigenomic profiles of 15 L-CDs resected with curative intent at Royal Brompton Hospital. We identified underlying mutations and structural abnormalities through whole-exome sequencing (WES) and single nucleotide polymorphism (SNP) genotyping. Transcriptomic clustering algorithms identified two distinct L-CD subtypes. These showed similarities either to pancreatic or neuroendocrine tumours at other sites and so were named respectively L-CD-PanC and L-CD-NeU. L-CD-PanC tumours featured upregulation of pancreatic and metabolic pathway genes matched by promoter hypomethylation of genes for beta cells and insulin secretion (p < 1 × 10-6). These tumours were centrally located and showed mutational signatures of activation-induced deaminase/apolipoprotein B editing complex activity, together with genome-wide DNA methylation loss enriched in repetitive elements (p = 2.2 × 10-16). By contrast, the L-CD-NeU group exhibited upregulation of neuronal markers (adjusted p < 0.01) and was characterised by focal spindle cell morphology (p = 0.04), peripheral location (p = 0.01), high mutational load (p = 2.17 × 10-4), recurrent copy number alterations, and enrichment for ACs. Mutations affected chromatin remodelling and SWI/SNF complex pathways. L-CD-NeU tumours carried a mutational signature attributable to aflatoxin and aristolochic acid (p = 0.05), suggesting a possible environmenta
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Journal articleChalmers JD, Shteinberg M, Mall MA, et al., 2024,
Cathepsin C (dipeptidyl peptidase 1) inhibition in adults with bronchiectasis: AIRLEAF®, a Phase II randomised, double-blind, placebo-controlled, dose-finding study.
, Eur Respir JBronchiectasis is characterised by uncontrolled neutrophil serine protease (NSP) activity. Cathepsin C (CatC; dipeptidyl peptidase 1) activates NSPs during neutrophil maturation. CatC inhibitors can potentially reduce neutrophil-mediated lung damage. This Phase II, randomised, double-blind, placebo-controlled trial (AIRLEAF®; NCT05238675) evaluated efficacy, safety and optimal dosing of BI 1291583, a novel, reversible CatC inhibitor, in adults with bronchiectasis.In total, 322 participants were randomised (2:1:1:2) to receive one of three oral doses of BI 1291583 (1 mg/2.5 mg/5 mg) or placebo for 24 to 48 weeks. A multiple comparison procedure and modelling approach was used to demonstrate a non-flat dose-response curve based on the time to first pulmonary exacerbation up to Week 48. In addition, efficacy of individual BI 1291583 doses was evaluated based on the frequency of exacerbations, severe exacerbations (fatal or leading to hospitalisation and/or intravenous antibiotic administration), lung function and quality of life.A significant dose-dependent benefit of BI 1291583 over placebo was established based on time to first exacerbation (shape: Emax; adjusted p-value: 0.0448). Treatment with BI 1291583 5 mg and 2.5 mg numerically reduced the risk of an exacerbation compared with placebo (hazard ratios: 0.71 and 0.66, 95% CIs 0.48-1.05 and 0.40-1.08; both p>0.05). BI 1291583 2.5 mg showed numerically better efficacy compared with 5 mg across several endpoints; 1 mg was similar to placebo. The safety profile of BI 1291583 was similar to placebo.Treatment with BI 1291583 resulted in a reduction in the risk of experiencing an exacerbation in adults with bronchiectasis.
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