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Journal articleWang Z, Cuthbertson LF, Thomas C, et al., 2024,
IL-1α is required for T cell driven weight loss after respiratory viral infection
, Mucosal Immunology, ISSN: 1933-0219Respiratory viral infections remain a major cause of hospitalization and death worldwide. Patients with respiratory infections often lose weight. While acute weight loss is speculated to be a tolerance mechanism to limit pathogen growth, severe weight loss following infection can cause quality of life deterioration. Despite the clinical relevance of respiratory infection-induced weight loss, its mechanism is not yet completely understood. We utilized a model of CD 8+ T cell-driven weight loss during respiratory syncytial virus (RSV) infection to dissect the immune regulation of post-infection weight loss. Supporting previous data, bulk RNA sequencing indicated significant enrichment of the interleukin (IL)-1 signaling pathway after RSV infection. Despite increased viral load, infection-associated weight loss was significantly reduced after IL-1α (but not IL-1β) blockade. IL-1α depletion resulted in a reversal of the gut microbiota changes observed following RSV infection. Direct nasal instillation of IL-1α also caused weight loss. Of note, we detected IL-1α in the brain after either infection or nasal delivery. This was associated with changes in genes controlling appetite after RSV infection and corresponding changes in signaling molecules such as leptin and growth/differentiation factor 15. Together, these findings indicate a lung-brain-gut signaling axis for IL-1α in regulating weight loss after RSV infection.
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Journal articleCuthbertson L, Löber U, Ish-Horowicz JS, et al., 2024,
Genomic attributes of airway commensal bacteria and mucosa
, Communications Biology, Vol: 7, ISSN: 2399-3642Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance.
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Journal articleWebster VL, Hemmings S, Pérez M, et al., 2024,
Revealing the genome of the microsporidian Vairimorpha bombi, a potential driver of bumble bee declines in North America
, G3: Genes, Genomes, Genetics, ISSN: 2160-1836Pollinators are vital for food security and the maintenance of terrestrial ecosystems. Bumblebees are important pollinators across northern temperate, arctic, and alpine ecosystems, yet are in decline across the globe. Vairimorpha bombi is a parasite belonging to the fungal class Microsporidia that has been implicated in rapid declines of bumblebees in North America, where it may be an emerging infectious disease. To investigate the evolutionary basis of pathogenicity of V. bombi, we sequenced and assembled its genome using Oxford Nanopore and Illumina technologies and performed phylogenetic and genomic evolutionary analyses. The genome assembly for V. bombi is 4.73 Mb, from which we predicted 1,870 protein coding genes and 179 tRNA genes. The genome assembly has low repetitive content and low GC content. V. bombi's genome assembly is the smallest of the Vairimorpha and closely related Nosema genera, but larger than those found in the Encephalitozoon and Ordospora sister clades. Orthology and phylogenetic analysis revealed 18 core conserved single-copy microsporidian genes including the Histone acetyltransferase (HAT) GCN5. Surprisingly, V. bombi was unique to the microsporidia in not encoding the 2nd predicted HAT ESA1. The V. bombi genome assembly annotation included 265 unique genes (i.e., not predicted in other microsporidia genome assemblies), 20% of which encode a secretion signal, which is a significant enrichment. Intriguingly, of the 36 microsporidian genomes we analysed, 26 also had a significant enrichment of secreted signals encoded by unique genes, ranging from 6% to 71% of those predicted genes. These results suggest that microsporidia are under selection to generate and purge diverse and unique genes encoding secreted proteins, potentially contributing to or facilitating infection of their diverse hosts. Furthermore, V. bombi has 5/7 conserved Spore Wall Proteins (SWPs) with its closest relative V. ceranae (that primarily infects honeybees), while als
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Journal articleWoubshete M, Cioccolo S, Byrne B, 2024,
Advances in membrane mimetic systems for manipulation and analysis of membrane proteins; detergents, polymers, lipids and scaffolds
, ChemPlusChem, ISSN: 2192-6506Extracting membrane proteins from the hydrophobic environment of the biological membrane, in a physiologically relevant and stable state, suitable for downstream analysis remains a challenge. The traditional route to membrane protein extraction has been to use detergents and the last 15 years or so have seen a veritable explosion in the development of novel detergents with improved properties, making them more suitable for individual proteins and specific applications. There have also been significant advances in the development of encapsulation of membrane proteins in lipid based nanodiscs, either directly from the native membrane using polymers allowing effective capture of the protein and protein-associated membrane lipids, or via reconstitution of detergent extracted and purified protein into nanodiscs of defined lipid composition. All of these advances have been successfully applied to the study of membrane proteins via a range of techniques and there have been some spectacular membrane protein structures solved. In addition, the first detailed structural and biophysical analyses of membrane proteins retained within a biological membrane have been reported. Here we summarise and review the recent advances with respect to these new agents and systems for membrane protein extraction, reconstitution and analysis.
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Journal articleGuder F, Coatsworth P, Bozkurt O, et al., 2024,
Time-resolved chemical monitoring of whole plant roots with printed electrochemical sensors and machine learning
, Science Advances, Vol: 10, ISSN: 2375-2548Traditional single-point measurements fail to capture dynamic chemical responses of plants, which are complex, nonequilibrium biological systems. We report TETRIS (time-resolved electrochemical technology for plant root environment in situ chemical sensing), a real-time chemical phenotyping system for continuously monitoring chemical signals in the often-neglected plant root environment. TETRIS consisted of low-cost, highly scalable screen-printed electrochemical sensors for monitoring concentrations of salt, pH, and H2O2 in the root environment of whole plants, where multiplexing allowed for parallel sensing operation. TETRIS was used to measure ion uptake in tomato, kale, and rice and detected differences between nutrient and heavy metal ion uptake. Modulation of ion uptake with ion channel blocker LaCl3 was monitored by TETRIS and machine learning used to predict ion uptake. TETRIS has the potential to overcome the urgent “bottleneck” in high-throughput screening in producing high-yielding plant varieties with improved resistance against stress.
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Journal articleWu Z, Smith DJF, Yazbeck L, et al., 2024,
Cough Severity Visual Analogue Scale Assesses Cough Burden and Predicts Survival in Idiopathic Pulmonary Fibrosis.
, Am J Respir Crit Care Med -
Journal articleMayer F, Prado-Roller A, Mautner A, et al., 2024,
Retain strength, gain ductility: tough and transparent nanopapers by mercerisation
, Cellulose, Vol: 31, Pages: 1533-1544, ISSN: 0969-0239Nanocellulose papers offer high tensile strength and modulus but suffer from drawbacks such as their brittle nature. We show that mercerisation of cellulose nanopapers in strong alkaline media for 2 min to 24 h results in the (partial) transformation of native cellulose I into the more ductile cellulose II allomorph. The strain to failure of mercerised nanopapers tripled compared to the original nanopapers while retaining their tensile strength in excess of 100 MPa at the expense of a slight drop in modulus resulting in a significant increase in toughness (total work of fracture). An additional advantage of mercerisation is a reduction in porosity of the nanopapers and increased transparency.
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Journal articleVerster R, Ghosh PN, Sewell TR, et al., 2024,
Environment predicts Batrachochytrium dendrobatidis lineage distribution and zones of recombination in South Africa
, Ecology and Evolution, Vol: 14, ISSN: 2045-7758The amphibian-infecting chytrid fungus, Batrachochytrium dendrobatidis (Bd), is widespread throughout Africa and is linked to declines of populations and species across the continent. While it is well established that the lineage of Bd encodes traits which determine disease severity, knowledge around how lineages are distributed according to environmental envelope is unclear. We here studied the distribution of Bd in South Africa based on the two lineages found, BdGPL and BdCAPE, in terms of their genome and environmental envelope statistically associated with their distribution. We used Bd surveillance data from published studies, as well as data collected during fieldwork from across South Africa, Lesotho, and eSwatini with samples collected along a transect spanning most of South Africa from Lesotho to the west coast. We utilized lineage-typing qPCR to resolve the spatial distribution of BdGPL and BdCAPE across South Africa and used the resulting surveillance data to create a predictive ecological niche model for Bd lineages in South Africa. Phylogenomic analyses were performed on isolates sourced from across the transect. We show that BdGPL demonstrates a strong isolation by distance suggestive of stepping-stone dispersal, while BdCAPE showed two distinct clusters within their genomic structure that appear geographically and temporally clustered, indicating two separate invasions. Our predictive niche model revealed that the two lineages tended to occur in different ecotypes; BdGPL was associated with lower altitude, arid regions while BdCAPE occurred across cooler, higher altitude environs. Niche predictions identified a zone of lineage contact, where genomics identified inter-lineage recombinants. We argue that this zone of recombination should be prioritized for disease surveillance as it is a potential hotspot for the evolution of variants of amphibian chytrid with novel traits that may be epidemiologically relevant.
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Journal articleBaltas I, Kavallieros K, Konstantinou G, et al., 2024,
The effect of ciprofloxacin prophylaxis during haematopoietic cell transplantation on infection episodes, exposure to treatment antimicrobials and antimicrobial resistance: a single-centre retrospective cohort study.
, JAC Antimicrob Resist, Vol: 6OBJECTIVES: Fluroquinolone prophylaxis during haematopoietic cell transplantation (HCT) remains contentious. We aimed to determine its effectiveness and association with exposure to treatment antimicrobials and antimicrobial resistance. METHODS: All admission episodes for HCT (N = 400 , 372 unique patients) in a tertiary centre between January 2020 and December 2022 were studied. Allogeneic HCT (allo-HCT) recipients received prophylaxis with ciprofloxacin during chemotherapy-induced neutropenia, while autologous HCT (auto-HCT) recipients did not. RESULTS: Allo-HCT was performed for 43.3% (173/400) of patients, auto-HCT for 56.7% (227/400). Allo-HCT was associated with an average of 1.01 fewer infection episodes per 100 admission days (95% CI 0.62-1.40, P < 0.001) compared with auto-HCT. In allo-HCT, the total exposure to all antimicrobials was higher [+24.8 days of therapy (DOT)/100 admission days, P < 0.001], as was exposure to ciprofloxacin (+40.5 DOT/100 admission days, P < 0.001). By contrast, exposure to meropenem (-4.5 DOT/100 admission days, P = 0.02), piperacillin/tazobactam (-5.2 DOT/100 admission days, P < 0.001), aminoglycosides (-4.5 DOT/100 admission days, P < 0.001) and glycopeptides (-6.4 DOT/100 admission days, P < 0.001) was reduced. Enterobacteriaceae isolated during allo-HCT were more resistant to ciprofloxacin (65.5%, 19/29 versus 6.1%, 2/33, P < 0001), ceftriaxone (65.5%, 19/29 versus 9.1%, 3/33, P < 0.001), other antimicrobial classes. Vancomycin-resistant enterococci were more common in allo-HCT recipients (11%, 19/173 versus 0.9%, 2/227, P < 0.001). Inpatient mortality during allo- and auto-HCT was 9.8% (17/173) and 0.4% (1/227). respectively (P < 0.001). CONCLUSIONS: Ciprofloxacin prophylaxis in allo-HCT was associated with fewer infection episodes and reduced exposure to treatment antimicrobials. Mortality in auto-HCT remained low. A significant burden of antimicrobial resistance was detected in allo-HCT recipi
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Journal articleMaher TM, Tudor VA, Saunders P, et al., 2024,
Rituximab compared to intravenous cyclophosphamide in adults with connective tissue disease-associated interstitial lung disease: the RECITAL RCT
, Efficacy and Mechanism Evaluation, Pages: 1-68, ISSN: 2050-4365<jats:sec id="abs1-1"><jats:title>Background</jats:title><jats:p>Interstitial lung disease frequently complicates systemic autoimmune disorders including scleroderma, idiopathic inflammatory myositis and mixed connective tissue disease, resulting in considerable morbidity and mortality. Based on the results of trials undertaken in scleroderma, cyclophosphamide is the standard of care for individuals with severe or progressive connective tissue disease-associated interstitial lung disease. Observational studies suggest that the anti-CD20 monoclonal antibody, rituximab is an effective rescue therapy in treatment of refractory connective tissue disease-associated interstitial lung disease, but it has not been studied as first-line therapy in clinical trials.</jats:p></jats:sec><jats:sec id="abs1-2"><jats:title>Objectives</jats:title><jats:p>To compare the safety and efficacy of rituximab against that of cyclophosphamide as treatment for individuals with severe, progressive interstitial lung disease associated with scleroderma, idiopathic inflammatory myositis or mixed connective tissue disease.</jats:p></jats:sec><jats:sec id="abs1-3"><jats:title>Methods</jats:title><jats:p>This was a Phase IIb, multicentre, randomised, double-blind, double-dummy study assessing the superiority of rituximab compared with cyclophosphamide, conducted in rheumatology or interstitial lung disease units at 11 UK centres. The study recruited individuals with extensive and/or progressive connective tissue disease-associated interstitial lung disease, excluding those with significant comorbidities, including airflow obstruction. Participants were randomised 1 : 1 to receive either rituximab 1 g given intravenously, twice at an interval of 2 weeks, or intravenous cyclophosphamide given monthly for 6 months at a dose of 600 mg/m<jats:sup>2</jats:sup> body surf
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