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Journal articleVerdross P, Guinchard S, Woodward RT, et al., 2023,
The production of thermosetting resins from lignin is a promising route to upcycle this biomaterial, currently overwhelmingly used as fuel. Raw kraft black liquor with no prior purification or treatment was derivatised using epichlorohydrin and an aniline catalyst to yield a black liquor-based epoxy resin (BLER). BLER is a liquid resin, which can be processed using conventional moulding techniques prior to curing into black liquor-based thermosets using maleic anhydride as hardener. We report the production of liquid lignin-based thermosets containing a biocarbon content of ∼ 16%. These thermosets possess Young's moduli and tensile strengths exceeding 1 GPa and 40 MPa, respectively. The chemical composition of the starting material and BLER were characterised, and the mechanisms of cure as well as the mechanical properties of lignin-based thermosets were determined.
Journal articleSole A, Davies JC, Quintana-Gallego E, 2023,
Journal articleAlmond M, Farne HA, Jackson MM, et al., 2023,
Obesity is a well-recognized risk factor for severe influenza infections but the mechanisms underlying susceptibility are poorly understood. Here, we identify that obese individuals have deficient pulmonary antiviral immune responses in bronchoalveolar lavage cells but not in bronchial epithelial cells or peripheral blood dendritic cells. We show that the obese human airway metabolome is perturbed with associated increases in the airway concentrations of the adipokine leptin which correlated negatively with the magnitude of ex vivo antiviral responses. Exogenous pulmonary leptin administration in mice directly impaired antiviral type I interferon responses in vivo and ex vivo in cultured airway macrophages. Obese individuals hospitalised with influenza showed dysregulated upper airway immune responses. These studies provide insight into mechanisms driving propensity to severe influenza infections in obesity and raise the potential for development of leptin manipulation or interferon administration as novel strategies for conferring protection from severe infections in obese higher risk individuals.
Journal articleEdmondson C, Westrupp N, Short C, et al., 2023,
Unsupervised home spirometry is not equivalent to supervised clinic spirometry in children and young people with cystic fibrosis: results from the CLIMB-CF study, Pediatric Pulmonology, Vol: 58, Pages: 2871-2880, ISSN: 1099-0496
BACKGROUND: Handheld spirometry allows monitoring of lung function at home, of particular importance during the COVID-19 pandemic. Pediatric studies are unclear on whether values are interchangeable with traditional, clinic-based spirometry. We aimed to assess differences between contemporaneous, home (unsupervised) and clinic (supervised) spirometry and the variability of the former. The accuracy of the commercially available spirometer used in the study was also tested. METHODS: Data from participants in the Clinical Monitoring and Biomarkers to stratify severity and predict outcomes in children with cystic fibrosisc (CLIMB-CF) Study aged ≥ 6 years who had paired (±1 day) clinic and home forced expiratory volume in 1 s (FEV1 ) readings were analyzed. Variability during clinical stability over 6-months was assessed. Four devices from Vitalograph were tested using 1 and 3 L calibration syringes. RESULTS: Sixty-seven participants (median [interquartile range] age 10.7 [7.6-13.9] years) provided home and clinic FEV1 data pairs. The mean (SD) FEV1 % bias was 6.5% [±8.2%]) with wide limits of agreement (-9.6% to +22.7%); 76.2% of participants recorded lower results at home. Coefficient of variation of home FEV1 % during stable periods was 9.9%. Data from the testing of the handheld device used in CLIMB-CF showed a potential underread. CONCLUSION: In children and adolescents, home spirometry using hand-held equipment cannot be used interchangeably with clinic spirometry. Home spirometry is moderately variable during clinical stability. New handheld devices underread, particularly at lower volumes of potential clinical significance for smaller patients; this suggests that supervision does not account fully for the discrepancy. Opportunities should be taken to obtain dual device measurements in clinic, so that trend data from home can be utilized more accurately.
Journal articleRitchie AI, Singayagam A, Mitchell S, et al., 2023,
The effect of inhaled corticosteroids on pneumonia risk in patients with COPD-bronchiectasis overlap: a UK population-based case-control study, Chest, Vol: 164, Pages: 875-884, ISSN: 0012-3692
BackgroundInhaled corticosteroids (ICS) increase the risk of pneumonia in COPD and are commonly used in patients with COPD-bronchiectasis overlap.Research QuestionIs the risk of pneumonia associated with ICS further heightened in COPD-bronchiectasis?Study Design and MethodsElectronic healthcare records (2004-2019) were used to obtain a cohort of COPD patients and a nested case-control (age-gender matched 1:4). Analyses were conducted to determine the risk of hospitalised pneumonia in COPD associated with ICS use in those with bronchiectasis. Findings were confirmed by several sensitivity analyses. Additionally, a smaller nested case-control, containing only patients with COPD-bronchiectasis overlap and those with recent blood eosinophil counts (BEC), was used to determine any association with BEC.Results316,663 were eligible for the COPD cohort; bronchiectasis significantly increased the risk of pneumonia (AHR=1.24, 95% CI 1.15-1.33). In the first nested case-control of 84,316 COPD patients, ICS was found to increase the odds of pneumonia (AOR=1.26, 95% CI 1.19-1.32), only if used in the previous 180 days. However, bronchiectasis was a significant modifier such that ICS use did not further augment the already elevated bronchiectasis-associated pneumonia risk (AOR, 95% CI: COPD-bronchiectasis=1.01, 0.8-1.28; no bronchiectasis=1.27, 1.20-1.34). Several sensitivity analyses and a second smaller nested case-control, confirmed these findings. Lastly, we found BEC modified the ICS-associated pneumonia risk in COPD-bronchiectasis overlap, where lower BEC was significantly associated with pneumonia (AOR, 95% CI: BEC≤3x109/L=1.56, 1.05-2.31, BEC>3x109/L=0.89, 0.53-1.24).InterpretationICS use does not further augment the already increased risk of hospitalised pneumonia associated with concomitant bronchiectasis in COPD.
Journal articleMayer-Hamblett N, Clancy JP, Jain R, et al., 2023,
Advancing the pipeline of cystic fibrosis clinical trials: a new roadmap with a global trial network perspective, The Lancet Respiratory Medicine, Vol: 11, Pages: 932-944, ISSN: 2213-2600
The growing use of modulator therapies aimed at restoring cystic fibrosis transmembrane conductance regulator (CFTR) protein function in people with cystic fibrosis has fundamentally altered clinical trial strategies needed to advance new therapeutics across an orphan disease population that is now divided by CFTR modulator eligibility. The development of a robust pipeline of nucleic acid-based therapies (NABTs)-initially directed towards the estimated 10% of the cystic fibrosis population who are genetically ineligible for, or intolerant of, CFTR modulators-is dependent on the optimisation of restricted trial participant resources across multiple development programmes, a challenge that will preclude the use of gold standard placebo-controlled trials. Advancement of a full pipeline of symptomatic therapies across the entire cystic fibrosis population will be challenged by smaller effect sizes and uncertainty regarding their clinical importance in a growing modulator-treated population with more mild and stable pulmonary disease. In this Series paper, we aim to lay the foundation for clinical trial strategy and community partnership that must deviate from established and familiar precedent to advance the future pipeline of cystic fibrosis therapeutics.
Journal articleHubert O, Todorovic N, Gonzalez LMR, et al., 2023,
Journal articleHewitt R, Puttur F, Gaboriau D, et al., 2023,
Aberrant expansion of KRT5+ basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+ cells in IPF have not been delineated. Here, we reveal a potential mechanism by which KRT5+ cells migrate within the fibrotic lung, navigating regional differences in collagen topography. In vitro, KRT5+ cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry- based proteomics revealed compositional differences in ECM components secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrix restricts KRT5+ cell migration in vitro. Together, our findings demonstrate how changes to the ECM in IPF directly influence KRT5+ cell behaviour and function contributing to remodelling events in the fibrotic niche.
Journal articleDrury F, Grover M, Hintze M, et al., 2023,
A PAX6-regulated receptor tyrosine kinase pairs with a pseudokinase to activate immune defense upon oomycete recognition in Caenorhabditis elegans., Proc Natl Acad Sci U S A, Vol: 120
Oomycetes were recently discovered as natural pathogens of Caenorhabditis elegans, and pathogen recognition alone was shown to be sufficient to activate a protective transcriptional program characterized by the expression of multiple chitinase-like (chil) genes. However, the molecular mechanisms underlying oomycete recognition in animals remain fully unknown. We performed here a forward genetic screen to uncover regulators of chil gene induction and found several independent loss-of-function alleles of old-1 and flor-1, which encode receptor tyrosine kinases belonging to the C. elegans-specific KIN-16 family. We report that OLD-1 and FLOR-1 are both necessary for mounting the immune response and act in the epidermis. FLOR-1 is a pseudokinase that acts downstream of the active kinase OLD-1 and regulates OLD-1 levels at the plasma membrane. Interestingly, the old-1 locus is adjacent to the chil genes in the C. elegans genome, thereby revealing a genetic cluster important for oomycete resistance. Furthermore, we demonstrate that old-1 expression at the anterior side of the epidermis is regulated by the VAB-3/PAX6 transcription factor, well known for its role in visual system development in other animals. Taken together, our study reveals both conserved and species-specific factors shaping the activation and spatial characteristics of the immune response to oomycete recognition.
Journal articleLedesma-Amaro R, Sun M, Ledesma Amaro R, et al., 2023,
In the post-genomic era, the demand for faster and more efficient protein production has increased, both in public laboratories and industry. In addition, with the expansion of protein sequences in databases, the range of possible enzymes of interest for a given application is also increasing. Faced with peer competition, budgetary, and time constraints, companies and laboratories must find ways to develop a robust manufacturing process for recombinant protein production. In this review, we explore high-throughput technologies for recombinant protein expression and present a holistic high-throughput process development strategy that spans from genes to proteins. We discuss the challenges that come with this task, the limitations of previous studies, and future research directions.
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