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Journal articleHubert O, Todorovic N, Rojas González LM, et al., 2023,
Structural supercapacitors are multifunctional devices able to bear mechanical load while storing electrical energy. Carbon fibres can be used as a bifunctional component within structural supercapacitors, acting both as current collector and mechanical reinforcement. A promising route to such devices is to increase the surface area of carbon fibres, which can be achieved by the deposition of active materials, and embed them into a structural electrolyte. A highly sulfonated, high porosity hypercrosslinked polymer was deposited onto carbon fibres by electrophoretic deposition from an aqueous suspension. We investigated the effect of polymer and binder concentration in the deposition suspension on the electrochemical properties of the coated carbon fibre electrodes. Multifunctional structural composite supercapacitors had a fibre volume fraction of only 21% and possessed a tensile strength and Young's modulus of 495 MPa and 49 GPa, respectively. A specific capacitance of 1.2 F/g was reached, comparable to graphene coated carbon fibre electrodes. At room temperature and ambient humidity an energy density of 39 mWh/kg and a power density of 15 W/kg were measured. We demonstrate that moisture plays a major role in the energy storage mechanism in these SCs.
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,
Journal articleKoudstaal T, Funke-Chambour M, Kreuter M, et al., 2023,
Pulmonary fibrosis (PF) encompasses a spectrum of chronic lung diseases that progressively impact the interstitium, resulting in compromised gas exchange, breathlessness, diminished quality of life (QoL), and ultimately respiratory failure and mortality. Various diseases can cause PF, with their underlying causes primarily affecting the lung interstitium, leading to their referral as interstitial lung diseases (ILDs). The current understanding is that PF arises from abnormal wound healing processes triggered by various factors specific to each disease, leading to excessive inflammation and fibrosis. While significant progress has been made in understanding the molecular mechanisms of PF, its pathogenesis remains elusive. This review provides an in-depth exploration of the latest insights into PF pathophysiology, diagnosis, treatment, and future perspectives.
Journal articleMcNally P, Lester K, Stone G, et al., 2023,
Improvement in Lung Clearance Index and Chest CT Scores with Elexacaftor/Tezacaftor/Ivacaftor Treatment in People with Cystic Fibrosis Aged 12 Years and Older - The RECOVER Study., Am J Respir Crit Care Med
RATIONALE: Clinical trials have shown that use of Elexacaftor/Tezacaftor/Ivacaftor (ETI) is associated with improvements in sweat chloride, pulmonary function, nutrition and quality of life in people with CF. Little is known about the impact of ETI on ventilation inhomogeneity and lung structure. OBJECTIVES: RECOVER is a real-world study, designed to measure the impact of ETI in people with CF. The primary endpoints were lung clearance (LCI2.5) and FEV1. Secondary endpoints included spirometry-controlled chest CT scores. METHODS: The study was conducted in seven sites in Ireland and the UK. Participants 12 years and older homozygous for the F508del mutation (F508del/F508del)) or heterozygous for F508del and a minimum function mutation (F508del/MF) were recruited prior to starting ETI and followed up over 12 months. LCI2.5 was measured using nitrogen multiple breath washout (MBW) at baseline, 6 and 12 months. Spirometry was performed as per ERS/ATS criteria. Spirometry controlled Chest CT scans were performed at baseline and 12 months. CT scans were scored using the Perth Rotterdam Annotated Grid Morphometric Analysis (PRAGMA) system. Other outcome measures include weight, height, Cystic Fibrosis Quality of Life, Revised (CFQ-R) questionnaire and sweat chloride. MEASUREMENTS AND MAIN RESULTS: 117 people with CF aged 12 and above were recruited to the study. Significant improvements were seen in LCI (-2.5, 95%CI -3.0, -2.0) and ppFEV1 (8.9, 95%CI 7.0 - 10.9), ppFVC (6.6, 95%CI 4.9 - 8.3) and ppFEF25-75% (12.4, 95%CI 7.8 - 17.0). Overall PRAGMA-CF scores reflecting airways disease (-3.46 , 95%CI -5.23 , -1.69). Scores for trapped air, mucus plugging and bronchial wall thickening improved significantly, but bronchiectasis scores did not. Sweat chloride levels decreased in both F508del/F508del (-43.1, 95%CI -47.4, -38.9) and F508del/MF (-42.8, 95%CI -48.5, -37.2) groups. CFQ-R Respiratory Domain (RD) scores improved by 14.2 points (95%CI 11.3, 17.2). At one year, sweat c
Journal articleHewitt R, Puttur F, Gaboriau D, et al., 2023,
Journal articleEllis T, Blount B, 2023,
Synthetic yeast chromosome XI design provides a testbed for the study of extrachromosomal circular DNA dynamics, Cell Genomics, ISSN: 2666-979X
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., Lancet Respir Med
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 articleBarnett JL, Maher TM, Quint JK, et al., 2023,
Combination of Bronchoalveolar Lavage and CT Differentiates Progressive and Non-Progressive Fibrotic Lung Diseases., Am J Respir Crit Care Med
RATIONALE: Identifying patients with pulmonary fibrosis (PF) at risk of progression can guide management. We explore the utility of combining baseline bronchoalveolar lavage (BAL) and CT in differentiating progressive and non-progressive PF. METHODS: The derivation cohort consisted of incident cases of PF, for whom BAL was performed as part of diagnostic work-up. A validation cohort were prospectively recruited with identical inclusion criteria. Baseline thoracic CTs were scored for fibrosis extent and UIP pattern. BAL lymphocyte proportion was recorded. Annualized forced vital capacity decline >10% or death within one year defined disease progression. Multivariable logistic regression identified determinants of outcome. Optimum binary thresholds (maximal Wilcoxon rank statistic) at which CT fibrosis extent and BAL lymphocyte proportion could distinguish disease progression were identified. RESULTS: BAL lymphocyte proportion, UIP pattern and fibrosis extent were significantly and independently associated with disease progression in the derivation cohort (n=240 individuals). Binary thresholds for raised BAL lymphocyte proportion and extensive fibrosis were identified as 25% and 20% respectively. Raised BAL lymphocyte proportion was rare in patients with a UIP pattern (8/135[5.9%]) or with extensive fibrosis (7/144[4.9%]). In the validation cohort (n=290 subjects), a raised BAL lymphocyte proportion was associated with a significantly lower probability of disease progression in patients with non-extensive fibrosis or a non-UIP pattern. CONCLUSIONS: BAL lymphocytosis is rare in patients with extensive fibrosis or a UIP pattern on CT. In patients without a UIP pattern or with limited fibrosis, a BAL lymphocyte proportion of ≥ 25% was associated with a lower likelihood of progression.
Journal articleYuen ELH, Shepherd S, Bozkurt TO, 2023,
Membrane trafficking pathways play a prominent role in plant immunity. The endomembrane transport system coordinates membrane-bound cellular organelles to ensure that immunological components are utilized effectively during pathogen resistance. Adapted pathogens and pests have evolved to interfere with aspects of membrane transport systems to subvert plant immunity. To do this, they secrete virulence factors known as effectors, many of which converge on host membrane trafficking routes. The emerging paradigm is that effectors redundantly target every step of membrane trafficking from vesicle budding to trafficking and membrane fusion. In this review, we focus on the mechanisms adopted by plant pathogens to reprogram host plant vesicle trafficking, providing examples of effector-targeted transport pathways and highlighting key questions for the field to answer moving forward.
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