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  • Journal article
    Furukawa T, van Rhijn N, Chown H, Rhodes J, Alfuraiji N, Fortune-Grant R, Bignell E, Fisher MC, Bromley Met al., 2022,

    Exploring a novel genomic safe-haven site in the human pathogenic mould br Aspergillus fumigatus

    , FUNGAL GENETICS AND BIOLOGY, Vol: 161, ISSN: 1087-1845
  • Journal article
    Wang Y, Xue T, Wang M, Ledesma-Amaro R, Lu Y, Hu X, Zhang T, Yang M, Li Y, Xiang J, Deng R, Ying B, Li Wet al., 2022,

    CRISPR-Cas13a cascade-based viral RNA assay for detecting SARS-CoV-2 and its mutations in clinical samples

    , Sensors and Actuators B: Chemical: international journal devoted to research and development of physical and chemical transducers, Vol: 362, ISSN: 0925-4005

    SARS-CoV-2 is one of the greatest threats to global human health. Point-of-care diagnostic tools for SARS-CoV-2 could facilitate rapid therapeutic intervention and mitigate transmission. In this work, we report CRISPR-Cas13a cascade-based viral RNA (Cas13C) assay for label-free and isothermal determination of SARS-CoV-2 and its mutations in clinical samples. Cas13a/crRNA was utilized to directly recognize the target of SARS-CoV-2 RNA, and the recognition events sequentially initiate the transcription amplification to produce light-up RNA aptamers for output fluorescence signal. The recognition of viral RNA via Cas13a-guide RNA ensures a high specificity to distinguish SARS-CoV-2 from MERS-CoV and SARS-CoV, as well as viral mutations. A post transcription amplification strategy was triggered after CRISPR-Cas13a recognition contributes to an amplification cascade that achieves high sensitivity for detecting SARS-CoV-2 RNA, with a limit of detection of 0.216 fM. In addition, the Cas13C assay could be able to discriminate single-nucleotide mutation, which was proven with N501Y in SARS-Cov-2 variant. This method was validated by a 100% agreement with RT-qPCR results from 12 clinical throat swab specimens. The Cas13C assay has the potential to be used as a routine nucleic acid test of SARS-CoV-2 virus in resource-limited regions.

  • Journal article
    Dobra R, Bentley S, Edmondson C, Ovens M, Saunders C, Short C, Wilson G, Davies JC, Bush Aet al., 2022,

    Going the Extra Mile: Why Clinical Research in Cystic Fibrosis Must Include Children

    , CHILDREN-BASEL, Vol: 9
  • Journal article
    Murphy R, Coates M, Thrane S, Sabnis A, Harrison J, Schelenz S, Edwards A, Vorup-Jensen T, Davies Jet al., 2022,

    Synergistic activity of repurposed peptide drug glatiramer acetate with tobramycin against cystic fibrosis Pseudomonas aeruginosa

    , Microbiology Spectrum, Vol: 10, ISSN: 2165-0497

    Pseudomonas aeruginosa is the most common pathogen infecting the lungs of people with cystic fibrosis (CF), causing both acute and chronic infections. Intrinsic and acquired antibiotic resistance, coupled with the physical barriers resulting from desiccated CF sputum, allow P. aeruginosa to colonize and persist in spite of antibiotic treatment. As well as the specific difficulties in eradicating P. aeruginosa from CF lungs, P. aeruginosa is also subject to the wider, global issue of antimicrobial resistance. Glatiramer acetate (GA) is a peptide drug, used in the treatment of multiple sclerosis (MS), which has been shown to have moderate antipseudomonal activity. Other antimicrobial peptides (AMPs) have been shown to be antibiotic resistance breakers, potentiating the activities of antibiotics when given in combination, restoring and/or enhancing antibiotic efficacy. Growth, viability, MIC determinations, and synergy analysis showed that GA improved the efficacy of tobramycin (TOB) against reference strains of P. aeruginosa, reducing TOB MICs and synergizing with the aminoglycoside. This was also the case for clinical strains from people with CF. GA significantly reduced the MIC50 of TOB for viable cells from 1.69 mg/L (95% confidence interval [CI], 0.26 to 8.97) to 0.62 mg/L (95% CI, 0.15 to 3.94; P = 0.002) and the MIC90 for viable cells from 7.00 mg/L (95% CI, 1.18 to 26.50) to 2.20 mg/L (95% CI, 0.99 to 15.03; P = 0.001), compared to results with TOB only. Investigation of mechanisms of GA activity showed that GA resulted in significant disruption of outer membranes, depolarization of cytoplasmic membranes, and permeabilization of P. aeruginosa and was the only agent tested (including cationic AMPs) to significantly affect all three mechanisms.

  • Journal article
    Zhang D, Povysil G, Kobeissy PH, Li Q, Wang B, Amelotte M, Jaouadi H, Newton CA, Maher TM, Molyneaux PL, Noth I, Martinez FJ, Raghu G, Todd JL, Palmer SM, Haefliger C, Platt A, Petrovski S, Garcia JA, Goldstein DB, Garcia CKet al., 2022,

    Rare and common variants in KIF15 contribute to genetic risk of idiopathic pulmonary fibrosis

    , American Journal of Respiratory and Critical Care Medicine, Vol: 206, ISSN: 1073-449X

    RATIONALE: Genetic studies of Idiopathic Pulmonary Fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified. OBJECTIVE: To identify genes enriched with rare deleterious variants in IPF and familial pulmonary fibrosis. METHODS: We performed gene burden analysis of whole exome data, tested single variants for disease association, conducted KIF15 functional studies, and examined human lung single cell RNA sequencing data. MEASUREMENT AND MAIN RESULTS: Gene burden analysis of 1,725 cases and 23,509 controls identified heterozygous rare deleterious variants in KIF15, a kinesin involved in spindle separation during mitosis, and three telomere-related genes (TERT, RTEL1, PARN). KIF15 was implicated in autosomal dominant models of rare deleterious variants (OR 4.9 [95%CI 2.7, 8.8] P=2.55x10-7) and rare protein-truncating variants (OR 7.6 [3.3, 17.1], P=8.12x10-7). Meta-analysis of the discovery and replication cohorts, including 2,966 cases and 29,817 controls, confirm the involvement of KIF15, plus the three telomere-related genes. A common variant within a KIF15 intron (rs74341405, OR 1.6 [1.4, 1.9], P=5.63x10-10) is associated with IPF risk, confirming a prior report. Lymphoblastoid cells from individuals heterozygous for the common variant have decreased KIF15 and reduced rates of cell growth. Cell proliferation is dependent on KIF15 in the presence of an inhibitor of Eg5/KIF11, which has partially redundant function. KIF15 is expressed specifically in replicating human lung cells, and shows diminished expression in replicating epithelial cells of IPF patients. CONCLUSIONS: Both rare deleterious variants and common variants in KIF15 link a non-telomerase pathway of cell proliferation with IPF susceptibility.

  • Journal article
    Sawicki GS, Chilvers M, McNamara J, Naehrlich L, Saunders C, Sermet-Gaudelus I, Wainwright CE, Ahluwalia N, Campbell D, Harris RS, Paz-Diaz H, Shih JL, Davies JCet al., 2022,

    A Phase 3, open-label, 96-week trial to study the safety, tolerability, and efficacy of tezacaftor/ivacaftor in children ≥ 6 years of age homozygous for F508del or heterozygous for F508del and a residual function CFTR variant.

    , J Cyst Fibros, Vol: 21, Pages: 675-683

    BACKGROUND: Two previous Phase 3 studies ("parent studies") showed that tezacaftor/ivacaftor was generally safe and efficacious for up to 24 weeks in children 6 through 11 years of age with cystic fibrosis (CF) and F508del/F508del (F/F) or F508del/residual function (F/RF) genotypes. We assessed the safety and efficacy of tezacaftor/ivacaftor in an open-label, 96-week extension study. METHODS: This was a Phase 3, 2-part, multicenter, open-label, extension study in children 6 through 11 years of age at treatment initiation (Study VX17-661-116; NCT03537651). The primary endpoint was safety and tolerability. Secondary endpoints were absolute change from baseline in lung clearance index2.5 (LCI2.5), sweat chloride (SwCl) concentration, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, and body mass index (BMI). RESULTS: One-hundred thirty children enrolled and received ≥ 1 dose of tezacaftor/ivacaftor; 109 completed treatment. Most (n = 129) had ≥ 1 treatment-emergent adverse event (TEAE), the majority of which were mild or moderate in severity and generally consistent with common manifestations of CF. Exposure-adjusted TEAE rates were similar to or lower than those in the parent studies. Five (3.8%) had TEAEs leading to treatment discontinuation. Efficacy results from the parent studies were maintained, with improvements in lung function, SwCl concentration, CFQ‑R respiratory domain score, and BMI observed from parent study baseline to Week 96. CONCLUSIONS: Tezacaftor/ivacaftor is generally safe and well tolerated, and treatment effects are maintained for up to 120 weeks. These results support long-term use of tezacaftor/ivacaftor in children ≥ 6 years of age with CF and F/F or F/RF genotypes.

  • Journal article
    King JA, Nichols A-L, Bentley S, Carr SB, Davies JCet al., 2022,

    An Update on CFTR Modulators as New Therapies for Cystic Fibrosis.

    , Paediatr Drugs, Vol: 24, Pages: 321-333

    Over the past decade there have been significant developments in the field of Cystic Fibrosis Transmembrane Regulator modulator drugs. Following treatment in patients with cystic fibrosis with common gating mutations using the potentiator drug ivacaftor, successive development of corrector drugs used in combination has led to highly effective modulator therapy being available to more than 85% of the cystic fibrosis population over 12 years of age in the form of elexacaftor/tezacaftor/ivacaftor. In this article, we review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extra-pulmonary manifestations of cystic fibrosis. As clinical trials progress to younger patient groups, we discuss the challenges to demonstrating drug efficacy in early life, and also consider practicalities of drug development in an ever-shrinking modulator-naïve population. Drug-drug interactions are an important consideration in people with cystic fibrosis, where polypharmacy is commonplace, but also as the modulated population look to remain healthier for longer, we identify trials that aim to address treatment burden too. Inequity of care, through drug cost or ineligibility for modulators by genotype, is widening without apparent strategies to address this; however, we present evidence of hopeful early-stage drug development for non-modulatable genes and summarise the current state of gene-therapy development.

  • Journal article
    Patil RH, Kotta-Loizou I, Palyzová A, Pluháček T, Coutts RHA, Stevens DA, Havlíček Vet al., 2022,

    Correction: Patil et al. Freeing Aspergillus fumigatus of Polymycovirus Infection Renders It More Resistant to Competition with Pseudomonas aeruginosa Due to Altered Iron-Acquiring Tactics. J. Fungi 2021, 7, 497

    , Journal of Fungi, Vol: 8, ISSN: 2309-608X

    In the original publication [...].

  • Journal article
    Masters-Clark E, Clark AJ, Stanley CE, 2022,

    Microfluidic Tools for Probing Fungal-Microbial Interactions at the Cellular Level.

    , J Vis Exp

    Filamentous fungi are successful inhabitants of soil and play a major role in soil ecosystems, such as in the decomposition of organic and inorganic matter, as well as regulation of nutrient levels. There they also find numerous opportunities to interact with a variety of other microbes such as bacteria or other fungi. Studying fungal interactions at the cellular level, however, can be challenging owing to the black box-like nature of soil. New microfluidic tools are being developed for the study of fungal interactions; two platforms designed to study bacterial-fungal and fungal-fungal interactions are highlighted. Within these microchannels, fungal-microbial interactions can be monitored in controlled physico-chemical environments at higher temporal and spatial resolution than previously possible. Application of these tools have yielded numerous novel biological insights, such as the observation of bacterial polar attachment to hyphae or revealing uncharacterised fungal-fungal antagonisms. A key feature of these methodologies regards the ease of use of this tool by non-experts, yielding highly translatable technologies for use in microbiology labs.

  • Journal article
    Faiez TS, Singanayagam A, 2022,

    Down to a T: The Functional Importance of Lymphopenia in Severe COVID-19

    , AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 205, Pages: 1370-1372, ISSN: 1073-449X

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