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  • Journal article
    Rawson TM, Brzeska-Trafny I, Maxfield R, Almeida M, Gilchrist M, Gonzalo X, Moore L, Donaldson H, Davies Fet al., 2022,

    A practical laboratory method to determine ceftazidime-avibactam-aztreonam synergy in patients with New Delhi Metallo-beta-lactamase (NDM) producing Enterobacterales infection

    , Journal of Global Antimicrobial Resistance, Vol: 29, Pages: 558-562, ISSN: 2213-7165

    Background:In response to infection with New Delhi Metallo-beta-lactamase (NDM) producing Enterobacterales, combination antimicrobial therapy with ceftazidime/avibactam (CAZ/AVI) plus aztreonam (ATM) has been explored. This study evaluated a practical laboratory method of testing for clinically significant synergy between CAZ/AVI+ATM in NDM producing Enterobacterales.Methods:Minimum inhibitory concentration (MIC) of clinical NDM producing isolates were determined for ATM alone and CAZ/AVI+ATM using broth dilution. Restoration of ATM breakpoint following the addition of CAZ/AVI was explored. A CAZ/AVI E-test/ATM disc method was compared to broth dilution.Results:Of 43 isolates, 33/43 (77%) isolates were ATM resistant (median [range] MIC=56 [16 – 512] mg/L). Addition of CAZ/AVI restored the ATM breakpoint (MIC <4mg/L) in 29/33 (89%) of resistant isolates. Overall, the E-test/disc method correlated with findings from broth dilution in 35/43 (81%) of cases. E-test/disc sensitivity was 77% and specificity 85%. Positive predictive value was 92% and negative predictive value 61%.Conclusion:CAZ/AVI+ATM demonstrated significant synergy in most ATM resistant NDM producing Enterobacterales. The E-test/disc method is a quick, reproducible, and reliable method of testing for clinically relevant synergy in the microbiology laboratory.

  • Journal article
    Balfour-Lynn IM, Puckey M, Simmonds NJ, Davies JCet al., 2022,

    Revisiting a diagnosis of cystic fibrosis - Uncertainties and considerations

    , PAEDIATRIC RESPIRATORY REVIEWS, Vol: 42, Pages: 29-34, ISSN: 1526-0542
  • Journal article
    Dixon E, Dick K, Ollosson S, Jones D, Mattock H, Bentley S, Saunders C, Matthews J, Dobra B, King J, Edmondson C, Davies JCet al., 2022,

    Telemedicine and cystic fibrosis: Do we still need face-to-face clinics?

    , PAEDIATRIC RESPIRATORY REVIEWS, Vol: 42, Pages: 23-28, ISSN: 1526-0542
  • Journal article
    Bhutada G, Menard G, Bhunia RK, Hapeta PP, Ledesma-Amaro R, Eastmond PJet al., 2022,

    Production of human milk fat substitute by engineered strains of Yarrowia lipolytica.

    , Metabolic Engineering Communications, Vol: 14, Pages: 1-10, ISSN: 2214-0301

    Human milk fat has a distinctive stereoisomeric structure where palmitic acid is esterified to the middle (sn-2) position on the glycerol backbone of the triacylglycerol and unsaturated fatty acids to the outer (sn-1/3) positions. This configuration allows for more efficient nutrient absorption in the infant gut. However, the fat used in most infant formulas originates from plants, which exclude palmitic acid from the sn-2 position. Oleaginous yeasts provide an alternative source of lipids for human nutrition. However, these yeasts also exclude palmitic acid from the sn-2 position of their triacylglycerol. Here we show that Yarrowia lipolytica can be engineered to produce triacylglycerol with more than 60% of the palmitic acid in the sn-2 position, by expression of lysophosphatidic acid acyltransferases with palmitoyl-Coenzyme A specificity. The engineered Y. lipolytica strains can be cultured on glycerol, glucose, palm oil or a mixture of substrates, under nitrogen limited condition, to produce triacylglycerol with a fatty acid composition that resembles human milk fat, in terms of the major molecular species (palmitic, oleic and linoleic acids). Culture on palm oil or a mixture of glucose and palm oil produced the highest lipid titre and a triacylglycerol composition that is most similar with human milk fat. Our data show that an oleaginous yeast can be engineered to produce a human milk fat substitute (β-palmitate), that could be used as an ingredient in infant formulas.

  • Journal article
    Ward VC, Ledesma-Amaro R, 2022,

    Editorial overview: chemical biotechnology.

    , Current Opinion in Biotechnology, Vol: 75, Pages: 102732-102732, ISSN: 0958-1669
  • Journal article
    Lv X, Jin K, Sun G, Ledesma Amaro R, Liu Let al., 2022,

    Microscopy imaging of living cells in metabolic engineering

    , Trends in Biotechnology, Vol: 40, Pages: 752-765, ISSN: 0167-7799

    Microscopy imaging of living cells is becoming a pivotal, noninvasive, and highly specific tool in metabolic engineering to visualize molecular dynamics in industrial microorganisms. This review describes the different microscopy methods, from fluorescence to super resolution, with application in microbial bioengineering. Firstly, the role and importance of microscopy imaging is analyzed in the context of strain design. Then, the advantages and disadvantages of different microscopy technologies are discussed, including confocal laser scanning microscopy (CLSM), spatial light interference microscopy (SLIM), and super-resolution microscopy, followed by their applications in synthetic biology. Finally, the future perspectives of live-cell imaging and their potential to transform microbial systems are analyzed. This review provides theoretical guidance and highlights the importance of microscopy in understanding and engineering microbial metabolism.

  • Journal article
    Kotta-Loizou I, Coutts RHA, Ictv Report Consortium, 2022,

    ICTV virus taxonomy profile: polymycoviridae 2022.

    , Journal of General Virology, Vol: 103, Pages: 1-2, ISSN: 0022-1317

    Members of the family Polymycoviridae are small viruses with multi-segmented and non-conventionally encapsidated double-stranded (ds) RNA genomes. Typically, polymycoviruses have four genomic segments, although some have up to eight. The genus Polymycovirus includes several species whose members infect fungi (ascomycetes and basidiomycetes), and oomycetes, altering host morphology, sporulation, growth and virulence. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Polymycoviridae, which is available at ictv.global/report/polymycoviridae.

  • Journal article
    Leong JX, Raffeiner M, Spinti D, Langin G, Franz-Wachtel M, Guzman AR, Kim J-G, Pandey P, Minina AE, Macek B, Hafren A, Bozkurt TO, Mudgett MB, Boernke F, Hofius D, Uestuen Set al., 2022,

    A bacterial effector counteracts host autophagy by promoting degradation of an autophagy component

    , EMBO JOURNAL, Vol: 41, ISSN: 0261-4189
  • Journal article
    Molyneaux PL, Maher TM, authors of CYFRA 21-1 predicts progression in IPF; a prospective longitudinal analysis of the PROFILE cohort, 2022,

    Reply to: the need for a CYFRA 21-1 cut-off value to predict clinical progression of IPF in clinical practice.

    , American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X
  • Journal article
    King J, Nichols A, Bentley S, Carr S, Davies Jet al., 2022,

    An update on CFTR modulators as new therapies for Cystic Fibrosis

    , Paediatric Drugs, Vol: 24, Pages: 321-333, ISSN: 1174-5878

    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.

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