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  • Journal article
    Barkan-Oeztuerk H, Menner A, Bismarck A, 2022,

    Polymerised high internal phase emulsion micromixers for continuous emulsification

  • Journal article
    Rhodes J, 2022,

    Population genomics confirms acquisition of drug resistant Aspergillus fumigatus infection by humans from the environment

    , Nature Microbiology, Vol: 7, ISSN: 2058-5276

    Infections caused by the fungal pathogen Aspergillus fumigatus are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about how susceptible patients acquire infection from drug resistant genotypes in the environment. Here, we present a population genomic analysis of 218 A. fumigatus from across the United Kingdom and Ireland (comprising 153 clinical isolates from 143 patients, and 65 environmental isolates). First, phylogenomic analysis shows strong genetic structuring into two clades (‘A’ and ‘B’) with little interclade recombination and the majority of environmental azole resistance found within Clade A. Secondly, we show occurrences where azole resistant isolates of near identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Third, genome-scans identified selective sweeps across multiple regions indicating a polygenic basis to the trait in some genetic backgrounds. These signatures of positive selection are seen for loci containing the canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, whilst other regions under selection have no defined function. Lastly, pangenome analysis identified genes linked to azole resistance and novel resistance mechanisms. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.

  • Journal article
    Lee HJ, Ehsan M, Zhang X, Katsube S, Munk CF, Wang H, Ahmed W, Kumar A, Byrne B, Loland CJ, Guan L, Liu X, Chae PSet al., 2022,

    Development of 1,3-acetonedicarboxylate-derived glucoside amphiphiles (ACAs) for membrane protein study

    , CHEMICAL SCIENCE, Vol: 13, Pages: 5750-5759, ISSN: 2041-6520
  • Journal article
    Sun M, Gao AX, Ledesma-Amaro R, Li A, Wang R, Nie J, Zheng P, Yang Y, Bai Z, Liu Xet al., 2022,

    Hypersecretion of OmlA antigen in Corynebacterium glutamicum through high-throughput based development process

    , Applied Microbiology and Biotechnology, Vol: 106, Pages: 2953-2967, ISSN: 0175-7598

    Outer membrane lipoprotein A (OmlA) is a vaccine antigen against porcine contagious pleuropneumonia (PCP), a disease severely affecting the swine industry. Here, we aimed to systematically potentiate the secretory production of OmlA in Corynebacterium glutamicum (C. glutamicum), a widely used microorganism in the food industry, by establishing a holistic development process based on our high-throughput culture platform. The expression patterns, expression element combinations, medium composition, and induction conditions were comprehensively screened or optimized in microwell plates (MWPs), followed by fermentation parameter optimization in a 4 × 1 L parallel fermentation system (CUBER4). An unprecedented yield of 1.01 g/L OmlA was ultimately achieved in a 5-L bioreactor following the scaling-up strategy of fixed oxygen mass transfer coefficient (kLa), and the produced OmlA antigen showed well-protective immunity against Actinobacillus pleuropneumoniae challenge. This result provides a rapid and reliable pipeline to achieve the hyper-production of OmlA, and possibly other recombinant vaccines, in C. glutamicum.Key Points• Established a holistic development process and applied it to potentiate the secretion of OmlA.• The secretion of OmlA reached an unprecedented yield of 1.01 g/L.• The recombinant OmlA antigen induced efficient protective immunity.

  • Journal article
    Fu M, Zhang H, Yin M, Han Z, Bai Q, Peng Y, Shafik K, Zhai L, Hong N, Xu W, Wang G, Kotta-Loizou Iet al., 2022,

    A novel heptasegmented positive-sense single-stranded RNA virus from the phytopathogenic fungus colletotrichum fructicola

    , Journal of Virology, Vol: 96, Pages: 1-14, ISSN: 0022-538X

    In this study, a novel positive-sense single-stranded RNA (+ssRNA) mycovirus, tentatively named Colletotrichum fructicola RNA virus 1 (CfRV1), was identified in the phytopathogenic fungus Colletotrichum fructicola. CfRV1 has seven genomic components, encoding seven proteins from open reading frames (ORFs) flanked by highly conserved untranslated regions (UTRs). Proteins encoded by ORFs 1, 2, 3, 5, and 6 are more similar to the putative RNA-dependent RNA polymerase (RdRp), hypothetical protein (P2), methyltransferase, and two hypothetical proteins of Hadaka virus 1 (HadV1), a capsidless 10- or 11-segmented +ssRNA virus, while proteins encoded by ORFs 4 and 7 showed no detectable similarity to any known proteins. Notably, proteins encoded by ORFs 1 to 3 also share considerably high similarity with the corresponding proteins of polymycoviruses. Phylogenetic analysis conducted based on the amino acid sequence of CfRV1 RdRp and related viruses placed CfRV1 and HadV1 together in the same clade, close to polymycoviruses and astroviruses. CfRV1-infected C. fructicola strains demonstrate a moderately attenuated growth rate and virulence compared to uninfected isolates. CfRV1 is capsidless and potentially encapsulated in vesicles inside fungal cells, as revealed by transmission electron microscopy. CfRV1 and HadV1 are +ssRNA mycoviruses closely related to polymycoviruses and astroviruses, represent a new linkage between +ssRNA viruses and the intermediate double-stranded RNA (dsRNA) polymycoviruses, and expand our understanding of virus diversity, taxonomy, evolution, and biological traits. IMPORTANCE A scenario proposing that dsRNA viruses evolved from +ssRNA viruses is still considered controversial due to intergroup knowledge gaps in virus diversity. Recently, polymycoviruses and hadakaviruses were found as intermediate dsRNA and +ssRNA stages, respectively, between +ssRNA and dsRNA viruses. Here, we identified a novel +ssRNA mycovirus, Colletotrichum fructicola RNA virus

  • Journal article
    Wang K, Shi T-Q, Wang J, Wei P, Ledesma-Amaro R, Ji X-Jet al., 2022,

    Engineering the lipid and fatty acid metabolism in Yarrowia lipolytica for sustainable production of high oleic oils

    , ACS Synthetic Biology, Vol: 11, Pages: 1542-1554, ISSN: 2161-5063

    Oleic acid is widely applied in the chemical, material, nutritional, and pharmaceutical industries. However, the current production of oleic acid via high oleic plant oils is limited by the long growth cycle and climatic constraints. Moreover, the global demand for high oleic plant oils, especially the palm oil, has emerged as the driver of tropical deforestation causing tropical rainforest destruction, climate change, and biodiversity loss. In the present study, an alternative and sustainable strategy for high oleic oil production was established by reprogramming the metabolism of the oleaginous yeast Yarrowia lipolytica using a two-layer "push-pull-block" strategy. Specifically, the fatty acid synthesis pathway was first engineered to increase oleic acid proportion by altering the fatty acid profiles. Then, the content of storage oils containing oleic acid was boosted by engineering the synthesis and degradation pathways of triacylglycerides. The strain resulting from this two-layer engineering strategy produced the highest titer of high oleic microbial oil reaching 56 g/L with 84% oleic acid in fed-batch fermentation, representing a remarkable improvement of a 110-fold oil titer and 2.24-fold oleic acid proportion compared with the starting strain. This alternative and sustainable method for high oleic oil production shows the potential of substitute planting.

  • Journal article
    van Tonder AJ, Ellis HC, Churchward CP, Kumar K, Ramadan N, Benson S, Parkhill J, Moffatt MF, Loebinger MR, Cookson WOCet al., 2022,

    <i>Mycobacterium avium</i> complex (MAC) genomics and transmission in a London hospital

    <jats:title>Abstract</jats:title><jats:p>Non-tuberculous mycobacteria (NTM) are ubiquitous environmental microorganisms and opportunistic pathogens in individuals with pre-existing lung conditions such as cystic fibrosis (CF) and non-CF bronchiectasis (BX). Whilst recent studies of <jats:italic>Mycobacterium abscessus</jats:italic> have identified transmission within single CF centres as well as nationally and globally, transmission of other NTM species is less well studied. We sequenced 996 Mycobacterium avium complex (MAC) isolates from CF and non-CF patients at the Royal Brompton Hospital (RBH), London. Genomic analysis was used to analyse local transmission. Epidemiological links were identified from patient records. These and previously published genomes were used to characterise global population structures. Analysis of the three predominant MAC species identified putative transmission clusters that contained patients with CF, BX and other lung conditions, although few epidemiological links could be identified. For <jats:italic>M. avium</jats:italic>, lineages were largely limited to single countries, whilst for <jats:italic>M. chimaera</jats:italic>, global transmission clusters previously associated with heater cooler units (HCUs) were found. However, the immediate ancestor of the lineage causing the major HCU-associated outbreak was a lineage already circulating in patients with pre-existing lung conditions. CF and non-CF patients shared transmission chains even in the presence of CF patient-focussed hospital control measures, although the lack of epidemiological links suggested that most transmission is indirect and may involve environmental intermediates or else asymptomatic carriage in the wider population. The major HCU-associated <jats:italic>M. chimaera</jats:italic> lineage being derived from an already circulating lineage, suggests that HCUs, while being responsible for a major global

  • Journal article
    Barber CM, Cullinan P, Feary J, Fishwick D, Hoyle J, Mainman H, Walters GIet al., 2022,

    British Thoracic Society Clinical Statement on occupational asthma

    , Thorax, Vol: 77, Pages: 433-442, ISSN: 0040-6376
  • Journal article
    Lamoriniere S, Jones MP, Ho K, Kalinka G, Shaffer MSP, Bismarck Aet al., 2022,

    Carbon nanotube enhanced carbon Fibre-Poly(ether ether ketone) interfaces in model hierarchical composites

  • Journal article
    Stone P, Minelli C, Feary J, Roberts CM, Quint J, Hurst JRet al., 2022,

    NEWS2’ as an objective assessment of hospitalised COPD exacerbation severity

    , International Journal of COPD, Vol: 17, Pages: 763-772, ISSN: 1176-9106

    Introduction: There is currently no accepted way to risk-stratify hospitalised exacerbations of chronic obstructive pulmonary disease (COPD). We hypothesised that the revised UK National Early Warning Score (NEWS2) calculated at admission would predict inpatient mortality, need for non-invasive ventilation (NIV) and length-of-stay.Methods: We included data from 52,284 admissions for exacerbation of COPD. Data were divided into development and validation cohorts. Logistic regression was used to examine relationships between admission NEWS2 and outcome measures. Predictive ability of NEWS2 was assessed using area under receiver operating characteristic curves (AUC). We assessed the benefit of including other baseline data in the prediction models and assessed whether these variables themselves predicted admission NEWS2.Results: 53% of admissions had low risk, 24% medium risk and 23% a high risk NEWS2 in the development cohort. The proportions dying as an inpatient were 2.2%, 3.6% and 6.5% by NEWS2 risk category, respectively. The proportions needing NIV were 4.4%, 9.2% and 18.0%, respectively. NEWS2 was poorly predictive of length-of-stay (AUC: 0.59[0.57– 0.61]). In the external validation cohort, the AUC (95% CI) for NEWS2 to predict inpatient death and need for NIV were 0.72 (0.68– 0.77) and 0.70 (0.67– 0.73). Inclusion of patient demographic factors, co-morbidity and COPD severity improved model performance. However, only 1.34% of the variation in admission NEWS2 was explained by these baseline variables.Conclusion: The generic NEWS2 risk assessment tool, readily calculated from simple physiological data, predicts inpatient mortality and need for NIV (but not length-of-stay) at exacerbations of COPD. NEWS2 therefore provides a classification of hospitalised COPD exacerbation severity.

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