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  • Journal article
    Bonturi N, Pinheiro MJ, de Oliveira PM, Rusadze E, Eichinger T, Liudžiūtė G, De Biaggi JS, Brauer A, Remm M, Miranda EA, Ledesma-Amaro R, Lahtvee P-Jet al., 2022,

    Development of a dedicated Golden Gate Assembly Platform (RtGGA) for Rhodotorula toruloides.

    , Metabolic Engineering Communications, Vol: 15, Pages: 1-10, ISSN: 2214-0301

    Rhodotorula toruloides is a potential chassis for microbial cell factories as this yeast can metabolise different substrates into a diverse range of natural products, but the lack of efficient synthetic biology tools hinders its applicability. In this study, the modular, versatile and efficient Golden Gate DNA assembly system (RtGGA) was adapted to the first basidiomycete, an oleaginous yeast R. toruloides. R. toruloides CCT 0783 was sequenced, and used for the GGA design. The DNA fragments were assembled with predesigned 4-nt overhangs and a library of standardized parts was created containing promoters, genes, terminators, insertional regions, and resistance genes. The library was combined to create cassettes for the characterization of promoters strength and to overexpress the carotenoid production pathway. A variety of reagents, plasmids, and strategies were used and the RtGGA proved to be robust. The RtGGA was used to build three versions of the carotenoid overexpression cassette by using different promoter combinations. The cassettes were transformed into R. toruloides and the three new strains were characterized. Total carotenoid concentration increased by 41%. The dedicated GGA platform fills a gap in the advanced genome engineering toolkit for R. toruloides, enabling the efficient design of complex metabolic pathways.

  • Journal article
    Cao L, Yin M, Shi T-Q, Lin L, Ledesma-Amaro R, Ji X-Jet al., 2022,

    Engineering Yarrowia lipolytica to produce nutritional fatty acids: Current status and future perspectives.

    , Synthetic and Systems Biotechnology, Vol: 7, Pages: 1024-1033, ISSN: 2405-805X

    Due to their vital physiological functions, nutritional fatty acids have great potential as nutraceutical food supplements for preventing an array of diseases such as inflammation, depression, arthritis, osteoporosis, diabetes and cancer. Microbial biosynthesis of fatty acids follows the trend of sustainable development, as it enables green, environmentally friendly and efficient production. As a natural oleaginous yeast, Yarrowia lipolytica is especially well-suited for the production of fatty acids. Moreover, it has a variety of genetic engineering tools and novel metabolic engineering strategies that make it a robust workhorse for the production of an array of value-added products. In this review, we summarize recent advances in metabolic engineering strategies for accumulating nutritional fatty acids in Y. lipolytica, including conjugated fatty acids and polyunsaturated fatty acids. In addition, the future prospects of nutritional fatty acid production using the Y. lipolytica platform are discussed in light of the current progress, challenges, and trends in this field. Finally, guidelines for future studies are also emphasized.

  • Journal article
    Short C, Abkir M, Pinnell S, Proctor O, Saunders CJ, Davies JCet al., 2022,

    Migration is not the perfect answer: how the cross‐talk error correction for multiple breath nitrogen washout (MBWN <sub>2</sub> ) parameters differs on directly collected vs legacy data

    , Pediatric Pulmonology, ISSN: 8755-6863
  • Journal article
    Dawes TJW, McCabe C, Dimopoulos K, Stewart I, Bax S, Harries C, Samaranayake CB, Kempny A, Molyneaux PL, Seitler S, Semple T, Li W, George PM, Kouranos V, Chua F, Renzoni EA, Kokosi M, Jenkins G, Wells AU, Wort SJ, Price LCet al., 2022,

    Phosphodiesterase 5 inhibitor treatment and survival in interstitial lung disease pulmonary hypertension: A Bayesian retrospective observational cohort study.

    , Respirology

    BACKGROUND AND OBJECTIVE: Pulmonary hypertension is a life-limiting complication of interstitial lung disease (ILD-PH). We investigated whether treatment with phosphodiesterase 5 inhibitors (PDE5i) in patients with ILD-PH was associated with improved survival. METHODS: Consecutive incident patients with ILD-PH and right heart catheterisation, echocardiography and spirometry data were followed from diagnosis to death, transplantation or censoring with all follow-up and survival data modelled by Bayesian methods. RESULTS: The diagnoses in 128 patients were idiopathic pulmonary fibrosis (n = 74, 58%), hypersensitivity pneumonitis (n = 17, 13%), non-specific interstitial pneumonia (n = 12, 9%), undifferentiated ILD (n = 8, 6%) and other lung diseases (n = 17, 13%). Final outcomes were death (n = 106, 83%), transplantation (n = 9, 7%) and censoring (n = 13, 10%). Patients treated with PDE5i (n = 50, 39%) had higher mean pulmonary artery pressure (median 38 mm Hg [interquartile range, IQR: 34, 43] vs. 35 mm Hg [IQR: 31, 38], p = 0.07) and percentage predicted forced vital capacity (FVC; median 57% [IQR: 51, 73] vs. 52% [IQR: 45, 66], p=0.08) though differences did not reach significance. Patients treated with PDE5i survived longer than untreated patients (median 2.18 years [95% CI: 1.43, 3.04] vs. 0.94 years [0.69, 1.51], p = 0.003) independent of all other prognostic markers by Bayesian joint-modelling (HR 0.39, 95% CI: 0.23, 0.59, p < 0.001) and propensity-matched analyses (HR 0.38, 95% CI: 0.22, 0.58, p < 0.001). Survival difference with treatment was significantly larger if right ventricular function was normal, rather than abnormal, at presentation (+2.55 years, 95% CI: -0.03, +3.97 vs. +0.98 years, 95% CI: +0.47, +2.00, p = 0.04). CONCLUSION: PDE5i treatment i

  • Journal article
    Darvishi F, Rafatiyan S, Abbaspour Motlagh Moghaddam MH, Atkinson E, Ledesma-Amaro Ret al., 2022,

    Applications of synthetic yeast consortia for the production of native and non-native chemicals.

    , Critical Reviews in Biotechnology, Pages: 1-16, ISSN: 0738-8551

    The application of microbial consortia is a new approach in synthetic biology. Synthetic yeast consortia, simple or complex synthetic mixed cultures, have been used for the production of various metabolites. Cooperation between the members of a consortium and cross-feeding can be applied to create stable microbial communication. These consortia can: consume a variety of substrates, perform more complex functions, produce metabolites in high titer, rate, and yield (TRY), and show higher stability during industrial fermentations. Due to the new research context of synthetic consortia, few yeasts were used to build these consortia, including Saccharomyces cerevisiae, Pichia pastoris, and Yarrowia lipolytica. Here, application of the yeasts for design of synthetic microbial consortia and their advantages and bottlenecks for effective and robust production of valuable metabolites from bioresource, including: cellulose, xylose, glycerol and so on, have been reviewed. Key trends and challenges are also discussed for the future development of synthetic yeast consortia.

  • Journal article
    Shaw W, Lu X, Ellis T, 2022,

    Screening microbially produced Δ9-tetrahydrocannabinol using a yeast biosensor workflow

    , Nature Communications, ISSN: 2041-1723

    Microbial production of cannabinoids promises to provide a consistent, cheaper, and more sustainable supply of these important therapeutic molecules. However, scaling production to compete with traditional plant-based sources is challenging. Our ability to make strain variants greatly exceeds our capacity to screen and identify high producers, creating a bottleneck in metabolic engineering efforts. Here, we present a yeast-based biosensor for detecting microbially produced Δ9-tetrahydrocannabinol (THC) to increase throughput and lower the cost of screening. We port five human cannabinoid G protein-coupled receptors (GPCRs) into yeast, showing the cannabinoid type 2 receptor, CB2R, can couple to the yeast pheromone response pathway and report on the concentration of a variety of cannabinoids over a wide dynamic and operational range. We demonstrate that our cannabinoid biosensor can detect THC from microbial cell culture and use this as a tool for measuring relative production yields from a library of Δ9-tetrahydrocannabinol acid synthase (THCAS) mutants.

  • Journal article
    Caro-Astorga J, Lee K, Ellis T, 2022,

    Increasing bacterial cellulose compression resilience with glycerol or PEG400 as a route to more robust engineered living materials

    , Carbohydrate Polymer Technologies and Applications, ISSN: 2666-8939

    Bacterial cellulose (BC) is one of the current natural materials at the edge of innovation in engineered living materials (ELMs) research due to its ease of growth and outstanding properties as a hydrogel. One of the main limitations of this material, however, is its quick dehydration in open environments as water molecules leave the porous network. Here we show that other solvents with higher evaporation temperatures, namely glycerol and polyethylene glycol (PEG), can play the same role as water within the BC structure interacting with cellulose fibres via hydrogen bonds. We demonstrate that these molecules provide up to a 130-fold improvement in the Young´s Modulus of BC hydrogels to compression forces in a concentration dependent manner. To take advantage of these effects for application in BC-based ELMs produced by Komagataeibacter rhaeticus, we also explored the effect of glycerol and PEG400 on the survival of the BC-producing bacteria in BC pieces. PEG400 at 20% doubled the material resilience to compression forces, still allowing bacteria to survive within the material for weeks. These results open further opportunities to explore new applications and stacked storage conditions.

  • Journal article
    Kotta-Loizou I, 2022,

    Molecular origins of transcriptional heterogeneity in diazotrophic Klebsiella oxytoca

    , mSystems, ISSN: 2379-5077

    Phenotypic heterogeneity in clonal bacterial batch cultures has been shown for a range of bacterial systems; however, the molecular origins of such heterogeneity and its magnitude are not well understood. Under conditions of extreme low-nitrogen stress in the model diazotroph Klebsiella oxytoca, we found remarkably high heterogeneity of nifHDK gene expression, which codes for the structural genes of nitrogenase, one key enzyme of the global nitrogen cycle. This heterogeneity limited the bulk observed nitrogen-fixing capacity of the population. Using dual-probe, single-cell RNA fluorescent in situ hybridization, we correlated nifHDK expression with that of nifLA and glnK-amtB, which code for the main upstream regulatory components. Through stochastic transcription models and mutual information analysis, we revealed likely molecular origins for heterogeneity in nitrogenase expression. In the wild type and regulatory variants, we found that nifHDK transcription was inherently bursty, but we established that noise propagation through signaling was also significant. The regulatory gene glnK had the highest discernible effect on nifHDK variance, while noise from factors outside the regulatory pathway were negligible. Understanding the basis of inherent heterogeneity of nitrogenase expression and its origins can inform biotechnology strategies seeking to enhance biological nitrogen fixation. Finally, we speculate on potential benefits of diazotrophic heterogeneity in natural soil environments.

  • Journal article
    McLachlan G, Alton EW, Boyd AC, Clark N, Davies JC, Gill DR, Griesenbach U, Hickmott J, Hyde SC, Miah K, Juarez Molina Cet al., 2022,

    Progress in Respiratory Gene Therapy.

    , Hum Gene Ther

    The prospect of gene therapy for inherited and acquired respiratory disease has energized the research community since the 1980s, with cystic fibrosis, as a monogenic disorder, driving early efforts to develop effective strategies. The fact that there are still no approved gene therapy products for the lung, despite many early phase clinical trials, illustrates the scale of the challenge: in the 1990s, first generation non-viral and viral vector systems demonstrated proof-of-concept but low efficacy. Since then, there has been steady progress towards improved vectors with the capacity to overcome at least some of the formidable barriers presented by the lung. In addition, the inclusion of features such as codon optimisation and promoters providing long-term expression have improved the expression characteristics of therapeutic transgenes. Early approaches were based on gene addition, where a new DNA copy of a gene is introduced to complement a genetic mutation: however, the advent of RNA-based products that can directly express a therapeutic protein or manipulate gene expression, together with the expanding range of tools for gene editing, has stimulated the development of alternative approaches. This review discusses the range of vector systems being evaluated for lung delivery; the variety of cargoes they deliver, including DNA, antisense oligonucleotides, mRNA, siRNA and peptide nucleic acids; and exemplifies progress in selected respiratory disease indications.

  • Journal article
    Schmeller DS, Urbach D, Bates K, Catalan J, Cogălniceanu D, Fisher MC, Friesen J, Füreder L, Gaube V, Haver M, Jacobsen D, Le Roux G, Lin Y-P, Loyau A, Machate O, Mayer A, Palomo I, Plutzar C, Sentenac H, Sommaruga R, Tiberti R, Ripple WJet al., 2022,

    Scientists' warning of threats to mountains.

    , Sci Total Environ, Vol: 853

    Mountains are an essential component of the global life-support system. They are characterized by a rugged, heterogenous landscape with rapidly changing environmental conditions providing myriad ecological niches over relatively small spatial scales. Although montane species are well adapted to life at extremes, they are highly vulnerable to human derived ecosystem threats. Here we build on the manifesto 'World Scientists' Warning to Humanity', issued by the Alliance of World Scientists, to outline the major threats to mountain ecosystems. We highlight climate change as the greatest threat to mountain ecosystems, which are more impacted than their lowland counterparts. We further discuss the cascade of "knock-on" effects of climate change such as increased UV radiation, altered hydrological cycles, and altered pollution profiles; highlighting the biological and socio-economic consequences. Finally, we present how intensified use of mountains leads to overexploitation and abstraction of water, driving changes in carbon stock, reducing biodiversity, and impacting ecosystem functioning. These perturbations can provide opportunities for invasive species, parasites and pathogens to colonize these fragile habitats, driving further changes and losses of micro- and macro-biodiversity, as well further impacting ecosystem services. Ultimately, imbalances in the normal functioning of mountain ecosystems will lead to changes in vital biological, biochemical, and chemical processes, critically reducing ecosystem health with widespread repercussions for animal and human wellbeing. Developing tools in species/habitat conservation and future restoration is therefore essential if we are to effectively mitigate against the declining health of mountains.

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