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Journal articleChen W, Park Y-K, Studená L, et al., 2024,
Synthetic, marine, light-driven, autotroph-heterotroph co-culture system for sustainable β-caryophyllene production
, Bioresource Technology, Vol: 410, ISSN: 0960-8524Applying low-cost substrate is critical for sustainable bioproduction. Co-culture of phototrophic and heterotrophic microorganisms can be a promising solution as they can use CO2 and light as feedstock. This study aimed to create a light-driven consortium using a marine cyanobacterium Synechococcus sp. PCC 7002 and an industrial yeast Yarrowia lipolytica. First, the cyanobacterium was engineered to accumulate and secrete sucrose by regulating the expression of genes involved in sucrose biosynthesis and transport, resulting in 4.0 g/L of sucrose secretion. Then, Yarrowia lipolytica was engineered to efficiently use sucrose and produce β-caryophyllene that has various industrial applications. Then, co- and sequential-culture were optimized with different induction conditions and media compositions. A maximum β-caryophyllene yield of 14.1 mg/L was obtained from the co-culture. This study successfully established an artificial light-driven consortium based on a marine cyanobacterium and Y. lipolytica, and provides a foundation for sustainable bioproduction from CO2 and light through co-culture systems.
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Journal articleQuintero Santofimio V, Knox-Brown B, Potts J, et al., 2024,
Small airways obstruction and mortality: findings from the UK Biobank
, Chest, Vol: 166, Pages: 712-720, ISSN: 0012-3692Background:Small airways obstruction (SAO) is common in general populations. It has been associated with respiratory symptoms, cardiometabolic diseases and progression to chronic obstructive pulmonary disease over time. Whether SAO predicts mortality is largely unknown.Research QuestionIs spirometry-defined SAO associated with increased mortality?Methods:We analysed data from 252,877 adult participants, aged 40-69 at baseline, in the UK Biobank who had provided good quality spirometry measurements. We defined SAO as the ratio of the forced expiratory volume in three seconds to the forced expiratory volume in six seconds less than the lower limit of normal (FEV3/FEV6<LLN). We considered SAO to be isolated if present when the forced expiratory volume in one second to FEV6 ratio was normal (FEV1/FEV6≥LLN). We used a multivariable Cox regression model to assess the association of SAO, and isolated SAO, with all-cause and disease-specific mortality. We investigated sex differences in these associations and repeated the primary analysis excluding ever smokers. All models were adjusted for potential confounders such as sex, body mass index, smoking status, smoking pack-years, assessment centre, Townsend deprivation index and ethnicity.Results:We identified 59,744 participants with SAO of which 24,004 had isolated SAO. A total of 5,009 deaths were reported over a median of 12.8 years of follow-up. Participants with SAO had increased all-cause (HR=1.31, 95%CI 1.26-1.36), cardiovascular (HR=1.39, 95%CI 1.29-1.51), respiratory (HR=2.20, 95%CI 1.92-2.51), and neoplasm (HR=1.23, 95%CI 1.17-1.29) mortality risk. These associations were not modified by sex. However, in never smokers, only respiratory and cardiovascular mortality risk was associated with SAO. Isolated SAO was also associated with an increased mortality risk (HR=1.14, 95%CI 1.07-1.20).Interpretation:Individuals with SAO have an increased risk of all-cause and disease-specific mortality. Further studies are nee
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Journal articleYuen ELH, Tumtas Y, King F, et al., 2024,
A pathogen effector co-opts a host RabGAP protein to remodel pathogen interface and subvert defense-related secretion
, Science Advances, Vol: 10, ISSN: 2375-2548Pathogens have evolved sophisticated mechanisms to manipulate host cell membrane dynamics, a crucial adaptation to survive in hostile environments shaped by innate immune responses. Plant-derived membrane interfaces, engulfing invasive hyphal projections of fungal and oomycete pathogens, are prominent junctures dictating infection outcomes. Understanding how pathogens transform these host-pathogen interfaces to their advantage remains a key biological question. Here, we identified a conserved effector, secreted by plant pathogenic oomycetes, that co-opts a host Rab GTPase-activating protein (RabGAP), TOPGAP, to remodel the host-pathogen interface. The effector, PiE354, hijacks TOPGAP as a susceptibility factor to usurp its GAP activity on Rab8a, a key Rab GTPase crucial for defense-related secretion. By hijacking TOPGAP, PiE354 purges Rab8a from the plasma membrane, diverting Rab8a-mediated immune trafficking away from the pathogen interface. This mechanism signifies an uncanny evolutionary adaptation of a pathogen effector in co-opting a host regulatory component to subvert defense-related secretion, thereby providing unprecedented mechanistic insights into the reprogramming of host membrane dynamics by pathogens.
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Journal articleKappel D, Gifford H, Brackin A, et al., 2024,
Genomic epidemiology describes introduction and outbreaks of antifungal drug-resistant Candida auris
, npj Antimicrobials and Resistance, Vol: 2, ISSN: 2731-8745Candida auris is a globally emerged fungal pathogen causing nosocomial invasive infections. Here, we use cutting-edge genomic approaches to elucidate the temporal and geographic epidemiology of drug-resistant C. auris within the UK. We analysed a representative sample of over 200 isolates from multiple UK hospitals to assess the number and timings of C. auris introductions and infer subsequent patterns of inter- and intra-hospital transmission of azole drug-resistant isolates. We identify at least one introduction from Clade I and two from Clade III into the UK, and observe temporal and geographical evidence for multiple transmission events of antifungal drug resistant isolates between hospitals and identified local within-hospital patient-to-patient transmission events. Our study confirms outbreaks of drug-resistant C. auris are linked and that transmission amongst patients occurs, explaining local hospital outbreaks, and demonstrating a need for improved epidemiological surveillance of C. auris to protect patients and healthcare services.
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Journal articleWang K, Yin M, Sun M-L, et al., 2024,
Engineering Yarrowia lipolytica for efficient synthesis of geranylgeraniol
, Journal of Agricultural and Food Chemistry, Vol: 72, Pages: 20568-20581, ISSN: 0021-8561Geranylgeraniol (GGOH) is a crucial component in fragrances and essential oils, and a valuable precursor of vitamin E. It is primarily extracted from the oleoresin of Bixa orellana, but is challenged by long plant growth cycles, severe environmental pollution, and low extraction efficiency. Chemically synthesized GGOH typically comprises a mix of isomers, making the separation process both challenging and costly. Advancements in synthetic biology have enabled the construction of microbial cell factories for GGOH production. In this study, Yarrowia lipolytica was engineered to efficiently synthesize GGOH by expressing heterologous phosphatase genes, enhancing precursor supplies of farnesyl diphosphate, geranylgeranyl pyrophosphate, and acetyl-CoA, and downregulating the squalene synthesis pathway by promoter engineering. Additionally, optimizing fermentation conditions and reducing reactive oxygen species significantly increased the GGOH titer to 3346.47 mg/L in a shake flask. To the best of our knowledge, this is the highest reported GGOH titer in shaking flasks to date, setting a new benchmark for terpenoid production.
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Journal articleFeary J, Devaraj A, Burton M, et al., 2024,
Artificial stone silicosis: a UK case series.
, Thorax, Vol: 79, Pages: 979-981Silicosis due to artificial stone (AS) has emerged over the last decade as an increasing global issue. We report the first eight UK cases. All were men; median age was 34 years (range 27-56) and median stone dust exposure was 12.5 years (range 4-40) but in 4 cases was 4-8 years. One is deceased; two were referred for lung transplant assessment. All cases were dry cutting and polishing AS worktops with inadequate safety measures. Clinical features of silicosis can closely mimic sarcoidosis. UK cases are likely to increase, with urgent action needed to identify cases and enforce regulations.
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Journal articleHowlett P, Gan J, Lesosky M, et al., 2024,
Relationship between cumulative silica exposure and silicosis: a systematic review and dose-response meta-analysis.
, Thorax, Vol: 79, Pages: 934-942BACKGROUND: Silicosis, a chronic respiratory disease caused by crystalline silica exposure, is a persistent global lung health issue. No systematic review of the relationship between cumulative respirable crystalline silica (RCS) exposure and silicosis exists. UK exposure limits are currently under review. We therefore performed a systematic review and dose-response meta-analysis of this relationship. METHODS: Web of Science, Medline and Embase were searched on 24 February 2023. Studies of radiographic, autopsy or death certificate silicosis, with an estimated average follow-up of over 20 years since first employment, were included. Cumulative silicosis risk methods were compared. The relative risks (RR) of silicosis at increasing cumulative exposures were calculated and used to estimate the absolute risk reduction (ARR). RESULTS: Eight eligible studies, including 10 cohorts, contributed 8792 cases of silicosis among 65 977 participants. Substantial differences in cumulative risk estimates between methodologies exist. Using the same method, we observed higher cumulative silicosis risks among mining compared with non-mining cohorts. A reduction from 4 to 2 mg/m³-years in cumulative RCS exposure corresponded to substantial risk reductions among miners (RR 0.23 (95% CI 0.18 to 0.29, I2=92.9%) with an ARR of 323 (95% CI 298 to 344) per 1000) and non-miners (RR 0.55 (95% CI 0.36 to 0.83, I2=77.0%) with an ARR of 23 (95% CI 9 to 33) per 1000). CONCLUSION: Despite significant heterogeneity, our findings support a reduction in permissible exposure limits from 0.1 mg/m3 to 0.05 mg/m³, particularly among mining populations. Further research is needed among non-miners as only two studies were eligible.
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Journal articleYu W, Jin K, Wang D, et al., 2024,
De novo engineering of programmable and multi-functional biomolecular condensates for controlled biosynthesis
, Nature Communications, Vol: 15, ISSN: 2041-1723There is a growing interest in the creation of engineered condensates formed via liquid-liquid phase separation (LLPS) to exert precise cellular control in prokaryotes. However, de novo design of cellular condensates to control metabolic flux or protein translation remains a challenge. Here, we present a synthetic condensate platform, generated through the incorporation of artificial, disordered proteins to realize specific functions in Bacillus subtilis. To achieve this, the "stacking blocks" strategy is developed to rationally design a series of LLPS-promoting proteins for programming condensates. Through the targeted recruitment of biomolecules, our investigation demonstrates that cellular condensates effectively sequester biosynthetic pathways. We successfully harness this capability to enhance the biosynthesis of 2'-fucosyllactose by 123.3%. Furthermore, we find that condensates can enhance the translation specificity of tailored enzyme fourfold, and can increase N-acetylmannosamine titer by 75.0%. Collectively, these results lay the foundation for the design of engineered condensates endowed with multifunctional capacities.
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Journal articleDavies JC, Polineni D, Boyd AC, et al., 2024,
Lentiviral Gene Therapy for Cystic Fibrosis: A Promising Approach and First-In-Human Trial.
, Am J Respir Crit Care MedCystic fibrosis is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. While cystic fibrosis is a multi-organ disease, the leading causes of morbidity and mortality are related to progressive lung disease. Current understanding of the effects of the broad spectrum of CFTR mutations on CFTR function has allowed for the development of CFTR modulator therapies. Despite the remarkable impact that these therapies have had, there remains a significant proportion of people with cystic fibrosis (estimated at 10-15% of the global cystic fibrosis population) who are genetically ineligible for, or intolerant to, current CFTR-targeting therapies and whose therapeutic needs remain unmet. Inhaled genetic therapies offer the prospect of addressing the unmet pulmonary treatment need in people with cystic fibrosis, with several approaches, including gene addition therapy (the focus of this review), RNA-based therapies, antisense oligonucleotides and gene editing, being explored. Various non-viral and viral vectors have been investigated for cystic fibrosis gene addition therapy for mutation-agnostic restoration of CFTR function in the lungs. Lentiviral vectors offer the prospect of highly efficient and long-lasting gene expression, and the potential to be safely and, in contrast to other commonly used viral vectors, effectively re-dosed. A third-generation lentiviral vector pseudotyped with Sendai virus F and HN envelope proteins (rSIV.F/HN) has been developed for the treatment of cystic fibrosis. Promising preclinical results support the progression of this vector carrying a full-length CFTR transgene (BI 3720931) into a first-in-human clinical trial expected to begin in 2024. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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Journal articleCioccolo S, Barritt JD, Pollock N, et al., 2024,
The mycobacterium lipid transporter MmpL3 is dimeric in detergent solution, SMALPs and reconstituted nanodiscs
, RSC Chemical Biology, Vol: 5, Pages: 901-913, ISSN: 2633-0679The mycobacterial membrane protein large 3 (MmpL3) transports key precursor lipids to the outer membrane of Mycobacterium species. Multiple structures of MmpL3 from both M. tuberculosis and M. smegmatis in various conformational states indicate that the protein is both structurally and functionally monomeric. However, most other resistance, nodulation and cell division (RND) transporters structurally characterised to date are either dimeric or trimeric. Here we present an in depth biophysical and computational analysis revealing that MmpL3 from M. smegmatis exists as a dimer in a variety of membrane mimetic systems (SMALPs, detergent-based solution and nanodiscs). Sucrose gradient separation of MmpL3 populations from M. smegmatis, reconstituted into nanodiscs, identified monomeric and dimeric populations of the protein using laser induced liquid bead ion desorption (LILBID), a native mass spectrometry technique. Preliminary cryo-EM analysis confirmed that MmpL3 forms physiological dimers. Untargeted lipidomics experiments on membrane protein co-purified lipids revealed PE and PG lipid classes were predominant. Molecular dynamics simulations, in the presence of physiologically-relevant lipid compositions revealed the likely dimer interface.
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