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Journal articleGerovasili V, Shah A, Singanayagam A, et al., 2022,
Journal articleMolyneaux PL, Fahy WA, Byrne AJ, et al., 2022,
OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a progressive and inevitably fatal condition for which there are a lack of effective biomarkers to guide therapeutic decision making. RATIONALE: To determine the relationship between serum levels of the cytokeratin fragment CYFRA 21-1 and disease progression and mortality in individuals with IPF enrolled in the PROFILE study. METHODS: CYFRA 21-1 was identified by immunohistochemistry in samples of human lung. Concentrations of CYFRA 21-1 were measured using an Elisa-based assay in serum, collected at baseline, 1- and 3-months, from 491 individuals with an incident diagnosis of IPF enrolled in the PROFILE study and from 100 control subjects. Study subjects were followed for a minimum of 3 years. MEASUREMENTS AND MAIN RESULTS: CYFRA 21-1 localises to hyperplastic epithelium in IPF lung. CYFRA 21-1 levels were significantly higher in IPF subjects compared to healthy controls in both discovery (n=132) (control 0.96±0.81 ng/mL versus IPF; 2.34±2.15 ng/mL, p < 0.0001) and validation (n=359) (control; 2.21±1.54 ng/mL and IPF; 4.13±2.77 ng/mL, p<0.0001) cohorts. Baseline levels of CYFRA 21-1 distinguished individuals at risk of 12-month disease progression (C-statistic 0.70 (95% CI 0.61-0.79), p < 0.0001) and were predictive of overall-mortality (HR 1.12 (1.06-1.19) per 1 ng/mL increase in CYFRA 21-1, p=0.0001). Furthermore, 3-month change in levels of CYFRA 21-1 separately predicted 12-month and overall survival in both the discovery and validation cohorts. CONCLUSIONS: CYFRA 21-1, a marker of epithelial damage and turnover, has the potential to be an important prognostic and therapeutic biomarker in individuals with IPF.
Journal articleFerrer J, Jiang Q, Menner A, et al., 2022,
Journal articleLedesma Amaro R, Stan G-B, Atkinson E, et al., 2022,
Resource-aware whole-cell model of division of labour in a two-strain consortium for complex substrate degradation, Microbial Cell Factories, Vol: 21, Pages: 1-12, ISSN: 1475-2859
BackgroundLow-cost sustainable feedstocks are essential for commercially viable biotechnologies. These feedstocks, often derived from plant or food waste, contain a multitude of different complex biomolecules which require multiple enzymes to hydrolyse and metabolise. Current standard biotechnology uses monocultures in which a single host expresses all the proteins required for the consolidated bioprocess. However, these hosts have limited capacity for expressing proteins before growth is impacted. This limitation may be overcome by utilising division of labour (DOL) in a consortium, where each member expresses a single protein of a longer degradation pathway.ResultsHere, we model a two-strain consortium, with one strain expressing an endohydrolase and a second strain expressing an exohydrolase, for cooperative degradation of a complex substrate. Our results suggest that there is a balance between increasing expression to enhance degradation versus the burden that higher expression causes. Once a threshold of burden is reached, the consortium will consistently perform better than an equivalent single-cell monoculture.ConclusionsWe demonstrate that resource-aware whole-cell models can be used to predict the benefits and limitations of using consortia systems to overcome burden. Our model predicts the region of expression where DOL would be beneficial for growth on starch, which will assist in making informed design choices for this, and other, complex-substrate degradation pathways.
Journal articleSeed MJ, Fowler K, Byrne L, et al., 2022,
Journal articleYu W, Jin K, Wu Y, et al., 2022,
A pathway independent multi-modular ordered control system based on thermosensors and CRISPRi improves bioproduction in Bacillus subtilis, Nucleic Acids Research, Vol: 50, Pages: 6587-6600, ISSN: 0305-1048
Dynamic regulation is an effective strategy for control of gene expression in microbial cell factories. In some pathway contexts, several metabolic modules must be controlled in a time dependent or ordered manner to maximize production, while the creation of genetic circuits with ordered regulation capacity still remains a great challenge. In this work, we develop a pathway independent and programmable system that enables multi-modular ordered control of metabolism in Bacillus subtilis. First, a series of thermosensors were created and engineered to expand their thresholds. Then we designed single-input-multi-output circuits for ordered control based on the use of thermosensors with different transition points. Meanwhile, a repression circuit was constructed by combining CRISPRi-based NOT gates. As a proof-of-concept, these genetic circuits were applied for multi-modular ordered control of 2′-fucosyllactose (2′-FL) biosynthesis, resulting in a production of 1839.7 mg/l in shake flask, which is 5.16-times that of the parental strain. In a 5-l bioreactor, the 2′-FL titer reached 28.2 g/l with down-regulation of autolysis. Taken together, this work provides programmable and versatile thermosensitive genetic toolkits for dynamic regulation in B. subtilis and a multi-modular ordered control framework that can be used to improve metabolic modules in other chassis cells and for other compounds.
Journal articleZhang D, Povysil G, Newton CA, et al., 2022,
Genome-wide rare variant studies of IPF patients of non-European ancestry have been understudied. Here, we evaluate the enrichment of rare genetic variants of 241 unrelated non-European cases, representing individuals of Latino, African, South Asian, East Asian, and Other Admixed ancestry. Gene burden analysis of deleterious rare (protein-truncating and missense) variants demonstrate an excess of TERT rare damaging variants (OR 67.1, 95% CI [23.1, 195.0], P = 9.4 x 10-14) in non-European subjects. Analysis by ancestry demonstrated an excess of rare, damaging TERT variants in the Latino subgroup (OR 80.9, 95% CI [17.3, 383.8], P = 2.6 x 10-8). Although the non-European group did not show enrichment of PARN, RTEL1, and KIF15 rare deleterious variants, these groups all showed a trend in the same direction as the European ancestry group. For TERT and KIF15, the inclusion of IPF patients of non-European ancestry led to a higher odds ratios and increased evidence in favor of rare deleterious variant contributions, thus demonstrating the increased power of multi-ethnic studies over single-ethnicity studies. To our knowledge, this is the first study that confirms the involvement of rare deleterious TERT variants for IPF patients of Latino and non-European ancestry. To better understand the genetic underpinnings of IPF patients of all ancestries, additional work will be needed to broaden patient recruitment to normalize imbalances.
Journal articleXu Y, Wang X, Zhang C, et al., 2022,
High-sugar diet causes health problems, many of which can be addressed with the use of sugar substitutes. Rubusoside and rebaudiosides are interesting molecules, considered the next generation of sugar substitutes due to their low-calorie, superior sweetness and organoleptic properties. However, their low abundance in nature makes the traditional plant extraction process neither economical nor environmental-friendly. Here we engineer baker’s yeast Saccharomyces cerevisiae as a chassis for the de novo production of rubusoside and rebaudiosides. In this process, we identify multiple issues that limit the production, including rate-liming steps, product stress on cellular fitness and unbalanced metabolic networks. We carry out a systematic engineering strategy to solve these issues, which produces rubusoside and rebaudiosides at titers of 1368.6 mg/L and 132.7 mg/L, respectively. The rubusoside chassis strain here constructed paves the way towards a sustainable, large-scale fermentation-based manufacturing of diverse rebaudiosides.
Journal articleBernier L, Stan G, Junier P, et al., 2022,
In recent years, microfluidic technologies have become widespread in biological science. However, the suitability of this technique for understanding different aspects of spore research has hardly been considered. Herein, we review recent developments in 'spores-on-a-chip' technologies, highlighting how they could be exploited to drive new frontiers in spore research.
Journal articleRafieenia R, Atkinson E, Ledesma-Amaro R, 2022,
In natural ecosystems, microorganisms live in communities where each member interacts with the others and with the environment to efficiently utilise available resources. Division of Labor (DOL) is an evolutionary strategy that evolved by microbial communities to accomplish complex tasks. Current bio-based technologies could also benefit from DOL in microbial communities to construct robust microbial cell factories with expanded metabolic capabilities. Here, we review some remarkable examples of how DOL is used by natural microbial consortia to utilize a range of substrates. Also, we review the most recent studies towards engineering DOL to design synthetic consortia for efficient substrate utilization for bioproduction.
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