| 1. |
- Wang, Jinpeng, et al.
(författare)
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Metabolic engineering for increased lipid accumulation in Yarrowia lipolytica – A Review
- 2020
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Ingår i: Bioresource Technology. - : Elsevier BV. - 0960-8524 .- 1873-2976. ; 313
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Forskningsöversikt (refereegranskat)abstract
- Current energy security and climate change policies encourage the development and utilization of bioenergy. Oleaginous yeasts provide a particularly attractive platform for the sustainable production of biofuels and industrial chemicals due to their ability to accumulate high amounts of lipids. In particular, microbial lipids in the form of triacylglycerides (TAGs) produced from renewable feedstocks have attracted considerable attention because they can be directly used in the production of biodiesel and oleochemicals analogous to petrochemicals. As an oleaginous yeast that is generally regarded as safe, Yarrowia lipolytica has been extensively studied, with large amounts of data on its lipid metabolism, genetic tools, and genome sequencing and annotation. In this review, we highlight the newest strategies for increasing lipid accumulation using metabolic engineering and summarize the research advances on the overaccumulation of lipids in Y. lipolytica. Finally, perspectives for future engineering approaches are proposed.
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| 2. |
- Abdel-Haleem, Alyaa M., et al.
(författare)
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Integrated Metabolic Modeling, Culturing, and Transcriptomics Explain Enhanced Virulence of Vibrio cholerae during Coinfection with Enterotoxigenic Escherichia coli
- 2020
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Ingår i: mSystems. - 2379-5077. ; 5:5
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Tidskriftsartikel (refereegranskat)abstract
- Gene essentiality is altered during polymicrobial infections. Nevertheless, most studies rely on single-species infections to assess pathogen gene essentiality. Here, we use genome-scale metabolic models (GEMs) to explore the effect of coinfection of the diarrheagenic pathogen Vibrio cholerae with another enteric pathogen, enterotoxigenic Escherichia coli (ETEC). Model predictions showed that V. cholerae metabolic capabilities were increased due to ample cross-feeding opportunities enabled by ETEC. This is in line with increased severity of cholera symptoms known to occur in patients with dual infections by the two pathogens. In vitro co-culture systems confirmed that V. cholerae growth is enhanced in cocultures relative to single cultures. Further, expression levels of several V. cholerae metabolic genes were significantly perturbed as shown by dual RNA sequencing (RNAseq) analysis of its cocultures with different ETEC strains. A decrease in ETEC growth was also observed, probably mediated by nonmetabolic factors. Single gene essentiality analysis predicted conditionally independent genes that are essential for the pathogen's growth in both single-infection and coinfection scenarios. Our results reveal growth differences that are of relevance to drug targeting and efficiency in polymicrobial infections. IMPORTANCE Most studies proposing new strategies to manage and treat infections have been largely focused on identifying druggable targets that can inhibit a pathogen's growth when it is the single cause of infection. In vivo, however, infections can be caused by multiple species. This is important to take into account when attempting to develop or use current antibacterials since their efficacy can change significantly between single infections and coinfections. In this study, we used genome-scale metabolic models (GEMs) to interrogate the growth capabilities of Vibrio cholerae in single infections and coinfections with enterotoxigenic E. coli (ETEC), which cooccur in a large fraction of diarrheagenic patients. Coinfection model predictions showed that V. cholerae growth capabilities are enhanced in the presence of ETEC relative to V. cholerae single infection, through cross-fed metabolites made available to V. cholerae by ETEC. In vitro, cocultures of the two enteric pathogens further confirmed model predictions showing an increased growth of V. cholerae in coculture relative to V. cholerae single cultures while ETEC growth was suppressed. Dual RNAseq analysis of the cocultures also confirmed that the transcriptome of V. cholerae was distinct during coinfection compared to single-infection scenarios where processes related to metabolism were significantly perturbed. Further, in silico gene-knockout simulations uncovered discrepancies in gene essentiality for V. cholerae growth between single infections and coinfections. Integrative model-guided analysis thus identified druggable targets that would be critical for V. cholerae growth in both single infections and coinfections; thus, designing inhibitors against those targets would provide a broader spectrum of coverage against cholera infections.
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| 3. |
- Chen, Xin, 1980, et al.
(författare)
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FMN reduces Amyloid-beta toxicity in yeast by regulating redox status and cellular metabolism
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) is defined by progressive neurodegeneration, with oligomerization and aggregation of amyloid-beta peptides (A beta) playing a pivotal role in its pathogenesis. In recent years, the yeast Saccharomyces cerevisiae has been successfully used to clarify the roles of different human proteins involved in neurodegeneration. Here, we report a genome-wide synthetic genetic interaction array to identify toxicity modifiers of A beta 42, using yeast as the model organism. We find that FMN1, the gene encoding riboflavin kinase, and its metabolic product flavin mononucleotide (FMN) reduce A beta 42 toxicity. Classic experimental analyses combined with RNAseq show the effects of FMN supplementation to include reducing misfolded protein load, altering cellular metabolism, increasing NADH/(NADH+NAD(+)) and NADPH/(NADPH+NADP(+)) ratios and increasing resistance to oxidative stress. Additionally, FMN supplementation modifies Htt103QP toxicity and alpha-synuclein toxicity in the humanized yeast. Our findings offer insights for reducing cytotoxicity of A beta 42, and potentially other misfolded proteins, via FMN-dependent cellular pathways.Saccharomyces cerevisiae is a model organism to study proteins involved in neurodegeneration. Here, the authors performed a yeast genome-wide synthetic genetic interaction array (SGA) to screen for toxicity modifiers of A beta 42 and identify riboflavin kinase and its metabolic product flavin mononucleotide as modulators that alleviate cellular A beta 42 toxicity, which is supported by further experimental analyses.
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| 4. |
- Limeta, Angelo, 1996, et al.
(författare)
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Meta-analysis of the gut microbiota in predicting response to cancer immunotherapy in metastatic melanoma.
- 2020
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Ingår i: JCI insight. - : American Society for Clinical Investigation. - 2379-3708. ; 5:23
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDIdentifying factors conferring responses to therapy in cancer is critical to select the best treatment for patients. For immune checkpoint inhibition (ICI) therapy, mounting evidence suggests that the gut microbiome can determine patient treatment outcomes. However, the extent to which gut microbial features are applicable across different patient cohorts has not been extensively explored.METHODSWe performed a meta-analysis of 4 published shotgun metagenomic studies (Ntot = 130 patients) investigating differential microbiome composition and imputed metabolic function between responders and nonresponders to ICI.RESULTSOur analysis identified both known microbial features enriched in responders, such as Faecalibacterium as the prevailing taxa, as well as additional features, including overrepresentation of Barnesiella intestinihominis and the components of vitamin B metabolism. A classifier designed to predict responders based on these features identified responders in an independent cohort of 27 patients with the area under the receiver operating characteristic curve of 0.625 (95% CI: 0.348-0.899) and was predictive of prognosis (HR = 0.35, P = 0.081).CONCLUSIONThese results suggest the existence of a fecal microbiome signature inherent across responders that may be exploited for diagnostic or therapeutic purposes.FUNDINGThis work was funded by the Knut and Alice Wallenberg Foundation, BioGaia AB, and Cancerfonden.
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| 5. |
- Shi, Xiao Jing, et al.
(författare)
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Systems Biology of Gastric Cancer: Perspectives on the Omics-Based Diagnosis and Treatment
- 2020
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Ingår i: Frontiers in Molecular Biosciences. - : Frontiers Media SA. - 2296-889X. ; 7
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Forskningsöversikt (refereegranskat)abstract
- Gastric cancer is the fifth most diagnosed cancer in the world, affecting more than a million people and causing nearly 783,000 deaths each year. The prognosis of advanced gastric cancer remains extremely poor despite the use of surgery and adjuvant therapy. Therefore, understanding the mechanism of gastric cancer development, and the discovery of novel diagnostic biomarkers and therapeutics are major goals in gastric cancer research. Here, we review recent progress in application of omics technologies in gastric cancer research, with special focus on the utilization of systems biology approaches to integrate multi-omics data. In addition, the association between gastrointestinal microbiota and gastric cancer are discussed, which may offer insights in exploring the novel microbiota-targeted therapeutics. Finally, the application of data-driven systems biology and machine learning approaches could provide a predictive understanding of gastric cancer, and pave the way to the development of novel biomarkers and rational design of cancer therapeutics.
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| 6. |
- Vaga, S., et al.
(författare)
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Compositional and functional differences of the mucosal microbiota along the intestine of healthy individuals
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Gut mucosal microbes evolved closest to the host, developing specialized local communities. There is, however, insufficient knowledge of these communities as most studies have employed sequencing technologies to investigate faecal microbiota only. This work used shotgun metagenomics of mucosal biopsies to explore the microbial communities' compositions of terminal ileum and large intestine in 5 healthy individuals. Functional annotations and genome-scale metabolic modelling of selected species were then employed to identify local functional enrichments. While faecal metagenomics provided a good approximation of the average gut mucosal microbiome composition, mucosal biopsies allowed detecting the subtle variations of local microbial communities. Given their significant enrichment in the mucosal microbiota, we highlight the roles of Bacteroides species and describe the antimicrobial resistance biogeography along the intestine. We also detail which species, at which locations, are involved with the tryptophan/indole pathway, whose malfunctioning has been linked to pathologies including inflammatory bowel disease. Our study thus provides invaluable resources for investigating mechanisms connecting gut microbiota and host pathophysiology.
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| 7. |
- Wang, Mengge, et al.
(författare)
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Advances in Metabolic Engineering of Saccharomyces cerevisiae for Cocoa Butter Equivalent Production
- 2020
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Ingår i: Frontiers in Bioengineering and Biotechnology. - : Frontiers Media SA. - 2296-4185. ; 8
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Forskningsöversikt (refereegranskat)abstract
- Cocoa butter is extracted from cocoa beans, and it is mainly used as the raw material for the production of chocolate and cosmetics. Increased demands and insufficient cocoa plants led to a shortage of cocoa butter supply, and there is therefore much interesting in finding an alternative cocoa butter supply. However, the most valuable component of cocoa butter is rarely available in other vegetable oils. Saccharomyces cerevisiae is an important industrial host for production of chemicals, enzyme and pharmaceuticals. Advances in synthetical biology and metabolic engineering had enabled high-level of triacylglycerols (TAG) production in yeast, which provided possible solutions for cocoa butter equivalents (CBEs) production. Diverse engineering strategies focused on the fatty acid-producing pathway had been applied in S. cerevisiae, and the key enzymes determining the TAG structure were considered as the main engineering targets. Recent development in phytomics and multi-omics technologies provided clues to identify potential targeted enzymes, which are responsible for CBE production. In this review, we have summarized recent progress in identification of the key plant enzymes for CBE production, and discussed recent and future metabolic engineering and synthetic biology strategies for increased CBE production in S. cerevisiae.
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