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  1. Article ; Online: Machine learning for data integration in human gut microbiome

    Peishun Li / Hao Luo / Boyang Ji / Jens Nielsen

    Microbial Cell Factories, Vol 21, Iss 1, Pp 1-

    2022  Volume 16

    Abstract: Abstract Recent studies have demonstrated that gut microbiota plays critical roles in various human diseases. High-throughput technology has been widely applied to characterize the microbial ecosystems, which led to an explosion of different types of ... ...

    Abstract Abstract Recent studies have demonstrated that gut microbiota plays critical roles in various human diseases. High-throughput technology has been widely applied to characterize the microbial ecosystems, which led to an explosion of different types of molecular profiling data, such as metagenomics, metatranscriptomics and metabolomics. For analysis of such data, machine learning algorithms have shown to be useful for identifying key molecular signatures, discovering potential patient stratifications, and particularly for generating models that can accurately predict phenotypes. In this review, we first discuss how dysbiosis of the intestinal microbiota is linked to human disease development and how potential modulation strategies of the gut microbial ecosystem can be used for disease treatment. In addition, we introduce categories and workflows of different machine learning approaches, and how they can be used to perform integrative analysis of multi-omics data. Finally, we review advances of machine learning in gut microbiome applications and discuss related challenges. Based on this we conclude that machine learning is very well suited for analysis of gut microbiome and that these approaches can be useful for development of gut microbe-targeted therapies, which ultimately can help in achieving personalized and precision medicine.
    Keywords Gut microbiome ; Data integration ; Machine learning ; Precision medicine ; Multi-omics ; Microbiology ; QR1-502
    Subject code 006
    Language English
    Publishing date 2022-11-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Expression of fungal biosynthetic gene clusters in S. cerevisiae for natural product discovery

    Zihe Liu / Zhenquan Lin / Jens Nielsen

    Synthetic and Systems Biotechnology, Vol 6, Iss 1, Pp 20-

    2021  Volume 22

    Abstract: Fungi are well known for production of antibiotics and other bioactive secondary metabolites, that can be served as pharmaceuticals, therapeutic agents and industrially useful compounds. However, compared with the characterization of prokaryotic ... ...

    Abstract Fungi are well known for production of antibiotics and other bioactive secondary metabolites, that can be served as pharmaceuticals, therapeutic agents and industrially useful compounds. However, compared with the characterization of prokaryotic biosynthetic gene clusters (BGCs), less attention has been paid to evaluate fungal BGCs. This is partially because heterologous expression of eukaryotic gene constructs often requires replacement of original promoters and terminators, as well as removal of intron sequences, and this substantially slow down the workflow in natural product discovery. It is therefore of interest to investigate the possibility and effectiveness of heterologous expression and library screening of intact BGCs without refactoring in industrial friendly microbial cell factories, such as the yeast Saccharomyces cerevisiae. Here, we discuss the importance of developing new research directions on library screening of fungal BGCs in yeast without refactoring, followed by outlooking prominent opportunities and challenges for future advancement.
    Keywords Natural product discovery ; Cross-species engineering ; Spliceosome ; High-throughput BGC cloning ; Synthetic biology ; Yeast ; Biotechnology ; TP248.13-248.65 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher KeAi Communications Co., Ltd.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Rewiring regulation on respiro-fermentative metabolism relieved Crabtree effects in Saccharomyces cerevisiae

    Yiming Zhang / Mo Su / Zheng Wang / Jens Nielsen / Zihe Liu

    Synthetic and Systems Biotechnology, Vol 7, Iss 4, Pp 1034-

    2022  Volume 1043

    Abstract: The respiro-fermentative metabolism in the yeast Saccharomyces cerevisiae, also called the Crabtree effect, results in lower energy efficiency and biomass yield which can impact yields of chemicals to be produced using this cell factory. Although it can ... ...

    Abstract The respiro-fermentative metabolism in the yeast Saccharomyces cerevisiae, also called the Crabtree effect, results in lower energy efficiency and biomass yield which can impact yields of chemicals to be produced using this cell factory. Although it can be engineered to become Crabtree negative, the slow growth and glucose consumption rate limit its industrial application. Here the Crabtree effect in yeast can be alleviated by engineering the transcription factor Mth1 involved in glucose signaling and a subunit of the RNA polymerase II mediator complex Med2. It was found that the mutant with the MTH1A81D&MED2*432Y allele could grow in glucose rich medium with a specific growth rate of 0.30 h−1, an ethanol yield of 0.10 g g−1, and a biomass yield of 0.21 g g−1, compared with a specific growth rate of 0.40 h−1, an ethanol yield of 0.46 g g−1, and a biomass yield of 0.11 g g−1 in the wild-type strain CEN.PK 113-5D. Transcriptome analysis revealed significant downregulation of the glycolytic process, as well as the upregulation of the TCA cycle and the electron transfer chain. Significant expression changes of several reporter transcription factors were also identified, which might explain the higher energy efficiencies in the engineered strain. We further demonstrated the potential of the engineered strain with the production of 3-hydroxypropionic acid at a titer of 2.04 g L−1, i.e., 5.4-fold higher than that of a reference strain, indicating that the alleviated glucose repression could enhance the supply of mitochondrial acetyl-CoA. These results suggested that the engineered strain could be used as an efficient cell factory for mitochondrial production of acetyl-CoA derived chemicals.
    Keywords Respiro-fermentation ; Crabtree effect ; Saccharomyces cerevisiae ; 3-Hydroxypropionic acid ; Biotechnology ; TP248.13-248.65 ; Biology (General) ; QH301-705.5
    Subject code 660
    Language English
    Publishing date 2022-12-01T00:00:00Z
    Publisher KeAi Communications Co., Ltd.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Synthetic Biology Advanced Natural Product Discovery

    Junyang Wang / Jens Nielsen / Zihe Liu

    Metabolites, Vol 11, Iss 785, p

    2021  Volume 785

    Abstract: A wide variety of bacteria, fungi and plants can produce bioactive secondary metabolites, which are often referred to as natural products. With the rapid development of DNA sequencing technology and bioinformatics, a large number of putative biosynthetic ...

    Abstract A wide variety of bacteria, fungi and plants can produce bioactive secondary metabolites, which are often referred to as natural products. With the rapid development of DNA sequencing technology and bioinformatics, a large number of putative biosynthetic gene clusters have been reported. However, only a limited number of natural products have been discovered, as most biosynthetic gene clusters are not expressed or are expressed at extremely low levels under conventional laboratory conditions. With the rapid development of synthetic biology, advanced genome mining and engineering strategies have been reported and they provide new opportunities for discovery of natural products. This review discusses advances in recent years that can accelerate the design, build, test, and learn (DBTL) cycle of natural product discovery, and prospects trends and key challenges for future research directions.
    Keywords natural products ; biosynthetic gene clusters ; synthetic biology ; genome mining and engineering strategies ; design-build-test-learn (DBTL) cycle ; Microbiology ; QR1-502
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Quantifying absolute gene expression profiles reveals distinct regulation of central carbon metabolism genes in yeast

    Rosemary Yu / Egor Vorontsov / Carina Sihlbom / Jens Nielsen

    eLife, Vol

    2021  Volume 10

    Abstract: In addition to controlled expression of genes by specific regulatory circuits, the abundance of proteins and transcripts can also be influenced by physiological states of the cell such as growth rate and metabolism. Here we examine the control of gene ... ...

    Abstract In addition to controlled expression of genes by specific regulatory circuits, the abundance of proteins and transcripts can also be influenced by physiological states of the cell such as growth rate and metabolism. Here we examine the control of gene expression by growth rate and metabolism, by analyzing a multi-omics dataset consisting of absolute-quantitative abundances of the transcriptome, proteome, and amino acids in 22 steady-state yeast cultures. We find that transcription and translation are coordinately controlled by the cell growth rate via RNA polymerase II and ribosome abundance, but they are independently controlled by nitrogen metabolism via amino acid and nucleotide availabilities. Genes in central carbon metabolism, however, are distinctly regulated and do not respond to the cell growth rate or nitrogen metabolism as all other genes. Understanding these effects allows the confounding factors of growth rate and metabolism to be accounted for in gene expression profiling studies.
    Keywords gene expression ; growth rate ; nitrogen metabolism ; central carbon metabolism ; amino acid metabolism ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 570 ; 612
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: BUTTERFLY

    Johan Gustafsson / Jonathan Robinson / Jens Nielsen / Lior Pachter

    Genome Biology, Vol 22, Iss 1, Pp 1-

    addressing the pooled amplification paradox with unique molecular identifiers in single-cell RNA-seq

    2021  Volume 18

    Abstract: Abstract The incorporation of unique molecular identifiers (UMIs) in single-cell RNA-seq assays makes possible the identification of duplicated molecules, thereby facilitating the counting of distinct molecules from sequenced reads. However, we show that ...

    Abstract Abstract The incorporation of unique molecular identifiers (UMIs) in single-cell RNA-seq assays makes possible the identification of duplicated molecules, thereby facilitating the counting of distinct molecules from sequenced reads. However, we show that the naïve removal of duplicates can lead to a bias due to a “pooled amplification paradox,” and we propose an improved quantification method based on unseen species modeling. Our correction called BUTTERFLY uses a zero truncated negative binomial estimator implemented in the kallisto bustools workflow. We demonstrate its efficacy across cell types and genes and show that in some cases it can invert the relative abundance of genes.
    Keywords Single-cell RNA-Seq ; UMI ; Droplet-based ; PCR ; Bias ; Amplification ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Advances in Metabolic Engineering of Saccharomyces cerevisiae for Cocoa Butter Equivalent Production

    Mengge Wang / Yongjun Wei / Boyang Ji / Jens Nielsen

    Frontiers in Bioengineering and Biotechnology, Vol

    2020  Volume 8

    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 ... ...

    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.
    Keywords cocoa butter equivalents ; Saccharomyces cerevisiae ; metabolic engineering ; synthetic biology ; lipid biosynthesis ; Biotechnology ; TP248.13-248.65
    Subject code 571
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Optimizing cultivation of Cordyceps militaris for fast growth and cordycepin overproduction using rational design of synthetic media

    Nachon Raethong / Hao Wang / Jens Nielsen / Wanwipa Vongsangnak

    Computational and Structural Biotechnology Journal, Vol 18, Iss , Pp 1-

    2020  Volume 8

    Abstract: Cordyceps militaris is an entomopathogenic fungus which is often used in Asia as a traditional medicine developed from age-old wisdom. Presently, cordycepin from C. militaris is a great interest in medicinal applications. However, cellular growth of C. ... ...

    Abstract Cordyceps militaris is an entomopathogenic fungus which is often used in Asia as a traditional medicine developed from age-old wisdom. Presently, cordycepin from C. militaris is a great interest in medicinal applications. However, cellular growth of C. militaris and the association with cordycepin production remain poorly understood. To explore the metabolism of C. militaris as potential cell factories in medical and biotechnology applications, this study developed a high-quality genome-scale metabolic model of C. militaris, iNR1329, based on its genomic content and physiological data. The model included a total of 1329 genes, 1821 biochemical reactions, and 1171 metabolites among 4 different cellular compartments. Its in silico growth simulation results agreed well with experimental data on different carbon sources. iNR1329 was further used for optimizing the growth and cordycepin overproduction using a novel approach, POPCORN, for rational design of synthetic media. In addition to the high-quality GEM iNR1329, the presented POPCORN approach was successfully used to rationally design an optimal synthetic medium with C:N ratio of 8:1 for enhancing 3.5-fold increase in cordycepin production. This study thus provides a novel insight into C. militaris physiology and highlights a potential GEM-driven method for synthetic media design and metabolic engineering application. The iNR1329 and the POPCORN approach are available at the GitHub repository: https://github.com/sysbiomics/Cordyceps_militaris-GEM.
    Keywords Cordycepin ; Cordyceps militaris ; Genome-scale modeling ; Synthetic media design ; Systems biology ; Biotechnology ; TP248.13-248.65
    Subject code 670
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Constraint-based modeling of yeast mitochondria reveals the dynamics of protein import and iron-sulfur cluster biogenesis

    Carl Malina / Francesca Di Bartolomeo / Eduard J. Kerkhoven / Jens Nielsen

    iScience, Vol 24, Iss 11, Pp 103294- (2021)

    2021  

    Abstract: Summary: Mitochondria are a hallmark of eukaryal cells and play an important role in cellular metabolism. There is a vast amount of knowledge available on mitochondrial metabolism and essential mitochondrial functions, such as protein import and iron- ... ...

    Abstract Summary: Mitochondria are a hallmark of eukaryal cells and play an important role in cellular metabolism. There is a vast amount of knowledge available on mitochondrial metabolism and essential mitochondrial functions, such as protein import and iron-sulfur cluster biosynthesis, including multiple studies on the mitochondrial proteome. Therefore, there is a need for in silico approaches to facilitate the analysis of these data. Here, we present a detailed model of mitochondrial metabolism Saccharomyces cerevisiae, including protein import, iron-sulfur cluster biosynthesis, and a description of the coupling between charge translocation processes and ATP synthesis. Model analysis implied a dual dependence of absolute levels of proteins in protein import, iron-sulfur cluster biogenesis and cluster abundance on growth rate and respiratory activity. The model is instrumental in studying dynamics and perturbations in these processes and given the high conservation of mitochondrial metabolism in humans, it can provide insight into their role in human disease.
    Keywords Cellular physiology ; Cell biology ; Integrative aspects of cell biology ; Systems biology ; In silico biology ; Science ; Q
    Subject code 570
    Language English
    Publishing date 2021-11-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Proteome allocations change linearly with the specific growth rate of Saccharomyces cerevisiae under glucose limitation

    Jianye Xia / Benjamin J. Sánchez / Yu Chen / Kate Campbell / Sergo Kasvandik / Jens Nielsen

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 12

    Abstract: Understanding how yeast organizes its functional proteome is a fundamental task in systems biology. Here, the authors conduct a multiomics analysis on yeast cells cultured with different growth rates, identifying a linear dependence of the functional ... ...

    Abstract Understanding how yeast organizes its functional proteome is a fundamental task in systems biology. Here, the authors conduct a multiomics analysis on yeast cells cultured with different growth rates, identifying a linear dependence of the functional proteome on the growth rate.
    Keywords Science ; Q
    Language English
    Publishing date 2022-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
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