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  1. Article ; Online: Qualitative Modeling, Analysis and Control of Synthetic Regulatory Circuits.

    Chaves, Madalena / de Jong, Hidde

    Methods in molecular biology (Clifton, N.J.)

    2021  Volume 2229, Page(s) 1–40

    Abstract: Qualitative modeling approaches are promising and still underexploited tools for the analysis and design of synthetic circuits. They can make predictions of circuit behavior in the absence of precise, quantitative information. Moreover, they provide ... ...

    Abstract Qualitative modeling approaches are promising and still underexploited tools for the analysis and design of synthetic circuits. They can make predictions of circuit behavior in the absence of precise, quantitative information. Moreover, they provide direct insight into the relation between the feedback structure and the dynamical properties of a network. We review qualitative modeling approaches by focusing on two specific formalisms, Boolean networks and piecewise-linear differential equations, and illustrate their application by means of three well-known synthetic circuits. We describe various methods for the analysis of state transition graphs, discrete representations of the network dynamics that are generated in both modeling frameworks. We also briefly present the problem of controlling synthetic circuits, an emerging topic that could profit from the capacity of qualitative modeling approaches to rapidly scan a space of design alternatives.
    MeSH term(s) Algorithms ; Computational Biology/methods ; Computer Simulation ; Gene Regulatory Networks ; Models, Genetic
    Language English
    Publishing date 2021-01-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-1032-9_1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Resource allocation accounts for the large variability of rate-yield phenotypes across bacterial strains.

    Baldazzi, Valentina / Ropers, Delphine / Gouzé, Jean-Luc / Gedeon, Tomas / de Jong, Hidde

    eLife

    2023  Volume 12

    Abstract: Different strains of a microorganism growing in the same environment display a wide variety of growth rates and growth yields. We developed a coarse-grained model to test the hypothesis that different resource allocation strategies, corresponding to ... ...

    Abstract Different strains of a microorganism growing in the same environment display a wide variety of growth rates and growth yields. We developed a coarse-grained model to test the hypothesis that different resource allocation strategies, corresponding to different compositions of the proteome, can account for the observed rate-yield variability. The model predictions were verified by means of a database of hundreds of published rate-yield and uptake-secretion phenotypes of
    MeSH term(s) Escherichia coli/metabolism ; Proteomics ; Metabolic Engineering/methods ; Ribosomes ; Resource Allocation
    Language English
    Publishing date 2023-05-31
    Publishing country England
    Document type Journal Article
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.79815
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Optimal protein production by a synthetic microbial consortium: coexistence, distribution of labor, and syntrophy.

    Martínez, Carlos / Cinquemani, Eugenio / Jong, Hidde de / Gouzé, Jean-Luc

    Journal of mathematical biology

    2023  Volume 87, Issue 1, Page(s) 23

    Abstract: The bacterium E. coli is widely used to produce recombinant proteins such as growth hormone and insulin. One inconvenience with E. coli cultures is the secretion of acetate through overflow metabolism. Acetate inhibits cell growth and represents a carbon ...

    Abstract The bacterium E. coli is widely used to produce recombinant proteins such as growth hormone and insulin. One inconvenience with E. coli cultures is the secretion of acetate through overflow metabolism. Acetate inhibits cell growth and represents a carbon diversion, which results in several negative effects on protein production. One way to overcome this problem is the use of a synthetic consortium of two different E. coli strains, one producing recombinant proteins and one reducing the acetate concentration. In this paper, we study a mathematical model of such a synthetic community in a chemostat where both strains are allowed to produce recombinant proteins. We give necessary and sufficient conditions for the existence of a coexistence equilibrium and show that it is unique. Based on this equilibrium, we define a multi-objective optimization problem for the maximization of two important bioprocess performance metrics, process yield and productivity. Solving numerically this problem, we find the best available trade-offs between the metrics. Under optimal operation of the mixed community, both strains must produce the protein of interest, and not only one (distribution instead of division of labor). Moreover, in this regime acetate secretion by one strain is necessary for the survival of the other (syntrophy). The results thus illustrate how complex multi-level dynamics shape the optimal production of recombinant proteins by synthetic microbial consortia.
    MeSH term(s) Microbial Consortia ; Escherichia coli/metabolism ; Recombinant Proteins/metabolism ; Acetates/metabolism ; Insulin/metabolism
    Chemical Substances Recombinant Proteins ; Acetates ; Insulin
    Language English
    Publishing date 2023-07-03
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 187101-8
    ISSN 1432-1416 ; 0303-6812
    ISSN (online) 1432-1416
    ISSN 0303-6812
    DOI 10.1007/s00285-023-01935-3
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  4. Article ; Online: Maturation models of fluorescent proteins are necessary for unbiased estimates of promoter activity.

    Pavlou, Antrea / Cinquemani, Eugenio / Geiselmann, Johannes / de Jong, Hidde

    Biophysical journal

    2022  Volume 121, Issue 21, Page(s) 4179–4188

    Abstract: Fluorescent proteins (FPs) are a powerful tool to quantitatively monitor gene expression. The dynamics of a promoter and its regulation can be inferred from fluorescence data. The interpretation of fluorescent data, however, is strongly dependent on the ... ...

    Abstract Fluorescent proteins (FPs) are a powerful tool to quantitatively monitor gene expression. The dynamics of a promoter and its regulation can be inferred from fluorescence data. The interpretation of fluorescent data, however, is strongly dependent on the maturation of FPs since different proteins mature in distinct ways. We propose a novel approach for analyzing fluorescent reporter data by incorporating maturation dynamics in the reconstruction of promoter activities. Our approach consists of developing and calibrating mechanistic maturation models for distinct FPs. These models are then used alongside a Bayesian approach to estimate promoter activities from fluorescence data. We demonstrate by means of targeted experiments in Escherichia coli that our approach provides robust estimates and that accounting for maturation is, in many cases, essential for the interpretation of gene expression data.
    MeSH term(s) Bayes Theorem ; Luminescent Proteins/genetics ; Luminescent Proteins/metabolism ; Promoter Regions, Genetic ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism
    Chemical Substances Luminescent Proteins ; Green Fluorescent Proteins (147336-22-9)
    Language English
    Publishing date 2022-09-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218078-9
    ISSN 1542-0086 ; 0006-3495
    ISSN (online) 1542-0086
    ISSN 0006-3495
    DOI 10.1016/j.bpj.2022.09.021
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  5. Article ; Online: Resource allocation accounts for the large variability of rate-yield phenotypes across bacterial strains

    Valentina Baldazzi / Delphine Ropers / Jean-Luc Gouzé / Tomas Gedeon / Hidde de Jong

    eLife, Vol

    2023  Volume 12

    Abstract: Different strains of a microorganism growing in the same environment display a wide variety of growth rates and growth yields. We developed a coarse-grained model to test the hypothesis that different resource allocation strategies, corresponding to ... ...

    Abstract Different strains of a microorganism growing in the same environment display a wide variety of growth rates and growth yields. We developed a coarse-grained model to test the hypothesis that different resource allocation strategies, corresponding to different compositions of the proteome, can account for the observed rate-yield variability. The model predictions were verified by means of a database of hundreds of published rate-yield and uptake-secretion phenotypes of Escherichia coli strains grown in standard laboratory conditions. We found a very good quantitative agreement between the range of predicted and observed growth rates, growth yields, and glucose uptake and acetate secretion rates. These results support the hypothesis that resource allocation is a major explanatory factor of the observed variability of growth rates and growth yields across different bacterial strains. An interesting prediction of our model, supported by the experimental data, is that high growth rates are not necessarily accompanied by low growth yields. The resource allocation strategies enabling high-rate, high-yield growth of E. coli lead to a higher saturation of enzymes and ribosomes, and thus to a more efficient utilization of proteomic resources. Our model thus contributes to a fundamental understanding of the quantitative relationship between rate and yield in E. coli and other microorganisms. It may also be useful for the rapid screening of strains in metabolic engineering and synthetic biology.
    Keywords resource allocation ; growth rate ; growth yield ; bacterial physiology ; metabolic regulation ; Escherichia coli ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2023-05-01T00:00:00Z
    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: Optimal proteome allocation and the temperature dependence of microbial growth laws

    Francis Mairet / Jean-Luc Gouzé / Hidde de Jong

    npj Systems Biology and Applications, Vol 7, Iss 1, Pp 1-

    2021  Volume 11

    Abstract: Abstract Although the effect of temperature on microbial growth has been widely studied, the role of proteome allocation in bringing about temperature-induced changes remains elusive. To tackle this problem, we propose a coarse-grained model of microbial ...

    Abstract Abstract Although the effect of temperature on microbial growth has been widely studied, the role of proteome allocation in bringing about temperature-induced changes remains elusive. To tackle this problem, we propose a coarse-grained model of microbial growth, including the processes of temperature-sensitive protein unfolding and chaperone-assisted (re)folding. We determine the proteome sector allocation that maximizes balanced growth rate as a function of nutrient limitation and temperature. Calibrated with quantitative proteomic data for Escherichia coli, the model allows us to clarify general principles of temperature-dependent proteome allocation and formulate generalized growth laws. The same activation energy for metabolic enzymes and ribosomes leads to an Arrhenius increase in growth rate at constant proteome composition over a large range of temperatures, whereas at extreme temperatures resources are diverted away from growth to chaperone-mediated stress responses. Our approach points at risks and possible remedies for the use of ribosome content to characterize complex ecosystems with temperature variation.
    Keywords Biology (General) ; QH301-705.5
    Subject code 669
    Language English
    Publishing date 2021-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Optimal proteome allocation and the temperature dependence of microbial growth laws.

    Mairet, Francis / Gouzé, Jean-Luc / de Jong, Hidde

    NPJ systems biology and applications

    2021  Volume 7, Issue 1, Page(s) 14

    Abstract: Although the effect of temperature on microbial growth has been widely studied, the role of proteome allocation in bringing about temperature-induced changes remains elusive. To tackle this problem, we propose a coarse-grained model of microbial growth, ... ...

    Abstract Although the effect of temperature on microbial growth has been widely studied, the role of proteome allocation in bringing about temperature-induced changes remains elusive. To tackle this problem, we propose a coarse-grained model of microbial growth, including the processes of temperature-sensitive protein unfolding and chaperone-assisted (re)folding. We determine the proteome sector allocation that maximizes balanced growth rate as a function of nutrient limitation and temperature. Calibrated with quantitative proteomic data for Escherichia coli, the model allows us to clarify general principles of temperature-dependent proteome allocation and formulate generalized growth laws. The same activation energy for metabolic enzymes and ribosomes leads to an Arrhenius increase in growth rate at constant proteome composition over a large range of temperatures, whereas at extreme temperatures resources are diverted away from growth to chaperone-mediated stress responses. Our approach points at risks and possible remedies for the use of ribosome content to characterize complex ecosystems with temperature variation.
    MeSH term(s) Bacteria/growth & development ; Computer Simulation ; Escherichia coli/metabolism ; Escherichia coli Proteins/metabolism ; Gene Expression/genetics ; Gene Expression Regulation, Bacterial/genetics ; Models, Biological ; Models, Theoretical ; Nutrients/metabolism ; Proteome/metabolism ; Proteome/physiology ; Proteomics/methods ; Ribosomes ; Systems Biology/methods ; Temperature
    Chemical Substances Escherichia coli Proteins ; Proteome
    Language English
    Publishing date 2021-03-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2056-7189
    ISSN (online) 2056-7189
    DOI 10.1038/s41540-021-00172-y
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  8. Article ; Online: Acetate Metabolism and the Inhibition of Bacterial Growth by Acetate.

    Pinhal, Stéphane / Ropers, Delphine / Geiselmann, Johannes / de Jong, Hidde

    Journal of bacteriology

    2019  Volume 201, Issue 13

    Abstract: During aerobic growth on glucose, ...

    Abstract During aerobic growth on glucose,
    MeSH term(s) Acetates/metabolism ; Biological Transport ; Escherichia coli/genetics ; Escherichia coli/growth & development ; Fermentation ; Gene Expression Regulation, Bacterial ; Glucose/metabolism ; Metabolic Networks and Pathways ; Mutation
    Chemical Substances Acetates ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2019-06-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2968-3
    ISSN 1098-5530 ; 0021-9193
    ISSN (online) 1098-5530
    ISSN 0021-9193
    DOI 10.1128/JB.00147-19
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  9. Article ; Online: Enhanced production of heterologous proteins by a synthetic microbial community: Conditions and trade-offs.

    Mauri, Marco / Gouzé, Jean-Luc / de Jong, Hidde / Cinquemani, Eugenio

    PLoS computational biology

    2020  Volume 16, Issue 4, Page(s) e1007795

    Abstract: Synthetic microbial consortia have been increasingly utilized in biotechnology and experimental evidence shows that suitably engineered consortia can outperform individual species in the synthesis of valuable products. Despite significant achievements, ... ...

    Abstract Synthetic microbial consortia have been increasingly utilized in biotechnology and experimental evidence shows that suitably engineered consortia can outperform individual species in the synthesis of valuable products. Despite significant achievements, though, a quantitative understanding of the conditions that make this possible, and of the trade-offs due to the concurrent growth of multiple species, is still limited. In this work, we contribute to filling this gap by the investigation of a known prototypical synthetic consortium. A first E. coli strain, producing a heterologous protein, is sided by a second E. coli strain engineered to scavenge toxic byproducts, thus favoring the growth of the producer at the expense of diverting part of the resources to the growth of the cleaner. The simplicity of the consortium is ideal to perform an in depth-analysis and draw conclusions of more general interest. We develop a coarse-grained mathematical model that quantitatively accounts for literature data from different key growth phenotypes. Based on this, assuming growth in chemostat, we first investigate the conditions enabling stable coexistence of both strains and the effect of the metabolic load due to heterologous protein production. In these conditions, we establish when and to what extent the consortium outperforms the producer alone in terms of productivity. Finally, we show in chemostat as well as in a fed-batch scenario that gain in productivity comes at the price of a reduced yield, reflecting at the level of the consortium resource allocation trade-offs that are well-known for individual species.
    MeSH term(s) Escherichia coli/genetics ; Escherichia coli/metabolism ; Metabolic Engineering/methods ; Microbiota/genetics ; Microbiota/physiology ; Models, Biological ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Synthetic Biology/methods
    Chemical Substances Recombinant Proteins
    Language English
    Publishing date 2020-04-13
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1007795
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  10. Article ; Online: Enhanced production of heterologous proteins by a synthetic microbial community

    Marco Mauri / Jean-Luc Gouzé / Hidde de Jong / Eugenio Cinquemani

    PLoS Computational Biology, Vol 16, Iss 4, p e

    Conditions and trade-offs.

    2020  Volume 1007795

    Abstract: Synthetic microbial consortia have been increasingly utilized in biotechnology and experimental evidence shows that suitably engineered consortia can outperform individual species in the synthesis of valuable products. Despite significant achievements, ... ...

    Abstract Synthetic microbial consortia have been increasingly utilized in biotechnology and experimental evidence shows that suitably engineered consortia can outperform individual species in the synthesis of valuable products. Despite significant achievements, though, a quantitative understanding of the conditions that make this possible, and of the trade-offs due to the concurrent growth of multiple species, is still limited. In this work, we contribute to filling this gap by the investigation of a known prototypical synthetic consortium. A first E. coli strain, producing a heterologous protein, is sided by a second E. coli strain engineered to scavenge toxic byproducts, thus favoring the growth of the producer at the expense of diverting part of the resources to the growth of the cleaner. The simplicity of the consortium is ideal to perform an in depth-analysis and draw conclusions of more general interest. We develop a coarse-grained mathematical model that quantitatively accounts for literature data from different key growth phenotypes. Based on this, assuming growth in chemostat, we first investigate the conditions enabling stable coexistence of both strains and the effect of the metabolic load due to heterologous protein production. In these conditions, we establish when and to what extent the consortium outperforms the producer alone in terms of productivity. Finally, we show in chemostat as well as in a fed-batch scenario that gain in productivity comes at the price of a reduced yield, reflecting at the level of the consortium resource allocation trade-offs that are well-known for individual species.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-04-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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