Dataset Information

A global resource allocation strategy governs growth transition kinetics of Escherichia coli.

ABSTRACT: A grand challenge of systems biology is to predict the kinetic responses of living systems to perturbations starting from the underlying molecular interactions. Changes in the nutrient environment have long been used to study regulation and adaptation phenomena in microorganisms and they remain a topic of active investigation. Although much is known about the molecular interactions that govern the regulation of key metabolic processes in response to applied perturbations, they are insufficiently quantified for predictive bottom-up modelling. Here we develop a top-down approach, expanding the recently established coarse-grained proteome allocation models from steady-state growth into the kinetic regime. Using only qualitative knowledge of the underlying regulatory processes and imposing the condition of flux balance, we derive a quantitative model of bacterial growth transitions that is independent of inaccessible kinetic parameters. The resulting flux-controlled regulation model accurately predicts the time course of gene expression and biomass accumulation in response to carbon upshifts and downshifts (for example, diauxic shifts) without adjustable parameters. As predicted by the model and validated by quantitative proteomics, cells exhibit suboptimal recovery kinetics in response to nutrient shifts owing to a rigid strategy of protein synthesis allocation, which is not directed towards alleviating specific metabolic bottlenecks. Our approach does not rely on kinetic parameters, and therefore points to a theoretical framework for describing a broad range of such kinetic processes without detailed knowledge of the underlying biochemical reactions.

SUBMITTER: Erickson DW

PROVIDER: S-EPMC5901684 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A global resource allocation strategy governs growth transition kinetics of Escherichia coli.

Erickson David W DW Schink Severin J SJ Patsalo Vadim V Williamson James R JR Gerland Ulrich U Hwa Terence T

Nature 20171025 7678

A grand challenge of systems biology is to predict the kinetic responses of living systems to perturbations starting from the underlying molecular interactions. Changes in the nutrient environment have long been used to study regulation and adaptation phenomena in microorganisms and they remain a topic of active investigation. Although much is known about the molecular interactions that govern the regulation of key metabolic processes in response to applied perturbations, they are insufficiently ...[more]

PMID: 29072300

Similar Datasets

Project description:BackgroundPlasmids are being reconsidered as viable vector alternatives to viruses for gene therapies and vaccines because they are safer, non-toxic, and simpler to produce. Accordingly, there has been renewed interest in the production of plasmid DNA itself as the therapeutic end-product of a bioprocess. Improvement to the best current yields and productivities of such emerging processes would help ensure economic feasibility on the industrial scale. Our goal, therefore, was to develop a stoichiometric model of Escherichia coli metabolism in order to (1) determine its maximum theoretical plasmid-producing capacity, and to (2) identify factors that significantly impact plasmid production.ResultsSuch a model was developed for the production of a high copy plasmid under conditions of batch aerobic growth on glucose minimal medium. The objective of the model was to maximize plasmid production. By employing certain constraints and examining the resulting flux distributions, several factors were determined that significantly impact plasmid yield. Acetate production and constitutive expression of the plasmid's antibiotic resistance marker exert negative effects, while low pyruvate kinase (Pyk) flux and the generation of NADPH by transhydrogenase activity offer positive effects. The highest theoretical yield (592 mg/g) resulted under conditions of no marker or acetate production, nil Pyk flux, and the maximum allowable transhydrogenase activity. For comparison, when these four fluxes were constrained to wild-type values, yields on the order of tens of mg/g resulted, which are on par with the best experimental yields reported to date.ConclusionThese results suggest that specific plasmid yields can theoretically reach 12 times their current experimental maximum (51 mg/g). Moreover, they imply that abolishing Pyk activity and/or transhydrogenase up-regulation would be useful strategies to implement when designing host strains for plasmid production; mutations that reduce acetate production would also be advantageous. The results further suggest that using some other means for plasmid selection than antibiotic resistance, or at least weakening the marker's expression, would be beneficial because it would allow more precursor metabolites, energy, and reducing power to be put toward plasmid production. Thus far, the impact of eliminating Pyk activity has been explored experimentally, with significantly higher plasmid yields resulting.

Project description:International institutions provide well over US$10 billion in development assistance for health (DAH) annually and between 1990 and 2014, DAH disbursements totaled $458 billion but how do they decide who gets what, and for what purpose? In this article, we explore how allocation decisions were made by the nine convening agencies of the Equitable Access Initiative. We provide clear, plain language descriptions of the complete process from resource mobilization to allocation for the nine multilateral agencies with prominent agendas in global health. Then, through a comparative analysis we illuminate the choices and strategies employed in the nine international institutions. We find that resource allocation in all reviewed institutions follow a similar pattern, which we categorized in a framework of five steps: strategy definition, resource mobilization, eligibility of countries, support type and funds allocation. All the reviewed institutions generate resource allocation decisions through well-structured and fairly complex processes. Variations in those processes seem to reflect differences in institutional principles and goals. However, these processes have serious shortcomings. Technical problems include inadequate flexibility to account for or meet country needs. Although aid effectiveness and value for money are commonly referenced, we find that neither performance nor impact is a major criterion for allocating resources. We found very little formal consideration of the incentives generated by allocation choices. Political issues include non-transparent influence on allocation processes by donors and bureaucrats, and the common practice of earmarking funds to bypass the normal allocation process entirely. Ethical deficiencies include low accountability and transparency at international institutions, and limited participation by affected citizens or their representatives. We find that recipient countries have low influence on allocation processes themselves, although within these processes they have some influence in relatively narrow areas.

Dataset Information

A global resource allocation strategy governs growth transition kinetics of Escherichia coli.

Publications

A global resource allocation strategy governs growth transition kinetics of Escherichia coli.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets