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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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All sourcesNASA NTRSDOE OSTI
NASA NTRS2021

Chapter 5: Extravehicular Activity Metabolic Rate Model: Metabolic Rate Estimated from Heart Rate

In-flight monitoring of crew metabolic rates during extravehicular activity (EVA) provides crucial information in mitigating injury. The purpose of this study was to investigate the relationship of crewmember heart rate (HR) and metabolic rate (MR) during EVA operations to develop a predictive linear model. HR and MR data was collected from 132 EVAs from Shuttle and International Space Station (ISS) missions. MR was collected every 2-min from portable life support system delta oxygen decay, while HR was collected every 20-sec via electrocardiogram. HR was down sampled to every 2-min to match MR during EVA for evaluation. Further, a new metric was observed from direct relations between metabolic rate with HR over EVA time (MR/HR) measured as a BTU/beat. A range of BTU/beat was collected as a conversion scale between MR and HR at different EVA workloads categorized by increased MR. Both HR and MR values were observed to decrease through the duration of EVA. Similarly, HR and MR slopes decreased at start of EVA compared to end of EVA. MR/HR values were used to predict MR from HR over the entire duration of EVA with root mean square error less than 200 BTU/Hr. Additionally, MR was predicted based on HR values during EVA via a calculated simple linear regression. A regression equation was found for each EVA drawing relations between HR and MR (F (2923.84) and P<0.0001) with an R(sup 2) value of 0.402. Individual crew regressions improved prediction and R(sup 2) to greater than 0.82. Two models are presented to determine metabolic rate from heart rate during EVA. Results draw correlations for heart rate and metabolic rate fluctuations during EVA for individualized crew predictions during future operations. The linear models correlate to Apollo prediction data during historic EVAs.

Metabolic rate predictions↗
DOE OSTI2016

Microbial Community Metabolic Modeling: A Community Data-Driven Network Reconstruction: COMMUNITY DATA-DRIVEN METABOLIC NETWORK MODELING

Metabolic network modeling of microbial communities provides an in-depth understanding of community-wide metabolic and regulatory processes. Compared to single organism analyses, community metabolic network modeling is more complex because it needs to account for interspecies interactions. To date, most approaches focus on reconstruction of high-quality individual networks so that, when combined, they can predict community behaviors as a result of interspecies interactions. However, this conventional method becomes ineffective for communities whose members are not well characterized and cannot be experimentally interrogated in isolation. Here, we tested a new approach that uses community-level data as a critical input for the network reconstruction process. This method focuses on directly predicting interspecies metabolic interactions in a community, when axenic information is insufficient. We validated our method through the case study of a bacterial photoautotroph-heterotroph consortium that was used to provide data needed for a community-level metabolic network reconstruction. Resulting simulations provided experimentally validated predictions of how a photoautotrophic cyanobacterium supports the growth of an obligate heterotrophic species by providing organic carbon and nitrogen sources.

compartmentalized metabolic network↗
DOE OSTI2018

Accelerating flux balance calculations in genome-scale metabolic models by localizing the application of loopless constraints

Abstract Background Genome-scale metabolic network models and constraint-based modeling techniques have become important tools for analyzing cellular metabolism. Thermodynamically infeasible cycles (TICs) causing unbounded metabolic flux ranges are often encountered. TICs satisfy the mass balance and directionality constraints but violate the second law of thermodynamics. Current practices involve implementing additional constraints to ensure not only optimal but also loopless flux distributions. However, the mixed integer linear programming problems required to solve become computationally intractable for genome-scale metabolic models. Results We aimed to identify the fewest needed constraints sufficient for optimality under the loopless requirement. We found that loopless constraints are required only for the reactions that share elementary flux modes representing TICs with reactions that are part of the objective function. We put forth the concept of localized loopless constraints (LLCs) to enforce this minimal required set of loopless constraints. By combining with a novel procedure for minimal null-space calculation, the computational time for loopless flux variability analysis (ll-FVA) is reduced by a factor of 10–150 compared to the original loopless constraints and by 4–20 times compared to the current fastest method Fast-SNP with the percent improvement increasing with model size. Importantly, LLCs offer a scalable strategy for loopless flux calculations for multi-compartment/multi-organism models of large sizes, for example, shortening the CPU time for ll-FVA from 35 h to less than 2 h for a model with more than104 reactions. Availability and implementation Matlab functions are available in the Supplementary Material or at https://github.com/maranasgroup/lll-FVA Supplementary information Supplementary data are available at Bioinformatics online.

Chan, Siu H. J. (ORCID:000000027707656X)↗
DOE OSTI2015

Improved evidence-based genome-scale metabolic models for maize leaf, embryo, and endosperm

There is a growing demand for genome-scale metabolic reconstructions for plants, fueled by the need to understand the metabolic basis of crop yield and by progress in genome and transcriptome sequencing. Methods are also required to enable the interpretation of plant transcriptome data to study how cellular metabolic activity varies under different growth conditions or even within different organs, tissues, and developmental stages. Such methods depend extensively on the accuracy with which genes have been mapped to the biochemical reactions in the plant metabolic pathways. Errors in these mappings lead to metabolic reconstructions with an inflated number of reactions and possible generation of unreliable metabolic phenotype predictions. Here we introduce a new evidence-based genome-scale metabolic reconstruction of maize, with significant improvements in the quality of the gene-reaction associations included within our model. We also present a new approach for applying our model to predict active metabolic genes based on transcriptome data. This method includes a minimal set of reactions associated with low expression genes to enable activity of a maximum number of reactions associated with high expression genes. We apply this method to construct an organ-specific model for the maize leaf, and tissue specific models for maize embryo and endosperm cells. We validate our models using fluxomics data for the endosperm and embryo, demonstrating an improved capacity of our models to fit the available fluxomics data. All models are publicly available via the DOE Systems Biology Knowledgebase and PlantSEED, and our new method is generally applicable for analysis transcript profiles from any plant, paving the way for further in silico studies with a wide variety of plant genomes.

flux balance analysis↗
DOE OSTI2015

Integrative Analysis of Metabolic Models – from Structure to Dynamics

The characterization of biological systems with respect to their behavior and functionality based on versatile biochemical interactions is a major challenge. To understand these complex mechanisms at systems level modeling approaches are investigated. Different modeling formalisms allow metabolic models to be analyzed depending on the question to be solved, the biochemical knowledge and the availability of experimental data. Here, we describe a method for an integrative analysis of the structure and dynamics represented by qualitative and quantitative metabolic models. Using various formalisms, the metabolic model is analyzed from different perspectives. Determined structural and dynamic properties are visualized in the context of the metabolic model. Interaction techniques allow the exploration and visual analysis thereby leading to a broader understanding of the behavior and functionality of the underlying biological system. The System Biology Metabolic Model Framework (SBM{sup 2} – Framework) implements the developed method and, as an example, is applied for the integrative analysis of the crop plant potato.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

MEMOTE for standardized genome-scale metabolic model testing

Reconstructing metabolic reaction networks enables the development of testable hypotheses of an organism’s metabolism under different conditions. State-of-the-art genome-scale metabolic models (GEMs) can include thousands of metabolites and reactions that are assigned to subcellular locations. Gene–protein–reaction (GPR) rules and annotations using database information can add meta-information to GEMs. GEMs with metadata can be built using standard reconstruction protocols, and guidelines have been put in place for tracking provenance and enabling interoperability, but a standardized means of quality control for GEMs is lacking. Here we report a community effort to develop a test suite named MEMOTE (for metabolic model tests) to assess GEM quality.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Integrating proteomic or transcriptomic data into metabolic models using linear bound flux balance analysis

Abstract Motivation Transcriptomics and proteomics data have been integrated into constraint-based models to influence flux predictions. However, it has been reported recently for Escherichia coli and Saccharomyces cerevisiae, that model predictions from parsimonious flux balance analysis (pFBA), which does not use expression data, are as good or better than predictions from various algorithms that integrate transcriptomics or proteomics data into constraint-based models. Results In this paper, we describe a novel constraint-based method called Linear Bound Flux Balance Analysis (LBFBA), which uses expression data (either transcriptomic or proteomic) to predict metabolic fluxes. The method uses expression data to place soft constraints on individual fluxes, which can be violated. Parameters in the soft constraints are first estimated from a training expression and flux dataset before being used to predict fluxes from expression data in other conditions. We applied LBFBA to E.coli and S.cerevisiae datasets and found that LBFBA predictions were more accurate than pFBA predictions, with average normalized errors roughly half of those from pFBA. For the first time, we demonstrate a computational method that integrates expression data into constraint-based models and improves quantitative flux predictions over pFBA. Availability and implementation Code is available in the Supplementary data available at Bioinformatics online. Supplementary information Supplementary data are available at Bioinformatics online.

Tian, Mingyuan↗
DOE OSTI2021

Bayesian Inference for Integrating Yarrowia lipolytica Multiomics Datasets with Metabolic Modeling

Optimizing the metabolism of microbial cell factories for yields and titers is a critical step for economically viable production of bioproducts and biofuels. In this process, tuning the expression of individual enzymes to obtain the desired pathway flux is a challenging step, in which data from separate multiomics techniques must be integrated with existing biological knowledge to determine where changes should be made. Following a design-build-test-learn strategy, building on recent advances in Bayesian metabolic control analysis, we identify in this work key enzymes in the oleaginous yeast Yarrowia lipolytica that correlate with the production of itaconate by integrating a metabolic model with multiomics measurements. To this extent, we quantify the uncertainty for a variety of key parameters, known as flux control coefficients (FCCs), needed to improve the bioproduction of target metabolites and statistically obtain key correlations between the measured enzymes and boundary flux. Based on the top five significant FCCs and five correlated enzymes, our results show phosphoglycerate mutase, acetyl-CoA synthetase (ACSm), carbonic anhydrase (HCO3E), pyrophosphatase (PPAm), and homoserine dehydrogenase (HSDxi) enzymes in rate-limiting reactions that can lead to increased itaconic acid production.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Unique attributes of cyanobacterial metabolism revealed by improved genome-scale metabolic modeling and essential gene analysis

Significance Genome-scale models of metabolism are important tools for metabolic engineering and production strain development. We present an experimentally validated and manually curated model of metabolism in Synechococcus elongatus PCC 7942 that ( i ) leads to discovery of unique metabolic characteristics, such as the importance of a truncated, linear TCA pathway, ( ii ) highlights poorly understood areas of metabolism as exemplified by knowledge gaps in nucleotide salvage, and ( iii ) accurately quantifies light input and self-shading. We now have a metabolic model that can be used as a basis for metabolic design in S. elongatus .

09 BIOMASS FUELS↗
DOE OSTI2019

Emergent Subpopulation Behavior Uncovered with a Community Dynamic Metabolic Model of Escherichia coli Diauxic Growth

ABSTRACT Microbes have adapted to greatly variable environments in order to survive both short-term perturbations and permanent changes. A classical and yet still actively studied example of adaptation to dynamic environments is the diauxic shift of Escherichia coli , in which cells grow on glucose until its exhaustion and then transition to using previously secreted acetate. Here we tested different hypotheses concerning the nature of this transition by using dynamic metabolic modeling. To reach this goal, we developed an open source modeling framework integrating dynamic models (ordinary differential equation systems) with structural models (metabolic networks) which can take into account the behavior of multiple subpopulations and smooth flux transitions between time points. We used this framework to model the diauxic shift, first with a single E. coli model whose metabolic state represents the overall population average and then with a community of two subpopulations, each growing exclusively on one carbon source (glucose or acetate). After introduction of an environment-dependent transition function that determined the balance between subpopulations, our model generated predictions that are in strong agreement with published data. Our results thus support recent experimental evidence that diauxie, rather than a coordinated metabolic shift, would be the emergent pattern of individual cells differentiating for optimal growth on different substrates. This work offers a new perspective on the use of dynamic metabolic modeling to investigate population heterogeneity dynamics. The proposed approach can easily be applied to other biological systems composed of metabolically distinct, interconverting subpopulations and could be extended to include single-cell-level stochasticity. IMPORTANCE Escherichia coli diauxie is a fundamental example of metabolic adaptation, a phenomenon that is not yet completely understood. Further insight into this process can be achieved by integrating experimental and computational modeling methods. We present a dynamic metabolic modeling approach that captures diauxie as an emergent property of subpopulation dynamics in E. coli monocultures. Without fine-tuning the parameters of the E. coli core metabolic model, we achieved good agreement with published data. Our results suggest that single-organism metabolic models can only approximate the average metabolic state of a population, therefore offering a new perspective on the use of such modeling approaches. The open source modeling framework that we provide can be applied to model general subpopulation systems in more-complex environments and can be extended to include single-cell-level stochasticity.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Advances in gap-filling genome-scale metabolic models and model-driven experiments lead to novel metabolic discoveries

With rapid improvements in next-generation sequencing technologies, our knowledge about metabolism of many organisms is rapidly increasing. However, gaps in metabolic networks exist due to incomplete knowledge (e.g., missing reactions, unknown pathways, unannotated and misannotated genes, promiscuous enzymes, and underground metabolic pathways). Here in this review, we discuss recent advances in gap-filling algorithms based on genome-scale metabolic models and the importance of both high-throughput experiments and detailed biochemical characterization, which work in concert with in silico methods, to allow a more accurate and comprehensive understanding of metabolism.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

A standardized workflow for kinetic metabolic model curation and dissemination

Kinetic metabolic models provide invaluable insights into cellular metabolism, supporting applications in synthetic biology, metabolic engineering, and systems biology. However, reproducibility and utility of these models hinge on clear and rigorous documentation, standardized annotation, and accessible visualization. This paper presents a workflow for building, annotating, visualizing, and sharing kinetic metabolic models. Our method integrates community standards and open-source tools to ensure reproducibility, interoperability, and user accessibility. This procedure enables researchers to produce reusable and well-documented kinetic models, advancing their role as powerful tools in metabolic research.

Cook, Margaret [Univ. of Washington, Seattle, WA (↗
DOE OSTI2014

Likelihood-based gene annotations for gap filling and quality assessment in genome-scale metabolic models

Genome-scale metabolic models provide a powerful means to harness information from genomes to deepen biological insights. With exponentially increasing sequencing capacity, there is an enormous need for automated reconstruction techniques that can provide more accurate models in a short time frame. Current methods for automated metabolic network reconstruction rely on gene and reaction annotations to build draft metabolic networks and algorithms to fill gaps in these networks. However, automated reconstruction is hampered by database inconsistencies, incorrect annotations, and gap filling largely without considering genomic information. Here we develop an approach for applying genomic information to predict alternative functions for genes and estimate their likelihoods from sequence homology. We show that computed likelihood values were significantly higher for annotations found in manually curated metabolic networks than those that were not. We then apply these alternative functional predictions to estimate reaction likelihoods, which are used in a new gap filling approach called likelihood-based gap filling to predict more genomically consistent solutions. To validate the likelihood-based gap filling approach, we applied it to models where essential pathways were removed, finding that likelihood-based gap filling identified more biologically relevant solutions than parsimony-based gap filling approaches. We also demonstrate that models gap filled using likelihood-based gap filling provide greater coverage and genomic consistency with metabolic gene functions compared to parsimony-based approaches. Interestingly, despite these findings, we found that likelihoods did not significantly affect consistency of gap filled models with Biolog and knockout lethality data. This indicates that the phenotype data alone cannot necessarily be used to discriminate between alternative solutions for gap filling and therefore, that the use of other information is necessary to obtain a more accurate network. All described workflows are implemented as part of the DOE Systems Biology Knowledgebase (KBase) and are publicly available via API or command-line web interface.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2012

MicrobesFlux: a web platform for drafting metabolic models from the KEGG database

Concurrent with the efforts currently underway in mapping microbial genomes using high-throughput sequencing methods, systems biologists are building metabolic models to characterize and predict cell metabolisms. One of the key steps in building a metabolic model is using multiple databases to collect and assemble essential information about genome-annotations and the architecture of the metabolic network for a specific organism. To speed up metabolic model development for a large number of microorganisms, we need a user-friendly platform to construct metabolic networks and to perform constraint-based flux balance analysis based on genome databases and experimental results. We have developed a semi-automatic, web-based platform (MicrobesFlux) for generating and reconstructing metabolic models for annotated microorganisms. MicrobesFlux is able to automatically download the metabolic network (including enzymatic reactions and metabolites) of ~1,200 species from the KEGG database (Kyoto Encyclopedia of Genes and Genomes) and then convert it to a metabolic model draft. The platform also provides diverse customized tools, such as gene knockouts and the introduction of heterologous pathways, for users to reconstruct the model network. The reconstructed metabolic network can be formulated to a constraint-based flux model to predict and analyze the carbon fluxes in microbial metabolisms. The simulation results can be exported in the SBML format (The Systems Biology Markup Language). Furthermore, we also demonstrated the platform functionalities by developing an FBA model (including 229 reactions) for a recent annotated bioethanol producer, Thermoanaerobacter sp. strain X514, to predict its biomass growth and ethanol production. MicrobesFlux is an installation-free and open-source platform that enables biologists without prior programming knowledge to develop metabolic models for annotated microorganisms in the KEGG database. Our system facilitates users to reconstruct metabolic networks of organisms based on experimental information. Through human-computer interaction, MicrobesFlux provides users with reasonable predictions of microbial metabolism via flux balance analysis. This prototype platform can be a springboard for advanced and broad-scope modeling of complex biological systems by integrating other “omics” data or 13 C- metabolic flux analysis results.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2016

From DNA to FBA: How to Build Your Own Genome-Scale Metabolic Model

Microbiological studies are increasingly relying on in silico methods to perform exploration and rapid analysis of genomic data, and functional genomics studies are supplemented by the new perspectives that genome-scale metabolic models offer. A mathematical model consisting of a microbe’s entire metabolic map can be rapidly determined from whole-genome sequencing and annotating the genomic material encoded in its DNA. Flux-balance analysis (FBA), a linear programming technique that uses metabolic models to predict the phenotypic responses imposed by environmental elements and factors, is the leading method to simulate and manipulate cellular growth in silico. However, the process of creating an accurate model to use in FBA consists of a series of steps involving a multitude of connections between bioinformatics databases, enzyme resources, and metabolic pathways. We present the methodology and procedure to obtain a metabolic model using PyFBA, an extensible Pythonbased open-source software package aimed to provide a platform where functional annotations are used to build metabolic models (http://linsalrob.github.io/PyFBA). Backed by the Model SEED biochemistry database, PyFBA contains methods to reconstruct a microbe’s metabolic map, run FBA upon different media conditions, and gap-fill its metabolism. The extensibility of PyFBA facilitates novel techniques in creating accurate genome-scale metabolic models.

genome annotation↗