Model-based assessment of mammalian cell metabolic functionalities using omics data.

in Cell reports methods (2021), 1(3),

Omics experiments are ubiquitous in biological studies, leading to a deluge of data. However, it is still challenging to connect changes in these data to changes in cell functions because of complex ... [more ▼]

Omics experiments are ubiquitous in biological studies, leading to a deluge of data. However, it is still challenging to connect changes in these data to changes in cell functions because of complex interdependencies between genes, proteins, and metabolites. Here, we present a framework allowing researchers to infer how metabolic functions change on the basis of omics data. To enable this, we curated and standardized lists of metabolic tasks that mammalian cells can accomplish. Genome-scale metabolic networks were used to define gene sets associated with each metabolic task. We further developed a framework to overlay omics data on these sets and predict pathway usage for each metabolic task. We demonstrated how this approach can be used to quantify metabolic functions of diverse biological samples from the single cell to whole tissues and organs by using multiple transcriptomic datasets. To facilitate its adoption, we integrated the approach into GenePattern (www.genepattern.org-CellFie). [less ▲]

COBREXA.jl: constraint-based reconstruction and exascale analysis

in Bioinformatics (2021)

COBREXA.jl is a Julia package for scalable, high-performance constraint-based reconstruction and analysis of very large-scale biological models. Its primary purpose is to facilitate the integration of ... [more ▼]

COBREXA.jl is a Julia package for scalable, high-performance constraint-based reconstruction and analysis of very large-scale biological models. Its primary purpose is to facilitate the integration of modern high performance computing environments with the processing and analysis of large-scale metabolic models of challenging complexity. We report the architecture of the package, and demonstrate how the design promotes analysis scalability on several use-cases with multi-organism community models.https://doi.org/10.17881/ZKCR-BT30.Supplementary data are available at Bioinformatics online. [less ▲]

Systematic assessment of secondary bile acid metabolism in gut microbes reveals distinct metabolic capabilities in inflammatory bowel disease

in Microbiome (2019)

Background The human gut microbiome performs important functions in human health and disease. A classic example for host-gut microbial co-metabolism is host biosynthesis of primary bile acids and their ... [more ▼]

Background The human gut microbiome performs important functions in human health and disease. A classic example for host-gut microbial co-metabolism is host biosynthesis of primary bile acids and their subsequent deconjugation and transformation by the gut microbiome. To understand these system-level host-microbe interactions, a mechanistic, multi-scale computational systems biology approach that integrates the different types of omic data is needed. Here, we use a systematic workflow to computationally model bile acid metabolism in gut microbes and microbial communities. Results Therefore, we first performed a comparative genomic analysis of bile acid deconjugation and biotransformation pathways in 693 human gut microbial genomes and expanded 232 curated genome-scale microbial metabolic reconstructions with the corresponding reactions (available at https://vmh.life). We then predicted the bile acid biotransformation potential of each microbe and in combination with other microbes. We found that each microbe could produce maximally six of the 13 secondary bile acids in silico, while microbial pairs could produce up to 12 bile acids, suggesting bile acid biotransformation being a microbial community task. To investigate the metabolic potential of a given microbiome, publicly available metagenomics data from healthy Western individuals, as well as inflammatory bowel disease patients and healthy controls, were mapped onto the genomes of the reconstructed strains. We constructed for each individual a large-scale personalized microbial community model that takes into account strain-level abundances. Using flux balance analysis, we found considerable variation in the potential to deconjugate and transform primary bile acids between the gut microbiomes of healthy individuals. Moreover, the microbiomes of pediatric inflammatory bowel disease patients were significantly depleted in their bile acid production potential compared with that of controls. The contributions of each strain to overall bile acid production potential across individuals were found to be distinct between inflammatory bowel disease patients and controls. Finally, bottlenecks limiting secondary bile acid production potential were identified in each microbiome model. Conclusions This large-scale modeling approach provides a novel way of analyzing metagenomics data to accelerate our understanding of the metabolic interactions between the host and gut microbiomes in health and diseases states. Our models and tools are freely available to the scientific community. [less ▲]

Lubrication mechanism design for aircraft landing gear bearings

Patent (2018)

A shock absorber with lubricated bearings for an aircraft landing gear includes a piston that is received in a cylinder, and an upper bearing fixed to the piston that slidably engages an inner surface of ... [more ▼]

A shock absorber with lubricated bearings for an aircraft landing gear includes a piston that is received in a cylinder, and an upper bearing fixed to the piston that slidably engages an inner surface of the cylinder. A lower bearing extends inwardly from a lower portion of the cylinder and engages an outer surface of the piston. The lower bearing has a center axis and defines an annular bearing surface configured to slidably engage the piston outer surface. The annular bearing surface has a first portion that extends circumferentially more than one hundred eighty degrees about the center axis at a constant radius, defining a circular annular segment. A second portion closes the circular annular segment and defines a shallow channel or pocket in the annular bearing surface. In some embodiments the lower bearing further comprises oppositely disposed frustoconical thrust portions. [less ▲]

The Virtual Metabolic Human database: integrating human and gut microbiome metabolism with nutrition and disease

in Nucleic Acids Research (2018)

A multitude of factors contribute to complex diseases and can be measured with ‘omics’ methods. Databases facilitate data interpretation for underlying mechanisms. Here, we describe the Virtual Metabolic ... [more ▼]

A multitude of factors contribute to complex diseases and can be measured with ‘omics’ methods. Databases facilitate data interpretation for underlying mechanisms. Here, we describe the Virtual Metabolic Human (VMH, www.vmh.life) database encapsulating current knowledge of human metabolism within five interlinked resources ‘Human metabolism’, ‘Gut microbiome’, ‘Disease’, ‘Nutrition’, and ‘ReconMaps’. The VMH captures 5180 unique metabolites, 17 730 unique reactions, 3695 human genes, 255 Mendelian diseases, 818 microbes, 632 685 microbial genes and 8790 food items. The VMH’s unique features are (i) the hosting of the metabolic reconstructions of human and gut microbes amenable for metabolic modeling; (ii) seven human metabolic maps for data visualization; (iii) a nutrition designer; (iv) a user-friendly webpage and application-programming interface to access its content; (v) user feedback option for community engagement and (vi) the connection of its entities to 57 other web resources. The VMH represents a novel, interdisciplinary database for data interpretation and hypothesis generation to the biomedical community. [less ▲]

Aircraft landing gear thermo-tribomechanical model development

Doctoral thesis (2015)

A transient numerical model for studying the thermo-tribomechanical behavior of an aircraft landing gear is presented. The study reveals the major heat sources and heat sinks that impact the ... [more ▼]

A transient numerical model for studying the thermo-tribomechanical behavior of an aircraft landing gear is presented. The study reveals the major heat sources and heat sinks that impact the characteristic thermal behavior of the landing gear shock absorber. The severe in-service performance degradation and reported structural damage can be explained as a consequence of the heat generated by the high drag loads induced by rough runways on the bearings, and by the high sliding velocities of the piston. A conclusive model may lead to improved landing gear performance once the transient process of heat generation in a phase-changing grease-lubricated lower bearing is fundamentally understood. A novel tribotopological lubrication theory is derived in order to take into account all distinct physical phases of the non-Newtonian Bingham lubricant. The governing equations are solved using a hybrid numerical solver that is optimized for numerical efficiency and fast convergence. The proposed framework is validated against existing theories and results, and it demonstrates accurate predictions of the thermal performance of the landing gear. Strategies to passively optimize the lower bearing lubrication mechanism are further suggested in order to achieve optimal thermal performance of future aircraft landing gear. [less ▲]

Aircraft Landing Gear Thermo-Tribomechanical Model and Sensitivity Study

in Journal of Aircraft (2014), 51(2), 511-519

A methodology for characterizing the thermo-tribomechanical response of an aircraft landing gear shock absorber is presented. Structural damage has been reported as a consequence of heat generated by high ... [more ▼]

A methodology for characterizing the thermo-tribomechanical response of an aircraft landing gear shock absorber is presented. Structural damage has been reported as a consequence of heat generated by high loads induced by rough runways on the shock absorber bearings and by the high sliding velocities of the shock absorber piston. Therefore, a model that reveals the characteristics of the thermal behavior, and identifies heat sources and sinks in the landing gear shock absorber is developed. The thermo-tribomechanical model framework is presented with representative development of each component. In addition, a sensitivity study of the maximum heat flux to variations of key input parameters is investigated. The numerical results indicate that the runway amplitude dominates the landing gear thermal response. [less ▲]