References of "Price, Nathan D"
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See detailRare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
Sims, Rebecca; van der Lee, Sven J.; Naj, Adam C. et al

in Nature Genetics (2017), 49

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See detailThe P4 Health Spectrum - A Predictive, Preventive, Personalized and Participatory Continuum for Promoting Healthspan.
Sagner, Michael; McNeil, Amy; Puska, Pekka et al

in Progress in cardiovascular diseases (2017), 59(5), 506-521

Chronic diseases (i.e., noncommunicable diseases), mainly cardiovascular disease, cancer, respiratory diseases and type-2-diabetes, are now the leading cause of death, disability and diminished quality of ... [more ▼]

Chronic diseases (i.e., noncommunicable diseases), mainly cardiovascular disease, cancer, respiratory diseases and type-2-diabetes, are now the leading cause of death, disability and diminished quality of life on the planet. Moreover, these diseases are also a major financial burden worldwide, significantly impacting the economy of many countries. Healthcare systems and medicine have progressively improved upon the ability to address infectious diseases and react to adverse health events through both surgical interventions and pharmacology; we have become efficient in delivering reactive care (i.e., initiating interventions once an individual is on the verge of or has actually suffered a negative health event). However, with slowly progressing and often 'silent' chronic diseases now being the main cause of illness, healthcare and medicine must evolve into a proactive system, moving away from a merely reactive approach to care. Minimal interactions among the specialists and limited information to the general practitioner and to the individual receiving care lead to a fragmented health approach, non-concerted prescriptions, a scattered follow-up and a suboptimal cost-effectiveness ratio. A new approach in medicine that is predictive, preventive, personalized and participatory, which we label here as "P4" holds great promise to reduce the burden of chronic diseases by harnessing technology and an increasingly better understanding of environment-biology interactions, evidence-based interventions and the underlying mechanisms of chronic diseases. In this concept paper, we propose a 'P4 Health Continuum' model as a framework to promote and facilitate multi-stakeholder collaboration with an orchestrated common language and an integrated care model to increase the healthspan. [less ▲]

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See detailDo Genome-scale Models Need Exact Solvers or Clearer Standards?
Ebrahim, Ali; Almaas, Eivind; Bauer, Eugen UL et al

in Molecular Systems Biology (2015), 11(10), 1

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See detailMediaDB: A Database of Microbial Growth Conditions in Defined Media
Richards, Matthew A.; Cassen, Victor; Heavner, Benjamin D. et al

in PLoS ONE (2014), 9(8), 103548

Isolating pure microbial cultures and cultivating them in the laboratory on defined media is used to more fully characterize the metabolism and physiology of organisms. However, identifying an appropriate ... [more ▼]

Isolating pure microbial cultures and cultivating them in the laboratory on defined media is used to more fully characterize the metabolism and physiology of organisms. However, identifying an appropriate growth medium for a novel isolate remains a challenging task. Even organisms with sequenced and annotated genomes can be difficult to grow, despite our ability to build genome-scale metabolic networks that connect genomic data with metabolic function. The scientific literature is scattered with information about defined growth media used successfully for cultivating a wide variety of organisms, but to date there exists no centralized repository to inform efforts to cultivate less characterized organisms by bridging the gap between genomic data and compound composition for growth media. Here we present MediaDB, a manually curated database of defined media that have been used for cultivating organisms with sequenced genomes, with an emphasis on organisms with metabolic network models. The database is accessible online, can be queried by keyword searches or downloaded in its entirety, and can generate exportable individual media formulation files. The data assembled in MediaDB facilitate comparative studies of organism growth media, serve as a starting point for formulating novel growth media, and contribute to formulating media for in silico investigation of metabolic networks. MediaDB is freely available for public use at https://mediadb.systemsbiology.net. [less ▲]

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See detailA Guide to Integrating Transcriptional Regulatory and Metabolic Networks Using PROM (Probabilistic Regulation of Metabolism)
Simeonidis, Evangelos UL; Chandrasekaran, Sriram; Price, Nathan D.

in Methods in Molecular Biology (2013), 985

The integration of transcriptional regulatory and metabolic networks is a crucial step in the process of predicting metabolic behaviors that emerge from either genetic or environmental changes. Here, we ... [more ▼]

The integration of transcriptional regulatory and metabolic networks is a crucial step in the process of predicting metabolic behaviors that emerge from either genetic or environmental changes. Here, we present a guide to PROM (probabilistic regulation of metabolism), an automated method for the construction and simulation of integrated metabolic and transcriptional regulatory networks that enables large-scale phenotypic predictions for a wide range of model organisms. [less ▲]

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See detailMechanistic modeling of aberrant energy metabolism in human disease.
Sangar, Vineet; Eddy, James A.; Simeonidis, Evangelos UL et al

in Frontiers in Physiology (2012), 3

Dysfunction in energy metabolism-including in pathways localized to the mitochondria-has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases ... [more ▼]

Dysfunction in energy metabolism-including in pathways localized to the mitochondria-has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases to type II diabetes. The inherent complexities of energy and mitochondrial metabolism present a significant obstacle in the effort to understand the role that these molecular processes play in the development of disease. To help unravel these complexities, systems biology methods have been applied to develop an array of computational metabolic models, ranging from mitochondria-specific processes to genome-scale cellular networks. These constraint-based (CB) models can efficiently simulate aspects of normal and aberrant metabolism in various genetic and environmental conditions. Development of these models leverages-and also provides a powerful means to integrate and interpret-information from a wide range of sources including genomics, proteomics, metabolomics, and enzyme kinetics. Here, we review a variety of mechanistic modeling studies that explore metabolic functions, deficiency disorders, and aberrant biochemical pathways in mitochondria and related regions in the cell. [less ▲]

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See detailCandidate states of Helicobacter pylori's genome-scale metabolic network upon application of "loop law" thermodynamic constraints.
Price, Nathan D.; Thiele, Ines UL; Palsson, Bernhard O.

in Biophysical Journal (2006), 90(11), 3919-28

Constraint-based modeling has proven to be a useful tool in the analysis of biochemical networks. To date, most studies in this field have focused on the use of linear constraints, resulting from mass ... [more ▼]

Constraint-based modeling has proven to be a useful tool in the analysis of biochemical networks. To date, most studies in this field have focused on the use of linear constraints, resulting from mass balance and capacity constraints, which lead to the definition of convex solution spaces. One additional constraint arising out of thermodynamics is known as the "loop law" for reaction fluxes, which states that the net flux around a closed biochemical loop must be zero because no net thermodynamic driving force exists. The imposition of the loop-law can lead to nonconvex solution spaces making the analysis of the consequences of its imposition challenging. A four-step approach is developed here to apply the loop-law to study metabolic network properties: 1), determine linear equality constraints that are necessary (but not necessarily sufficient) for thermodynamic feasibility; 2), tighten V(max) and V(min) constraints to enclose the remaining nonconvex space; 3), uniformly sample the convex space that encloses the nonconvex space using standard Monte Carlo techniques; and 4), eliminate from the resulting set all solutions that violate the loop-law, leaving a subset of steady-state solutions. This subset of solutions represents a uniform random sample of the space that is defined by the additional imposition of the loop-law. This approach is used to evaluate the effect of imposing the loop-law on predicted candidate states of the genome-scale metabolic network of Helicobacter pylori. [less ▲]

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See detailCandidate metabolic network states in human mitochondria. Impact of diabetes, ischemia, and diet.
Thiele, Ines UL; Price, Nathan D.; Vo, Thuy D. et al

in Journal of Biological Chemistry (2005), 280(12), 11683-95

The human mitochondrial metabolic network was recently reconstructed based on proteomic and biochemical data. Linear programming and uniform random sampling were applied herein to identify candidate ... [more ▼]

The human mitochondrial metabolic network was recently reconstructed based on proteomic and biochemical data. Linear programming and uniform random sampling were applied herein to identify candidate steady states of the metabolic network that were consistent with the imposed physico-chemical constraints and available experimental data. The activity of the mitochondrion was studied under four metabolic conditions: normal physiologic, diabetic, ischemic, and dietetic. Pairwise correlations between steady-state reaction fluxes were calculated in each condition to evaluate the dependence among the reactions in the network. Applying constraints on exchange fluxes resulted in predictions for intracellular fluxes that agreed with experimental data. Analyses of the steady-state flux distributions showed that the experimentally observed reduced activity of pyruvate dehydrogenase in vivo could be a result of stoichiometric constraints and therefore would not necessarily require enzymatic inhibition. The observed changes in the energy metabolism of the mitochondrion under diabetic conditions were used to evaluate the impact of previously suggested treatments. The results showed that neither normalized glucose uptake nor decreased ketone body uptake have a positive effect on the mitochondrial energy metabolism or network flexibility. Taken together, this study showed that sampling of the steady-state flux space is a powerful method to investigate network properties under different conditions and provides a basis for in silico evaluations of effects of potential disease treatments. [less ▲]

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See detailExpanded metabolic reconstruction of Helicobacter pylori (iIT341 GSM/GPR): an in silico genome-scale characterization of single- and double-deletion mutants.
Thiele, Ines UL; Vo, Thuy D.; Price, Nathan D. et al

in Journal of Bacteriology (2005), 187(16), 5818-30

Helicobacter pylori is a human gastric pathogen infecting almost half of the world population. Herein, we present an updated version of the metabolic reconstruction of H. pylori strain 26695 based on the ... [more ▼]

Helicobacter pylori is a human gastric pathogen infecting almost half of the world population. Herein, we present an updated version of the metabolic reconstruction of H. pylori strain 26695 based on the revised genome annotation and new experimental data. This reconstruction, iIT341 GSM/GPR, represents a detailed review of the current literature about H. pylori as it integrates biochemical and genomic data in a comprehensive framework. In total, it accounts for 341 metabolic genes, 476 intracellular reactions, 78 exchange reactions, and 485 metabolites. Novel features of iIT341 GSM/GPR include (i) gene-protein-reaction associations, (ii) elementally and charge-balanced reactions, (iii) more accurate descriptions of isoprenoid and lipopolysaccharide metabolism, and (iv) quantitative assessments of the supporting data for each reaction. This metabolic reconstruction was used to carry out in silico deletion studies to identify essential and conditionally essential genes in H. pylori. A total of 128 essential and 75 conditionally essential metabolic genes were identified. Predicted growth phenotypes of single knockouts were validated using published experimental data. In addition, in silico double-deletion studies identified a total of 47 synthetic lethal mutants involving 67 different metabolic genes in rich medium. [less ▲]

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