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- Martin, F. P. J., et al.
(author)
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Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model
- 2008
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In: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 4, s. 157-
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Journal article (peer-reviewed)abstract
- The transgenomic metabolic effects of exposure to either Lactobacillus paracasei or Lactobacillus rhamnosus probiotics have been measured and mapped in humanized extended genome mice (germ-free mice colonized with human baby flora). Statistical analysis of the compartmental fluctuations in diverse metabolic compartments, including biofluids, tissue and cecal short-chain fatty acids (SCFAs) in relation to microbial population modulation generated a novel top-down systems biology view of the host response to probiotic intervention. Probiotic exposure exerted microbiome modification and resulted in altered hepatic lipid metabolism coupled with lowered plasma lipoprotein levels and apparent stimulated glycolysis. Probiotic treatments also altered a diverse range of pathways outcomes, including amino-acid metabolism, methylamines and SCFAs. The novel application of hierarchical-principal component analysis allowed visualization of multicompartmental transgenomic metabolic interactions that could also be resolved at the compartment and pathway level. These integrated system investigations demonstrate the potential of metabolic profiling as a top-down systems biology driver for investigating the mechanistic basis of probiotic action and the therapeutic surveillance of the gut microbial activity related to dietary supplementation of probiotics.
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| 3. |
- Clayton, T. Andrew, et al.
(author)
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Pharmaco-metabonomic phenotyping and personalized drug treatment.
- 2006
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In: Nature. - 1476-4687. ; 440:7087, s. 1073-7
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Journal article (peer-reviewed)abstract
- There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions. However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination. After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion. For instance, a major factor underlying inter-individual variation in drug effects is variation in metabolic phenotype, which is influenced not only by genotype but also by environmental factors such as nutritional status, the gut microbiota, age, disease and the co- or pre-administration of other drugs. Thus, although genetic variation is clearly important, it seems unlikely that personalized drug therapy will be enabled for a wide range of major diseases using genomic knowledge alone. Here we describe an alternative and conceptually new 'pharmaco-metabonomic' approach to personalizing drug treatment, which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. We provide proof-of-principle for this new approach, which is sensitive to both genetic and environmental influences, with a study of paracetamol (acetaminophen) administered to rats. We show pre-dose prediction of an aspect of the urinary drug metabolite profile and an association between pre-dose urinary composition and the extent of liver damage sustained after paracetamol administration.
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| 4. |
- Kendler, Kenneth S., et al.
(author)
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A longitudinal twin study of fears from middle childhood to early adulthood : evidence for a developmentally dynamic genome
- 2008
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In: Archives of General Psychiatry. - : American Medical Association (AMA). - 0003-990X .- 1538-3636. ; 65:4, s. 421-429
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Journal article (peer-reviewed)abstract
- Context: While the nature of common fears changes over development, we do not know whether genetic effects on fear-proneness are developmentally stable or developmentally dynamic. Objective: To determine the temporal pattern of genetic and environmental effects on the level of intensity of common fears. Design: Prospective, 4-wave longitudinal twin study. Structural modeling was performed with Mx. Setting: General community. Participants: Two thousand four hundred ninety twins and their parents from the Swedish Twin Study of Child and Adolescent Development. Main Outcome Measure: The level of parent- and/or self-reported fears obtained at ages 8 to 9, 13 to 14, 16 to 17, and 19 to 20 years. Results: Thirteen questionnaire items formed 3 distinct fear factors: situational, animal, and blood/injury. For all 3 fears, the best-fit model revealed developmentally dynamic effects and, in particular, evidence for both genetic attenuation and innovation. That is, genetic factors influencing fear intensity at age 8 to 9 years decline substantially in importance over time. Furthermore, new sets of genetic risk factors impacting fear intensity "come on line" in early adolescence, late adolescence, and early adulthood. As the twins aged, the influence of the shared environment declined and unique environment increased. No sex effects were found for situational fears while for animal and blood/injury fears, genetic factors in males and females were correlated but not identical. Shared environmental factors were both more important and,more stable for animal fears than for situational or blood/injury fears. Conclusions: Genetic effects on fear are developmentally dynamic from middle childhood to young adulthood. As children age, familial-environmental influences on fears decline in importance.
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