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| 2. |
- Babaei, Parizad, 1990, et al.
(författare)
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Challenges in modeling the human gut microbiome
- 2018
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Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 36:8, s. 682-686
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Caspeta-Guadarrama, Luis, 1974, et al.
(författare)
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Genome-scale metabolic reconstructions of Pichia stipitis and Pichia pastoris and in-silico evaluation of their potentials
- 2012
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Ingår i: BMC Systems Biology. - : Springer Science and Business Media LLC. - 1752-0509. ; 6:24
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPichia stipitis and Pichia pastoris have long been investigated due to their native abilities to metabolize every sugar from lignocellulose and to modulate methanol consumption, respectively. The latter has been driving the production of several recombinant proteins. As a result, significant advances in their biochemical knowledge, as well as in genetic engineering and fermentation methods have been generated. The release of their genome sequences has allowed systems level research. ResultsIn this work, genome-scale metabolic models (GEMs) of P. stipitis (iSS884) and P. pastoris (iLC915) were reconstructed. iSS884 includes 1332 reactions, 922 metabolites, and 4 compartments. iLC915 contains 1423 reactions, 899 metabolites, and 7 compartments. Compared with the previous GEMs of P. pastoris, PpaMBEL1254 and iPP668, iLC915 contains more genes and metabolic functions, as well as improved predictive capabilities. Simulations of physiological responses for the growth of both yeasts on selected carbon sources using iSS884 and iLC915 closely reproduced the experimental data. Additionally, the iSS884 model was used to predict ethanol production from xylose at different oxygen uptake rates. Simulations with iLC915 closely reproduced the effect of oxygen uptake rate on physiological states of P. pastoris expressing a recombinant protein. The potential of P. stipitis for the conversion of xylose and glucose into ethanol using reactors in series, and of P. pastoris to produce recombinant proteins using mixtures of methanol and glycerol or sorbitol are also discussed. ConclusionsIn conclusion the first GEM of P. stipitis (iSS884) was reconstructed and validated. The expanded version of the P. pastoris GEM, iLC915, is more complete and has improved capabilities over the existing models. Both GEMs are useful frameworks to explore the versatility of these yeasts and to capitalize on their biotechnological potentials.
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| 4. |
- El-Semman, Ibrahim, 1977, et al.
(författare)
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Genome-scale metabolic reconstructions of Bifidobacterium adolescentis L2-32 and Faecalibacterium prausnitzii A2-165 and their interaction
- 2014
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Ingår i: BMC Systems Biology. - : Springer Science and Business Media LLC. - 1752-0509. ; 8:41
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Tidskriftsartikel (refereegranskat)abstract
- Background: The gut microbiota plays an important role in human health and disease by acting as a metabolic organ. Metagenomic sequencing has shown how dysbiosis in the gut microbiota is associated with human metabolic diseases such as obesity and diabetes. Modeling may assist to gain insight into the metabolic implication of an altered microbiota. Fast and accurate reconstruction of metabolic models for members of the gut microbiota, as well as methods to simulate a community of microorganisms, are therefore needed. The Integrated Microbial Genomes (IMG) database contains functional annotation for nearly 4,650 bacterial genomes. This tremendous new genomic information adds new opportunities for systems biology to reconstruct accurate genome scale metabolic models (GEMs). Results: Here we assembled a reaction data set containing 2,340 reactions obtained from existing genome-scale metabolic models, where each reaction is assigned with KEGG Orthology. The reaction data set was then used to reconstruct two genome scale metabolic models for gut microorganisms available in the IMG database Bifidobacterium adolescentis L2-32, which produces acetate during fermentation, and Faecalibacterium prausnitzii A2-165, which consumes acetate and produces butyrate. F. prausnitzii is less abundant in patients with Crohn's disease and has been suggested to play an anti-inflammatory role in the gut ecosystem. The B. adolescentis model, iBif452, comprises 699 reactions and 611 unique metabolites. The F. prausnitzii model, iFap484, comprises 713 reactions and 621 unique metabolites. Each model was validated with in vivo data. We used OptCom and Flux Balance Analysis to simulate how both organisms interact. Conclusions: The consortium of iBif452 and iFap484 was applied to predict F. prausnitzii's demand for acetate and production of butyrate which plays an essential role in colonic homeostasis and cancer prevention. The assembled reaction set is a useful tool to generate bacterial draft models from KEGG Orthology.
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| 5. |
- El-Semman, Ibrahim, 1977, et al.
(författare)
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Systems biology analysis of hepatitis C virus infection reveals the role of copy number increases in regions of chromosome 1q in hepatocellular carcinoma metabolism
- 2016
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Ingår i: Molecular Biosystems. - : Royal Society of Chemistry. - 1742-206X .- 1742-2051. ; 12:5, s. 1496-1506
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Tidskriftsartikel (refereegranskat)abstract
- Hepatitis C virus (HCV) infection is a worldwide healthcare problem; however, traditional treatment methods have failed to cure all patients, and HCV has developed resistance to new drugs. Systems biology-based analyses could play an important role in the holistic analysis of the impact of HCV on hepatocellular metabolism. Here, we integrated HCV assembly reactions with a genome-scale hepatocyte metabolic model to identify metabolic targets for HCV assembly and metabolic alterations that occur between different HCV progression states (cirrhosis, dysplastic nodule, and early and advanced hepatocellular carcinoma (HCC)) and healthy liver tissue. We found that diacylglycerolipids were essential for HCV assembly. In addition, the metabolism of keratan sulfate and chondroitin sulfate was significantly changed in the cirrhosis stage, whereas the metabolism of acyl-carnitine was significantly changed in the dysplastic nodule and early HCC stages. Our results explained the role of the upregulated expression of BCAT1, PLOD3 and six other methyltransferase genes involved in carnitine biosynthesis and S-adenosylmethionine metabolism in the early and advanced HCC stages. Moreover, GNPAT and BCAP31 expression was upregulated in the early and advanced HCC stages and could lead to increased acyl-CoA consumption. By integrating our results with copy number variation analyses, we observed that GNPAT, PPOX and five of the methyltransferase genes (ASH1L, METTL13, SMYD2, TARBP1 and SMYD3), which are all located on chromosome 1q, had increased copy numbers in the cancer samples relative to the normal samples. Finally, we confirmed our predictions with the results of metabolomics studies and proposed that inhibiting the identified targets has the potential to provide an effective treatment strategy for HCV-associated liver disorders.
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| 6. |
- Ghaffari Nouran, Pouyan, 1980, et al.
(författare)
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Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5, s. 8183-
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Tidskriftsartikel (refereegranskat)abstract
- Human cancer cell lines are used as important model systems to study molecular mechanisms associated with tumor growth, hereunder how genomic and biological heterogeneity found in primary tumors affect cellular phenotypes. We reconstructed Genome scale metabolic models (GEMs) for eleven cell lines based on RNA-Seq data and validated the functionality of these models with data from metabolite profiling. We used cell line-specific GEMs to analyze the differences in the metabolism of cancer cell lines, and to explore the heterogeneous expression of the metabolic subsystems. Furthermore, we predicted 85 antimetabolites that can inhibit growth of, or even kill, any of the cell lines, while at the same time not being toxic for 83 different healthy human cell types. 60 of these antimetabolites were found to inhibit growth in all cell lines. Finally, we experimentally validated one of the predicted antimetabolites using two cell lines with different phenotypic origins, and found that it is effective in inhibiting the growth of these cell lines. Using immunohistochemistry, we also showed high or moderate expression levels of proteins targeted by the validated antimetabolite. Identified anti-growth factors for inhibition of cell growth may provide leads for the development of efficient cancer treatment strategies.
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| 7. |
- Hong, Kuk-ki, 1976, et al.
(författare)
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Dynamic (13) C-labelling experiments prove important differences in protein turnover rate between two Saccharomyces cerevisiae strains
- 2012
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Ingår i: FEMS Yeast Research. - : Oxford University Press (OUP). - 1567-1356 .- 1567-1364. ; 12:7, s. 741-747
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Tidskriftsartikel (refereegranskat)abstract
- We developed a method for quantification of protein turnover using (13) C-labelled substrates combined with analysis of the labeling pattern of proteinogenic amino acids. Using this method the specific amino acid turnover rates between proteins and the pool of free amino acids were determined for eight different amino acids (alanine, valine, proline, aspartic acid, glycine, leucine, isoleucine and threonine) in two Saccharomyces cerevisiae strains (CEN.PK 113-7D and YSBN2). Furthermore, proteasome activities were compared for both strains. Both results confirmed the hypothesis of a higher protein turnover rates in CEN.PK 113-7D, which was generated in a previous comparative systems biology study of these two yeast strains. The ATP costs associated with the observed differences in protein turnover were quantified and could explain accurately the differences in biomass yield between both strains that are observed in chemostat cultures. The percent of maintenance ATP associated to protein polymerization (polymerization for growth and re-polymerization due to turnover) and degradation was estimated to be 72% for YSBN2 and 79% for CEN.PK 113-7D, which makes these processes the dominant non-biosynthetic drain of ATP in living cells, and hence it represents an energetic parameter of great relevance.
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| 8. |
- Kovatcheva-Datchary, Petia, et al.
(författare)
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Simplified Intestinal Microbiota to Study Microbe-Diet-Host Interactions in a Mouse Model
- 2019
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 26:13
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Tidskriftsartikel (refereegranskat)abstract
- The gut microbiota can modulate human metabolism through interactions with macronutrients. However, microbiota-diet-host interactions are difficult to study because bacteria interact in complex food webs in concert with the host, and many of the bacteria are not yet characterized. To reduce the complexity, we colonize mice with a simplified intestinal microbiota (SIM) composed of ten sequenced strains isolated from the human gut with complementing pathways to metabolize dietary fibers. We feed the SIM mice one of three diets (chow [fiber rich], high-fat/high-sucrose, or zero-fat/high-sucrose diets [both low in fiber]) and investigate (1) how dietary fiber, saturated fat, and sucrose affect the abundance and transcriptome of the SIM community, (2) the effect of microbe-diet interactions on circulating metabolites, and (3) how microbiota-diet interactions affect host metabolism. Our SIM model can be used in future studies to help clarify how microbiota-diet interactions contribute to metabolic diseases.
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| 9. |
- Lam, S., et al.
(författare)
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A systems biology approach for studying neurodegenerative diseases
- 2020
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Ingår i: Drug Discovery Today. - : Elsevier BV. - 1359-6446 .- 1878-5832. ; 25:7, s. 1146-1159
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Tidskriftsartikel (refereegranskat)abstract
- Neurodegenerative diseases (NDDs), such as Alzheimer's (AD) and Parkinson's (PD), are among the leading causes of lost years of healthy life and exert a great strain on public healthcare systems. Despite being first described more than a century ago, no effective cure exists for AD or PD. Although extensively characterised at the molecular level, traditional neurodegeneration research remains marred by narrow-sense approaches surrounding amyloid beta (A beta), tau, and alpha-synuclein (alpha-syn). A systems biology approach enables the integration of multi-omics data and informs discovery of biomarkers, drug targets, and treatment strategies. Here, we present a comprehensive timeline of high-throughput data collection, and associated biotechnological advancements and computational analysis related to AD and PD. We hereby propose that a philosophical change in the definitions of AD and PD is now needed.
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| 10. |
- Mardinoglu, Adil, 1982, et al.
(författare)
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The gut microbiota modulates host amino acid and glutathione metabolism in mice
- 2015
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Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 11:10
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Tidskriftsartikel (refereegranskat)abstract
- The gut microbiota has been proposed as an environmental factor that promotes the progression of metabolic diseases. Here, we investigated how the gut microbiota modulates the global metabolic differences in duodenum, jejunum, ileum, colon, liver, and two white adipose tissue depots obtained from conventionally raised (CONV-R) and germ-free (GF) mice using gene expression data and tissue-specific genome-scale metabolic models (GEMs). We created a generic mouse metabolic reaction (MMR) GEM, reconstructed 28 tissue-specific GEMs based on proteomics data, and manually curated GEMs for small intestine, colon, liver, and adipose tissues. We used these functional models to determine the global metabolic differences between CONV-R and GF mice. Based on gene expression data, we found that the gut microbiota affects the host amino acid (AA) metabolism, which leads to modifications in glutathione metabolism. To validate our predictions, we measured the level of AAs and N-acetylated AAs in the hepatic portal vein of CONV-R and GF mice. Finally, we simulated the metabolic differences between the small intestine of the CONV-R and GF mice accounting for the content of the diet and relative gene expression differences. Our analyses revealed that the gut microbiota influences host amino acid and glutathione metabolism in mice.
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