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1.
Sci Data ; 6(1): 256, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672995

RESUMO

Multi-omics approaches use a diversity of high-throughput technologies to profile the different molecular layers of living cells. Ideally, the integration of this information should result in comprehensive systems models of cellular physiology and regulation. However, most multi-omics projects still include a limited number of molecular assays and there have been very few multi-omic studies that evaluate dynamic processes such as cellular growth, development and adaptation. Hence, we lack formal analysis methods and comprehensive multi-omics datasets that can be leveraged to develop true multi-layered models for dynamic cellular systems. Here we present the STATegra multi-omics dataset that combines measurements from up to 10 different omics technologies applied to the same biological system, namely the well-studied mouse pre-B-cell differentiation. STATegra includes high-throughput measurements of chromatin structure, gene expression, proteomics and metabolomics, and it is complemented with single-cell data. To our knowledge, the STATegra collection is the most diverse multi-omics dataset describing a dynamic biological system.

2.
Anal Chem ; 88(8): 4229-38, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-26959230

RESUMO

Complex shotgun proteomics peptide profiles obtained in quantitative differential protein expression studies, such as in biomarker discovery, may be affected by multiple experimental factors. These preanalytical factors may affect the measured protein abundances which in turn influence the outcome of the associated statistical analysis and validation. It is therefore important to determine which factors influence the abundance of peptides in a complex proteomics experiment and to identify those peptides that are most influenced by these factors. In the current study we analyzed depleted human serum samples to evaluate experimental factors that may influence the resulting peptide profile such as the residence time in the autosampler at 4 °C, stopping or not stopping the trypsin digestion with acid, the type of blood collection tube, different hemolysis levels, differences in clotting times, the number of freeze-thaw cycles, and different trypsin/protein ratios. To this end we used a two-level fractional factorial design of resolution IV (2(IV)(7-3)). The design required analysis of 16 samples in which the main effects were not confounded by two-factor interactions. Data preprocessing using the Threshold Avoiding Proteomics Pipeline (Suits, F.; Hoekman, B.; Rosenling, T.; Bischoff, R.; Horvatovich, P. Anal. Chem. 2011, 83, 7786-7794, ref 1) produced a data-matrix containing quantitative information on 2,559 peaks. The intensity of the peaks was log-transformed, and peaks having intensities of a low t-test significance (p-value > 0.05) and a low absolute fold ratio (<2) between the two levels of each factor were removed. The remaining peaks were subjected to analysis of variance (ANOVA)-simultaneous component analysis (ASCA). Permutation tests were used to identify which of the preanalytical factors influenced the abundance of the measured peptides most significantly. The most important preanalytical factors affecting peptide intensity were (1) the hemolysis level, (2) stopping trypsin digestion with acid, and (3) the trypsin/protein ratio. This provides guidelines for the experimentalist to keep the ratio of trypsin/protein constant and to control the trypsin reaction by stopping it with acid at an accurately set pH. The hemolysis level cannot be controlled tightly as it depends on the status of a patient's blood (e.g., red blood cells are more fragile in patients undergoing chemotherapy) and the care with which blood was sampled (e.g., by avoiding shear stress). However, its level can be determined with a simple UV spectrophotometric measurement and samples with extreme levels or the peaks affected by hemolysis can be discarded from further analysis. The loadings of the ASCA model led to peptide peaks that were most affected by a given factor, for example, to hemoglobin-derived peptides in the case of the hemolysis level. Peak intensity differences for these peptides were assessed by means of extracted ion chromatograms confirming the results of the ASCA model.


Assuntos
Peptídeos/sangue , Análise de Componente Principal , Proteínas/análise , Proteômica , Análise de Variância , Humanos
3.
Metabolomics ; 11(6): 1587-1597, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26491418

RESUMO

Metabolomics has become a crucial phenotyping technique in a range of research fields including medicine, the life sciences, biotechnology and the environmental sciences. This necessitates the transfer of experimental information between research groups, as well as potentially to publishers and funders. After the initial efforts of the metabolomics standards initiative, minimum reporting standards were proposed which included the concepts for metabolomics databases. Built by the community, standards and infrastructure for metabolomics are still needed to allow storage, exchange, comparison and re-utilization of metabolomics data. The Framework Programme 7 EU Initiative 'coordination of standards in metabolomics' (COSMOS) is developing a robust data infrastructure and exchange standards for metabolomics data and metadata. This is to support workflows for a broad range of metabolomics applications within the European metabolomics community and the wider metabolomics and biomedical communities' participation. Here we announce our concepts and efforts asking for re-engagement of the metabolomics community, academics and industry, journal publishers, software and hardware vendors, as well as those interested in standardisation worldwide (addressing missing metabolomics ontologies, complex-metadata capturing and XML based open source data exchange format), to join and work towards updating and implementing metabolomics standards.

4.
Artigo em Inglês | MEDLINE | ID: mdl-24951433

RESUMO

Modern chromatography-based metabolomics measurements generate large amounts of data in the form of abundances of metabolites. An increasingly popular way of representing and analyzing such data is by means of association networks. Ideally, such a network can be interpreted in terms of the underlying biology. A property of chromatography-based metabolomics data is that the measurement error structure is complex: apart from the usual (random) instrumental error there is also correlated measurement error. This is intrinsic to the way the samples are prepared and the analyses are performed and cannot be avoided. The impact of correlated measurement errors on (partial) correlation networks can be large and is not always predictable. The interplay between relative amounts of uncorrelated measurement error, correlated measurement error and biological variation defines this impact. Using chromatography-based time-resolved lipidomics data obtained from a human intervention study we show how partial correlation based association networks are influenced by correlated measurement error. We show how the effect of correlated measurement error on partial correlations is different for direct and indirect associations. For direct associations the correlated measurement error usually has no negative effect on the results, while for indirect associations, depending on the relative size of the correlated measurement error, results can become unreliable. The aim of this paper is to generate awareness of the existence of correlated measurement errors and their influence on association networks. Time series lipidomics data is used for this purpose, as it makes it possible to visually distinguish the correlated measurement error from a biological response. Underestimating the phenomenon of correlated measurement error will result in the suggestion of biologically meaningful results that in reality rest solely on complicated error structures. Using proper experimental designs that allow for the quantification of the size of correlated and uncorrelated errors, can help to identify suspicious connections in association networks constructed from (partial) correlations.


Assuntos
Metabolômica/métodos , Metabolômica/normas , Benzodiazepinas/farmacologia , Cromatografia Líquida , Simulação por Computador , Humanos , Lipídeos/sangue , Espectrometria de Massas , Redes e Vias Metabólicas , Metaboloma/efeitos dos fármacos , Olanzapina , Reprodutibilidade dos Testes
5.
Anal Chim Acta ; 801: 34-42, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24139572

RESUMO

Because of its high sensitivity and specificity, hyphenated mass spectrometry has become the predominant method to detect and quantify metabolites present in bio-samples relevant for all sorts of life science studies being executed. In contrast to targeted methods that are dedicated to specific features, global profiling acquisition methods allow new unspecific metabolites to be analyzed. The challenge with these so-called untargeted methods is the proper and automated extraction and integration of features that could be of relevance. We propose a new algorithm that enables untargeted integration of samples that are measured with high resolution liquid chromatography-mass spectrometry (LC-MS). In contrast to other approaches limited user interaction is needed allowing also less experienced users to integrate their data. The large amount of single features that are found within a sample is combined to a smaller list of, compound-related, grouped feature-sets representative for that sample. These feature-sets allow for easier interpretation and identification and as important, easier matching over samples. We show that the automatic obtained integration results for a set of known target metabolites match those generated with vendor software but that at least 10 times more feature-sets are extracted as well. We demonstrate our approach using high resolution LC-MS data acquired for 128 samples on a lipidomics platform. The data was also processed in a targeted manner (with a combination of automatic and manual integration) using vendor software for a set of 174 targets. As our untargeted extraction procedure is run per sample and per mass trace the implementation of it is scalable. Because of the generic approach, we envision that this data extraction lipids method will be used in a targeted as well as untargeted analysis of many different kinds of TOF-MS data, even CE- and GC-MS data or MRM. The Matlab package is available for download on request and efforts are directed toward a user-friendly Windows executable.


Assuntos
Algoritmos , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Estatística como Assunto/métodos , Software
6.
Anal Chem ; 85(7): 3576-83, 2013 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-23368721

RESUMO

Metabolite identification is one of the biggest bottlenecks in metabolomics. Identifying human metabolites poses experimental, analytical, and computational challenges. Here we present a pipeline of previously developed cheminformatic tools and demonstrate how it facilitates metabolite identification using solely LC/MS(n) data. These tools process, annotate, and compare MS(n) data, and propose candidate structures for unknown metabolites either by identity assignment of identical mass spectral trees or by de novo identification using substructures of similar trees. The working and performance of this metabolite identification pipeline is demonstrated by applying it to LC/MS(n) data of urine samples. From human urine, 30 MS(n) trees of unknown metabolites were acquired, processed, and compared to a reference database containing MS(n) data of known metabolites. From these 30 unknowns, we could assign a putative identity for 10 unknowns by finding identical fragmentation trees. For 11 unknowns no similar fragmentation trees were found in the reference database. On the basis of elemental composition only, a large number of candidate structures/identities were possible, so these unknowns remained unidentified. The other 9 unknowns were also not found in the database, but metabolites with similar fragmentation trees were retrieved. Computer assisted structure elucidation was performed for these 9 unknowns: for 4 of them we could perform de novo identification and propose a limited number of candidate structures, and for the other 5 the structure generation process could not be constrained far enough to yield a small list of candidates. The novelty of this work is that it allows de novo identification of metabolites that are not present in a database by using MS(n) data and computational tools. We expect this pipeline to be the basis for the computer-assisted identification of new metabolites in future metabolomics studies, and foresee that further additions will allow the identification of even a larger fraction of the unknown metabolites.


Assuntos
Espectrometria de Massas/métodos , Metabolômica/métodos , Urina/química , Cromatografia Líquida , Bases de Dados Factuais , Humanos , Software
7.
Eur J Hum Genet ; 21(1): 95-101, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22713803

RESUMO

Twin and family studies are typically used to elucidate the relative contribution of genetic and environmental variation to phenotypic variation. Here, we apply a quantitative genetic method based on hierarchical clustering, to blood plasma lipidomics data obtained in a healthy cohort consisting of 37 monozygotic and 28 dizygotic twin pairs, and 52 of their biological nontwin siblings. Such data are informative of the concentrations of a wide range of lipids in the studied blood samples. An important advantage of hierarchical clustering is that it can be applied to a high-dimensional 'omics' type data, whereas the use of many other quantitative genetic methods for analysis of such data is hampered by the large number of correlated variables. For this study we combined two lipidomics data sets, originating from two different measurement blocks, which we corrected for block effects by 'quantile equating'. In the analysis of the combined data, average similarities of lipidomics profiles were highest between monozygotic (MZ) cotwins, and became progressively lower between dizygotic (DZ) cotwins, among sex-matched nontwin siblings and among sex-matched unrelated participants, respectively. Our results suggest that (1) shared genetic background, shared environment, and similar age contribute to similarities in blood plasma lipidomics profiles among individuals; and (2) that the power of quantitative genetic analyses is enhanced by quantile equating and combination of data sets obtained in different measurement blocks.


Assuntos
Análise por Conglomerados , Lipídeos/sangue , Lipídeos/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adolescente , Proteína C-Reativa/genética , Proteína C-Reativa/metabolismo , Feminino , Interação Gene-Ambiente , Humanos , Masculino , Modelos Genéticos , Países Baixos , Linhagem
8.
Rapid Commun Mass Spectrom ; 26(19): 2275-86, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22956319

RESUMO

Metabolite identification plays a crucial role in the interpretation of metabolomics research results. Due to its sensitivity and widespread implementation, a favourite analytical method used in metabolomics is electrospray mass spectrometry. In this paper, we demonstrate our results in attempting to incorporate the potentials of multistage mass spectrometry into the metabolite identification routine. New software tools were developed and implemented which facilitate the analysis of multistage mass spectra and allow for efficient removal of spectral artefacts. The pre-processed fragmentation patterns are saved as fragmentation trees. Fragmentation trees are characteristic of molecular structure. We demonstrate the reproducibility and robustness of the acquisition of such trees on a model compound. The specificity of fragmentation trees allows for distinguishing structural isomers, as shown on a pair of isomeric prostaglandins. This approach to the analysis of the multistage mass spectral characterisation of compounds is an important step towards formulating a generic metabolite identification method.


Assuntos
Metabolômica/métodos , Modelos Químicos , Espectrometria de Massas por Ionização por Electrospray/métodos , Análise por Conglomerados , Eicosanoides/análise , Eicosanoides/química , Glutationa/análise , Glutationa/química , Íons/análise , Íons/química , Isomerismo , Estrutura Molecular , Reprodutibilidade dos Testes , Software
9.
PLoS One ; 7(9): e44331, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22984493

RESUMO

OBJECTIVE: The aim is to characterize subgroups or phenotypes of rheumatoid arthritis (RA) patients using a systems biology approach. The discovery of subtypes of rheumatoid arthritis patients is an essential research area for the improvement of response to therapy and the development of personalized medicine strategies. METHODS: In this study, 39 RA patients are phenotyped using clinical chemistry measurements, urine and plasma metabolomics analysis and symptom profiles. In addition, a Chinese medicine expert classified each RA patient as a Cold or Heat type according to Chinese medicine theory. Multivariate data analysis techniques are employed to detect and validate biochemical and symptom relationships with the classification. RESULTS: The questionnaire items 'Red joints', 'Swollen joints', 'Warm joints' suggest differences in the level of inflammation between the groups although c-reactive protein (CRP) and rheumatoid factor (RHF) levels were equal. Multivariate analysis of the urine metabolomics data revealed that the levels of 11 acylcarnitines were lower in the Cold RA than in the Heat RA patients, suggesting differences in muscle breakdown. Additionally, higher dehydroepiandrosterone sulfate (DHEAS) levels in Heat patients compared to Cold patients were found suggesting that the Cold RA group has a more suppressed hypothalamic-pituitary-adrenal (HPA) axis function. CONCLUSION: Significant and relevant biochemical differences are found between Cold and Heat RA patients. Differences in immune function, HPA axis involvement and muscle breakdown point towards opportunities to tailor disease management strategies to each of the subgroups RA patient.


Assuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/metabolismo , Metabolômica/métodos , Adulto , Idoso , Artrite Reumatoide/classificação , Proteína C-Reativa/biossíntese , Química Clínica/métodos , Temperatura Baixa , Feminino , Temperatura Alta , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Medicina Tradicional Chinesa , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Sistema Hipófise-Suprarrenal/fisiopatologia , Medicina de Precisão/métodos , Fator Reumatoide/sangue , Reumatologia/métodos , Inquéritos e Questionários
10.
J Cheminform ; 4(1): 21, 2012 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-22985496

RESUMO

Computer Assisted Structure Elucidation has been used for decades to discover the chemical structure of unknown compounds. In this work we introduce the first open source structure generator, Open Molecule Generator (OMG), which for a given elemental composition produces all non-isomorphic chemical structures that match that elemental composition. Furthermore, this structure generator can accept as additional input one or multiple non-overlapping prescribed substructures to drastically reduce the number of possible chemical structures. Being open source allows for customization and future extension of its functionality. OMG relies on a modified version of the Canonical Augmentation Path, which grows intermediate chemical structures by adding bonds and checks that at each step only unique molecules are produced. In order to benchmark the tool, we generated chemical structures for the elemental formulas and substructures of different metabolites and compared the results with a commercially available structure generator. The results obtained, i.e. the number of molecules generated, were identical for elemental compositions having only C, O and H. For elemental compositions containing C, O, H, N, P and S, OMG produces all the chemically valid molecules while the other generator produces more, yet chemically impossible, molecules. The chemical completeness of the OMG results comes at the expense of being slower than the commercial generator. In addition to being open source, OMG clearly showed the added value of constraining the solution space by using multiple prescribed substructures as input. We expect this structure generator to be useful in many fields, but to be especially of great importance for metabolomics, where identifying unknown metabolites is still a major bottleneck.

11.
Bioinformatics ; 28(20): 2707-9, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22851531

RESUMO

UNLABELLED: Identification of metabolites using high-resolution multi-stage mass spectrometry (MS(n)) data is a significant challenge demanding access to all sorts of computational infrastructures. MetiTree is a user-friendly, web application dedicated to organize, process, share, visualize and compare MS(n) data. It integrates several features to export and visualize complex MS(n) data, facilitating the exploration and interpretation of metabolomics experiments. A dedicated spectral tree viewer allows the simultaneous presentation of three related types of MS(n) data, namely, the spectral data, the fragmentation tree and the fragmentation reactions. MetiTree stores the data in an internal database to enable searching for similar fragmentation trees and matching against other MS(n) data. As such MetiTree contains much functionality that will make the difficult task of identifying unknown metabolites much easier. AVAILABILITY: MetiTree is accessible at http://www.MetiTree.nl. The source code is available at https://github.com/NetherlandsMetabolomicsCentre/metitree/wiki.


Assuntos
Espectrometria de Massas , Metabolômica/métodos , Software , Internet
12.
Anal Chem ; 84(13): 5524-34, 2012 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-22612383

RESUMO

Multistage mass spectrometry (MS(n)) generating so-called spectral trees is a powerful tool in the annotation and structural elucidation of metabolites and is increasingly used in the area of accurate mass LC/MS-based metabolomics to identify unknown, but biologically relevant, compounds. As a consequence, there is a growing need for computational tools specifically designed for the processing and interpretation of MS(n) data. Here, we present a novel approach to represent and calculate the similarity between high-resolution mass spectral fragmentation trees. This approach can be used to query multiple-stage mass spectra in MS spectral libraries. Additionally the method can be used to calculate structure-spectrum correlations and potentially deduce substructures from spectra of unknown compounds. The approach was tested using two different spectral libraries composed of either human or plant metabolites which currently contain 872 MS(n) spectra acquired from 549 metabolites using Orbitrap FTMS(n). For validation purposes, for 282 of these 549 metabolites, 765 additional replicate MS(n) spectra acquired with the same instrument were used. Both the dereplication and de novo identification functionalities of the comparison approach are discussed. This novel MS(n) spectral processing and comparison approach increases the probability to assign the correct identity to an experimentally obtained fragmentation tree. Ultimately, this tool may pave the way for constructing and populating large MS(n) spectral libraries that can be used for searching and matching experimental MS(n) spectra for annotation and structural elucidation of unknown metabolites detected in untargeted metabolomics studies.


Assuntos
Espectrometria de Massas/métodos , Metabolômica/métodos , Cromanos/química , Cromanos/metabolismo , Bases de Dados Factuais , Flavonas/química , Flavonas/metabolismo , Humanos , Hidroxilisina/química , Hidroxilisina/metabolismo , Metaboloma , Plantas/metabolismo , Ácido Úrico/análogos & derivados , Ácido Úrico/química , Ácido Úrico/metabolismo
13.
Metabolomics ; 8(2): 253-263, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22448154

RESUMO

Experimental Autoimmune Encephalomyelitis (EAE) is the most commonly used animal model for Multiple Sclerosis (MScl). CSF metabolomics in an acute EAE rat model was investigated using targetted LC-MS and GC-MS. Acute EAE in Lewis rats was induced by co-injection of Myelin Basic Protein with Complete Freund's Adjuvant. CSF samples were collected at two time points: 10 days after inoculation, which was during the onset of the disease, and 14 days after inoculation, which was during the peak of the disease. The obtained metabolite profiles from the two time points of EAE development show profound differences between onset and the peak of the disease, suggesting significant changes in CNS metabolism over the course of MBP-induced neuroinflammation. Around the onset of EAE the metabolome profile shows significant decreases in arginine, alanine and branched amino acid levels, relative to controls. At the peak of the disease, significant increases in concentrations of multiple metabolites are observed, including glutamine, O-phosphoethanolamine, branched-chain amino acids and putrescine. Observed changes in metabolite levels suggest profound changes in CNS metabolism over the course of EAE. Affected pathways include nitric oxide synthesis, altered energy metabolism, polyamine synthesis and levels of endogenous antioxidants. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-011-0306-3) contains supplementary material, which is available to authorized users.

14.
PLoS One ; 7(1): e30332, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22291936

RESUMO

BACKGROUND: Causes and consequences of the complex changes in lipids occurring in the metabolic syndrome are only partly understood. Several interconnected processes are deteriorating, which implies that multi-target approaches might be more successful than strategies based on a limited number of surrogate markers. Preparations from Chinese Medicine (CM) systems have been handed down with documented clinical features similar as metabolic syndrome, which might help developing new intervention for metabolic syndrome. The progress in systems biology and specific animal models created possibilities to assess the effects of such preparations. Here we report the plasma and liver lipidomics results of the intervention effects of a preparation SUB885C in apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE*3Leiden.CETP) mice. SUB885C was developed according to the principles of CM for treatment of metabolic syndrome. The cannabinoid receptor type 1 blocker rimonabant was included as a general control for the evaluation of weight and metabolic responses. METHODOLOGY/PRINCIPAL FINDINGS: ApoE*3Leiden.CETP mice with mild hypercholesterolemia were divided into SUB885C-, rimonabant- and non-treated control groups. SUB885C caused no weight loss, but significantly reduced plasma cholesterol (-49%, p<0.001), CETP levels (-31%, p<0.001), CETP activity (-74%, p<0.001) and increased HDL-C (39%, p<0.05). It influenced lipidomics classes of cholesterol esters and triglycerides the most. Rimonabant induced a weight loss (-9%, p<0.05), but only a moderate improvement of lipid profiles. In vitro, SUB885C extract caused adipolysis stimulation and adipogenesis inhibition in 3T3-L1 cells. CONCLUSIONS: SUB885C, a multi-components preparation, is able to produce anti-atherogenic changes in lipids of the ApoE*3Leiden.CETP mice, which are comparable to those obtained with compounds belonging to known drugs (e.g. rimonabant, atorvastatin, niacin). This study successfully illustrated the power of lipidomics in unraveling intervention effects and to help finding new targets or ingredients for lifestyle-related metabolic abnormality.


Assuntos
Apolipoproteína E3/genética , Proteínas de Transferência de Ésteres de Colesterol/genética , Metabolismo dos Lipídeos/genética , Lipídeos/análise , Metabolômica , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/fisiologia , Animais , Anticolesterolemiantes/farmacologia , Apolipoproteína E3/metabolismo , Bioquímica , Peso Corporal/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Lipídeos/química , Redes e Vias Metabólicas/efeitos dos fármacos , Metabolômica/métodos , Camundongos , Camundongos Transgênicos , Piperidinas/farmacologia , Pirazóis/farmacologia , Rimonabanto
15.
PLoS One ; 6(12): e28966, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22194963

RESUMO

While the entirety of 'Chemical Space' is huge (and assumed to contain between 10(63) and 10(200) 'small molecules'), distinct subsets of this space can nonetheless be defined according to certain structural parameters. An example of such a subspace is the chemical space spanned by endogenous metabolites, defined as 'naturally occurring' products of an organisms' metabolism. In order to understand this part of chemical space in more detail, we analyzed the chemical space populated by human metabolites in two ways. Firstly, in order to understand metabolite space better, we performed Principal Component Analysis (PCA), hierarchical clustering and scaffold analysis of metabolites and non-metabolites in order to analyze which chemical features are characteristic for both classes of compounds. Here we found that heteroatom (both oxygen and nitrogen) content, as well as the presence of particular ring systems was able to distinguish both groups of compounds. Secondly, we established which molecular descriptors and classifiers are capable of distinguishing metabolites from non-metabolites, by assigning a 'metabolite-likeness' score. It was found that the combination of MDL Public Keys and Random Forest exhibited best overall classification performance with an AUC value of 99.13%, a specificity of 99.84% and a selectivity of 88.79%. This performance is slightly better than previous classifiers; and interestingly we found that drugs occupy two distinct areas of metabolite-likeness, the one being more 'synthetic' and the other being more 'metabolite-like'. Also, on a truly prospective dataset of 457 compounds, 95.84% correct classification was achieved. Overall, we are confident that we contributed to the tasks of classifying metabolites, as well as to understanding metabolite chemical space better. This knowledge can now be used in the development of new drugs that need to resemble metabolites, and in our work particularly for assessing the metabolite-likeness of candidate molecules during metabolite identification in the metabolomics field.


Assuntos
Metabolômica/classificação , Fenômenos Químicos , Análise por Conglomerados , Bases de Dados como Assunto , Humanos , Análise de Componente Principal , Reprodutibilidade dos Testes
16.
Mol Biosyst ; 7(11): 3094-103, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21901208

RESUMO

Although a number of animal experiments and clinical trials have investigated the effects of ginseng roots on diabetes, the relationship between their therapeutic effects on diabetes and the quality and the growth age of this herb have not yet been reported. This study systematically investigated the effects of 3- to 6-year-old ginseng roots on glycemic and plasma lipid control in a rat model of type 2 diabetes. Six groups of male Goto-Kakizaki (GK) rats received either metformin, 3- to 6-year-old ginseng roots, or no treatment. The treatments were administered twice daily for 9 weeks. A combined approach was used that involved applying liquid chromatography-mass spectrometry-based lipidomics, measuring biochemical parameters and profiling the components of ginseng roots of different ages. Compared to the untreated controls, treatment with 4- and 6-year-old ginseng roots significantly improved glucose disposal, and 5-year-old ginseng treatment significantly increased high density lipoprotein cholesterol. Treatment with 6-year-old ginseng significantly decreased total plasma triacylglyceride (TG) and very-low-density lipoprotein cholesterol and improved plasma glycated hemoglobin (HbA1c). In addition, treatment with 4- to 6-year-old ginseng influenced plasma lipidomics in diabetic GK rats by reducing TG lipid species. Metformin significantly reduced fasting blood glucose by 41% and reduced HbA1c by 11%, but showed no effects on the plasma lipid parameters. The present study demonstrates that ginseng roots show growth age-dependent therapeutic effects on hyperlipidemia and hyperglycemia in diabetic GK rats. These age-dependent effects may be linked with the variation in both the ratios and concentrations of specific bioactive ginsenosides in ginseng roots of different growth ages. This study introduced novel systems biology-based approaches for linking biological activities with potential active components in herbal mixtures.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Panax/química , Preparações de Plantas/uso terapêutico , Animais , Cromatografia Líquida , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/uso terapêutico , Lipoproteínas VLDL/metabolismo , Masculino , Espectrometria de Massas , Metformina/uso terapêutico , Ratos , Ratos Endogâmicos , Biologia de Sistemas , Fatores de Tempo
17.
PLoS One ; 6(9): e24846, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21949766

RESUMO

BACKGROUND: The future of personalized medicine depends on advanced diagnostic tools to characterize responders and non-responders to treatment. Systems diagnosis is a new approach which aims to capture a large amount of symptom information from patients to characterize relevant sub-groups. METHODOLOGY: 49 patients with a rheumatic disease were characterized using a systems diagnosis questionnaire containing 106 questions based on Chinese and Western medicine symptoms. Categorical principal component analysis (CATPCA) was used to discover differences in symptom patterns between the patients. Two Chinese medicine experts where subsequently asked to rank the Cold and Heat status of all the patients based on the questionnaires. These rankings were used to study the Cold and Heat symptoms used by these practitioners. FINDINGS: The CATPCA analysis results in three dimensions. The first dimension is a general factor (40.2% explained variance). In the second dimension (12.5% explained variance) 'anxious', 'worrying', 'uneasy feeling' and 'distressed' were interpreted as the Internal disease stage, and 'aggravate in wind', 'fear of wind' and 'aversion to cold' as the External disease stage. In the third dimension (10.4% explained variance) 'panting s', 'superficial breathing', 'shortness of breath s', 'shortness of breath f' and 'aversion to cold' were interpreted as Cold and 'restless', 'nervous', 'warm feeling', 'dry mouth s' and 'thirst' as Heat related. 'Aversion to cold', 'fear of wind' and 'pain aggravates with cold' are most related to the experts Cold rankings and 'aversion to heat', 'fullness of chest' and 'dry mouth' to the Heat rankings. CONCLUSIONS: This study shows that the presented systems diagnosis questionnaire is able to identify groups of symptoms that are relevant for sub-typing patients with a rheumatic disease.


Assuntos
Doenças Reumáticas/classificação , Doenças Reumáticas/diagnóstico , Inquéritos e Questionários , Temperatura Baixa , Temperatura Alta , Humanos , Modelos Biológicos
18.
Bioinformatics ; 27(17): 2376-83, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21757467

RESUMO

MOTIVATION: Identification of metabolites is essential for its use as biomarkers, for research in systems biology and for drug discovery. The first step before a structure can be elucidated is to determine its elemental composition. High-resolution mass spectrometry, which provides the exact mass, together with common constraint rules, for rejecting false proposed elemental compositions, cannot always provide one unique elemental composition solution. RESULTS: The Multistage Elemental Formula (MEF) tool is presented in this article to enable the correct assignment of elemental composition to compounds, their fragment ions and neutral losses that originate from the molecular ion by using multistage mass spectrometry (MS(n)). The method provided by MEF reduces the list of predicted elemental compositions for each ion by analyzing the elemental compositions of its parent (precursor ion) and descendants (fragments). MS(n) data of several metabolites were processed using the MEF tool to assign the correct elemental composition and validate the efficacy of the method. Especially, the link between the mass accuracy needed to generate one unique elemental composition and the topology of the MS(n) tree (the width and the depth of the tree) was addressed. This method makes an important step toward semi-automatic de novo identification of metabolites using MS(n) data. AVAILABILITY: Software available at: http://abs.lacdr.gorlaeus.net/people/rojas-cherto CONTACT: m.rojas@lacdr.leidenuniv.nl; t.reijmers@lacdr.leidenuniv.nl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Espectrometria de Massas/métodos , Metabolômica/métodos , Algoritmos , Íons/química , Software
19.
PLoS One ; 6(5): e19423, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21611179

RESUMO

BACKGROUND: Lipids are known to play crucial roles in the development of life-style related risk factors such as obesity, dyslipoproteinemia, hypertension and diabetes. The first selective cannabinoid-1 receptor blocker rimonabant, an anorectic anti-obesity drug, was frequently used in conjunction with diet and exercise for patients with a body mass index greater than 30 kg/m(2) with associated risk factors such as type II diabetes and dyslipidaemia in the past. Less is known about the impact of this drug on the regulation of lipid metabolism in plasma and liver in the early stage of obesity. METHODOLOGY/PRINCIPAL FINDINGS: We designed a four-week parallel controlled intervention on apolipoprotein E3 Leiden cholesteryl ester transfer protein (ApoE*3Leiden.CETP) transgenic mice with mild overweight and hypercholesterolemia. A liquid chromatography-linear ion trap-Fourier transform ion cyclotron resonance-mass spectrometric approach was employed to investigate plasma and liver lipid responses to the rimonabant intervention. Rimonabant was found to induce a significant body weight loss (9.4%, p<0.05) and a significant plasma total cholesterol reduction (24%, p<0.05). Six plasma and three liver lipids in ApoE*3Leiden.CETP transgenic mice were detected to most significantly respond to rimonabant treatment. Distinct lipid patterns between the mice were observed for both plasma and liver samples in rimonabant treatment vs. non-treated controls. This study successfully applied, for the first time, systems biology based lipidomics approaches to evaluate treatment effects of rimonabant in the early stage of obesity. CONCLUSION: The effects of rimonabant on lipid metabolism and body weight reduction in the early stage obesity were shown to be moderate in ApoE*3Leiden.CETP mice on high-fat diet.


Assuntos
Apolipoproteína E3/genética , Proteínas de Transferência de Ésteres de Colesterol/genética , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Proteínas de Transferência de Ésteres de Colesterol/sangue , HDL-Colesterol/sangue , Comportamento Alimentar/efeitos dos fármacos , Humanos , Camundongos , Camundongos Transgênicos , Rimonabanto , Triglicerídeos/sangue
20.
Mol Plant ; 3(6): 1012-25, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20729474

RESUMO

Heterosis is a biological phenomenon whereby the offspring from two parents show improved and superior performance than either inbred parental lines. Hybrid rice is one of the most successful apotheoses in crops utilizing heterosis. Transcriptional profiling of F(1) super-hybrid rice Liangyou-2186 and its parents by serial analysis of gene expression (SAGE) revealed 1183 differentially expressed genes (DGs), among which DGs were found significantly enriched in pathways such as photosynthesis and carbon-fixation, and most of the key genes involved in the carbon-fixation pathway exhibited up-regulated expression in F(1) hybrid rice. Moreover, increased catabolic activity of corresponding enzymes and photosynthetic efficiency were also detected, which combined to indicate that carbon fixation is enhanced in F(1) hybrid, and might probably be associated with the yield vigor and heterosis in super-hybrid rice. By correlating DGs with yield-related quantitative trait loci (QTL), a potential relationship between differential gene expression and phenotypic changes was also found. In addition, a regulatory network involving circadian-rhythms and light signaling pathways was also found, as previously reported in Arabidopsis, which suggest that such a network might also be related with heterosis in hybrid rice. Altogether, the present study provides another view for understanding the molecular mechanism underlying heterosis in rice.


Assuntos
Perfilação da Expressão Gênica , Vigor Híbrido/genética , Hibridização Genética/genética , Oryza/genética , Transcrição Genética/genética , Ciclo do Carbono/genética , Redes Reguladoras de Genes/genética , Oryza/enzimologia , Oryza/metabolismo , Oryza/fisiologia , Fotossíntese/genética , Locos de Características Quantitativas/genética
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