PubMed

Related Articles Fast responses of metabolites in Vicia faba L. to moderate NaCl stress. Plant Physiol Biochem. 2015 Apr 11;92:19-29 Authors: Geilfus CM, Niehaus K, Gödde V, Hasler M, Zörb C, Gorzolka K, Jezek M, Senbayram M, Ludwig-Müller J, Mühling KH Abstract Salt stress impairs global agricultural crop production by reducing vegetative growth and yield. Despite this importance, a number of gaps exist in our knowledge about very early metabolic responses that ensue minutes after plants experience salt stress. Surprisingly, this early phase remains almost as a black box. Therefore, systematic studies focussing on very early plant physiological responses to salt stress (in this case NaCl) may enhance our understanding on strategies to develop crop plants with a better performance under saline conditions. In the present study, hydroponically grown Vicia faba L. plants were exposed to 90 min of NaCl stress, whereby every 15 min samples were taken for analyzing short-term physiologic responses. Gas chromatography-mass spectrometry-based metabolite profiles were analysed by calculating a principal component analysis followed by multiple contrast tests. Follow-up experiments were run to analyze downstream effects of the metabolic changes on the physiological level. The novelty of this study is the demonstration of complex stress-induced metabolic changes at the very beginning of a moderate salt stress in V. faba, information that are very scant for this early stage. This study reports for the first that the proline analogue trans-4-hydroxy-l-proline, known to inhibit cell elongation, was increasingly synthesized after NaCl-stress initiation. Leaf metabolites associated with the generation or scavenging of reactive oxygen species (ROS) were affected in leaves that showed a synchronized increase in ROS formation. A reduced glutamine synthetase activity indicated that disturbances in the nitrogen assimilation occur earlier than it was previously thought under salt stress. PMID: 25900421 [PubMed - as supplied by publisher]

Related Articles Metabolomics in pharmaceutical research and development. Curr Opin Biotechnol. 2015 Apr 16;35:73-77 Authors: Puchades-Carrasco L, Pineda-Lucena A Abstract Metabolomics has significant potential in pharmaceutical and clinical research, including the identification of new targets, the elucidation of the mechanism of action of new drugs, the characterization of safety and efficacy profiles, as well as the discovery of biomarkers for early disease diagnosis, prognosis, patient stratification, and treatment response monitorization. Metabolomics involves the analysis of small molecules and can lead to an improved understanding of drug candidate actions and to a better selection of targets. Although the application of metabolomics in the pharmaceutical industry is still at its infancy, this experimental approach has the possibility to transform our knowledge of drug action through the examination of drug-induced metabolic pathways associated to both drug efficacy and adverse drug reactions. PMID: 25900094 [PubMed - as supplied by publisher]

Related Articles Metabonomics Reveals Metabolite Changes in Biliary Atresia Infants. J Proteome Res. 2015 Apr 22; Authors: Zhou K, Xie G, Wang J, Zhao A, Liu J, Su M, Ni Y, Zhou Y, Pan W, Che Y, Zhang T, Xiao Y, Wang Y, Wen J, Jia W, Cai W Abstract Biliary atresia (BA) is a rare neonatal cholestatic disorder caused by obstruction of extra and intra hepatic bile ducts. If untreated, progressive liver cirrhosis will lead to death within two years. Early diagnosis and operation improve the outcome significantly. Infants with neonatal hepatitis syndrome (NHS) present similar symptoms, confounding the early diagnosis of BA. The lack of non-invasive diagnostic methods to differentiate BA from NHS greatly delays the surgery of BA infants, thus deteriorating the outcome. Here, we performed a metabolomics study in plasma of BA, NHS, and healthy infants using gas chromatography-time-of-flight mass spectrometry. Scores plots of orthogonal partial least square discriminant analysis clearly separated BA from NHS and healthy infants. Eighteen metabolites were found to be differentially expressed between BA and NHS, among which seven (L-glutamic acid, L-ornithine, L-isoleucine, L-lysine, L-valine, L-tryptophan, and L-serine) were amino acids. The altered amino acids were quantitatively verified using ultra-performance liquid chromatography-tandem mass spectrometry. Ingenuity pathway analysis revealed the network of "Cellular Function and Maintenance, Hepatic System Development and Function, Neurological Disease" was altered most significantly. This study suggests that plasma metabolic profiling has great potential in differentiating BA from NHS, and amino acid metabolism is significantly different between the two diseases. PMID: 25899098 [PubMed - as supplied by publisher]

Related Articles Genomics and metabolomics of muscular mass in community-based sample of UK females. Eur J Hum Genet. 2015 Apr 22; Authors: Korostishevsky M, Steves CJ, Malkin I, Spector T, Williams FM, Livshits G Abstract The contribution of specific molecular-genetic factors to muscle mass variation and sarcopenia remains largely unknown. To identify endogenous molecules and specific genetic factors associated with appendicular lean mass (APLM) in the general population, cross-sectional data from the TwinsUK Adult Twin Registry were used. Non-targeted mass spec-based metabolomic profiling was performed on plasma of 3953 females (mostly dizygotic and monozygotic twins). APLM was measured using dual-energy X-ray absorptiometry (DXA) and genotyping was genome-wide (GWAS). Specific metabolites were used as intermediate phenotypes in the identification of single-nucleotide polymorphisms associated with APLM using GWAS. In all, 162 metabolites were found significantly correlated with APLM, and explained 17.4% of its variation. However, the top three of them (unidentified substance X12063, urate, and mannose) explained 11.1% (P≤9.25 × 10(-26)) so each was subjected to GWAS. Each metabolite showed highly significant (P≤9.28 × 10(-46)) associations with genetic variants in the corresponding genomic regions. Mendelian randomization using these SNPs found no evidence for a direct causal effect of these metabolites on APLM. However, using a new software platform for bivariate analysis we showed that shared genetic factors contribute significantly (P≤4.31 × 10(-43)) to variance in both the metabolites and APLM - independent of the effect of the associated SNPs. There are several metabolites, having a clear pattern of genetic inheritance, which are highly significantly associated with APLM and may provide a cheap and readily accessible biomarker of muscle mass. However, the mechanism by which the genetic factor influences muscle mass remains to be discovered.European Journal of Human Genetics advance online publication, 22 April 2015; doi:10.1038/ejhg.2015.85. PMID: 25898920 [PubMed - as supplied by publisher]

Related Articles Heme exporter FLVCR is required for T cell development and peripheral survival. J Immunol. 2015 Feb 15;194(4):1677-85 Authors: Philip M, Funkhouser SA, Chiu EY, Phelps SR, Delrow JJ, Cox J, Fink PJ, Abkowitz JL Abstract All aerobic cells and organisms must synthesize heme from the amino acid glycine and the tricarboxylic acid cycle intermediate succinyl CoA for incorporation into hemoproteins, such as the cytochromes needed for oxidative phosphorylation. Most studies on heme regulation have been done in erythroid cells or hepatocytes; however, much less is known about heme metabolism in other cell types. The feline leukemia virus subgroup C receptor (FLVCR) is a 12-transmembrane domain surface protein that exports heme from cells, and it was shown to be required for erythroid development. In this article, we show that deletion of Flvcr in murine hematopoietic precursors caused a complete block in αβ T cell development at the CD4(+)CD8(+) double-positive stage, although other lymphoid lineages were not affected. Moreover, FLVCR was required for the proliferation and survival of peripheral CD4(+) and CD8(+) T cells. These studies identify a novel and unexpected role for FLVCR, a major facilitator superfamily metabolite transporter, in T cell development and suggest that heme metabolism is particularly important in the T lineage. PMID: 25582857 [PubMed - indexed for MEDLINE]

Related Articles Antibody-opsonized bacteria evoke an inflammatory dendritic cell phenotype and polyfunctional Th cells by cross-talk between TLRs and FcRs. J Immunol. 2015 Feb 15;194(4):1856-66 Authors: Bakema JE, Tuk CW, van Vliet SJ, Bruijns SC, Vos JB, Letsiou S, Dijkstra CD, van Kooyk Y, Brenkman AB, van Egmond M Abstract During secondary immune responses, Ab-opsonized bacteria are efficiently taken up via FcRs by dendritic cells. We now demonstrate that this process induces cross-talk between FcRs and TLRs, which results in synergistic release of several inflammatory cytokines, as well as altered lipid metabolite profiles. This altered inflammatory profile redirects Th1 polarization toward Th17 cell responses. Interestingly, GM-CSF-producing Th cells were synergistically evoked as well, which suggests the onset of polyfunctional Th17 cells. Synergistic cytokine release was dependent on activation via MyD88 and ITAM signaling pathways through TLRs and FcRs, respectively. Cytokine regulation occurred via transcription-dependent mechanisms for TNF-α and IL-23 and posttranscriptional mechanisms for caspase-1-dependent release of IL-1β. Furthermore, cross-talk between TLRs and FcRs was not restricted to dendritic cells. In conclusion, our results support that bacteria alone initiate fundamentally different immune responses compared with Ab-opsonized bacteria through the combined action of two classes of receptors and, ultimately, may refine new therapies for inflammatory diseases. PMID: 25582855 [PubMed - indexed for MEDLINE]

Related Articles Effects of R219K polymorphism of ATP-binding cassette transporter 1 gene on serum lipids ratios induced by a high-carbohydrate and low-fat diet in healthy youth. Biol Res. 2014;47:4 Authors: Liu H, Lin J, Zhu X, Li Y, Fan M, Zhang R, Fang D Abstract BACKGROUND: Diets are the important players in regulating plasma lipid profiles. And the R219K polymorphism at the gene of ATP-binding cassette transporter 1(ABCA1) was reported to be associated with the profiles. However, no efforts have been made to investigate the changes of lipid profiles after a high-carbohydrate and low-fat diet in different subjects with different genotypes of this polymorphism. This study was to evaluate the effects of ABCA1 R219K polymorphism on serum lipid and apolipoprotein (apo) ratios induced by a high-carbohydrate/low-fat (high-CHO) diet. After a washout diet of 54.1% carbohydrate for 7 days, 56 healthy young subjects (22.89 ± 1.80 years old) were given a high-CHO diet of 70.1% carbohydrate for 6 days. Height, weight, waist circumference, hip circumference, glucose (Glu), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apoA-1 and apoB-100 were measured on the 1st, 8th and 14th days of this study. Body mass index (BMI), waist-to-hip ratios (WHR), log(TG/HDL-C), TC/HDL-C, LDL-C/HDL-C and apoA-1/apoB-100 were calculated. ABCA1 R219K was analyzed by a PCR-RFLP method. RESULTS: The results indicate that the male subjects of all the genotypes had higher WHR than their female counterparts on the 1st, 8th and 14th days of this study. The male K carriers had higher log(TG/HDL-C) and TC/HDL-C than the female carriers on the 1st and 14th days, and higher LDL-C/HDL-C on the 14th day. When compared with that on the 8th day, TC/HDL-C was decreased regardless of the genotypes and genders on the 14th day. Log(TG/HDL-C) was increased in the males with the RR genotype and the female K carriers. Lowered BMI, Glu and LDL-C/HDL-C were found in the male K carriers, but only lowered BMI in the female K carriers and only lowered LDL-C/HDL-C in the females with the RR genotype. CONCLUSIONS: These results suggest that ABCA1 R219K polymorphism is associated differently in males and females with elevated log(TG/HDL-C) and decreased LDL-C/HDL-C induced by the high-CHO diet. PMID: 25027185 [PubMed - indexed for MEDLINE]

Related Articles Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats. Acta Pharmacol Sin. 2014 Mar;35(3):363-72 Authors: Zhang LF, Liu LS, Chu XM, Xie H, Cao LJ, Guo C, A JY, Cao B, Li MJ, Wang GJ, Hao HP Abstract AIM: To investigate the potential interactive effects of a high-fat diet (HFD) and valproic acid (VPA) on hepatic steatosis and hepatotoxicity in rats. METHODS: Male SD rats were orally administered VPA (100 or 500 mg·kg⁻¹·d⁻¹) combined with HFD or a standard diet for 8 weeks. Blood and liver samples were analyzed to determine lipid levels and hepatic function biomarkers using commercial kit assays. Low-molecular-weight compounds in serum, urine and bile samples were analyzed using a metabonomic approach based on GC/TOF-MS. RESULTS: HFD alone induced extensive hepatocyte steatosis and edema in rats, while VPA alone did not cause significant liver lesions. VPA significantly aggravated HFD-induced accumulation of liver lipids, and caused additional spotty or piecemeal necrosis, accompanied by moderate infiltration of inflammatory cells in the liver. Metabonomic analysis of serum, urine and bile samples revealed that HFD significantly increased the levels of amino acids, free fatty acids (FFAs) and 3-hydroxy-butanoic acid, whereas VPA markedly decreased the levels of amino acids, FFAs and the intermediate products of the tricarboxylic acid cycle (TCA) compared with the control group. HFD aggravated VPA-induced inhibition on lipid and amino acid metabolism. CONCLUSION: HFD magnifies VPA-induced impairment of mitochondrial β-oxidation of FFAs and TCA, thereby increases hepatic steatosis and hepatotoxicity. The results suggest the patients receiving VPA treatment should be advised to avoid eating HFD. PMID: 24442146 [PubMed - indexed for MEDLINE]

29 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2015/04/22PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

T-cell metabolism in autoimmune disease. Arthritis Res Ther. 2015;17(1):29 Authors: Yang Z, Matteson EL, Goronzy JJ, Weyand CM Abstract Cancer cells have long been known to fuel their pathogenic growth habits by sustaining a high glycolytic flux, first described almost 90 years ago as the so-called Warburg effect. Immune cells utilize a similar strategy to generate the energy carriers and metabolic intermediates they need to produce biomass and inflammatory mediators. Resting lymphocytes generate energy through oxidative phosphorylation and breakdown of fatty acids, and upon activation rapidly switch to aerobic glycolysis and low tricarboxylic acid flux. T cells in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have a disease-specific metabolic signature that may explain, at least in part, why they are dysfunctional. RA T cells are characterized by low adenosine triphosphate and lactate levels and increased availability of the cellular reductant NADPH. This anti-Warburg effect results from insufficient activity of the glycolytic enzyme phosphofructokinase and differentiates the metabolic status in RA T cells from those in cancer cells. Excess production of reactive oxygen species and a defect in lipid metabolism characterizes metabolic conditions in SLE T cells. Owing to increased production of the glycosphingolipids lactosylceramide, globotriaosylceramide and monosialotetrahexosylganglioside, SLE T cells change membrane raft formation and fail to phosphorylate pERK, yet hyperproliferate. Borrowing from cancer metabolomics, the metabolic modifications occurring in autoimmune disease are probably heterogeneous and context dependent. Variations of glucose, amino acid and lipid metabolism in different disease states may provide opportunities to develop biomarkers and exploit metabolic pathways as therapeutic targets. PMID: 25890351 [PubMed - as supplied by publisher]

Increased levels of choline metabolites are an early marker of docetaxel treatment response in BRCA1-mutated mouse mammary tumors: an assessment by ex vivo proton magnetic resonance spectroscopy. J Transl Med. 2015;13(1):114 Authors: van Asten JJ, Vettukattil R, Buckle T, Rottenberg S, van Leeuwen F, Bathen TF, Heerschap A Abstract BACKGROUND: Docetaxel is one of the most frequently used drugs to treat breast cancer. However, resistance or incomplete response to docetaxel is a major challenge. The aim of this study was to utilize MR metabolomics to identify potential biomarkers of docetaxel resistance in a mouse model for BRCA1-mutated breast cancer. METHODOLOGY: High resolution magic angle spinning (HRMAS) (1)H MR spectroscopy was performed on tissue samples obtained from docetaxel-sensitive or -resistant BRCA1-mutated mammary tumors in mice. Measurements were performed on samples obtained before treatment and at 1-2, 3-5 and 6-7 days after a 25 mg/kg dose of docetaxel. The MR spectra were analyzed by multivariate analysis, followed by analysis of the signals of individual compounds by peak fitting and integration with normalization to the integral of the creatine signal and of all signals between 2.9 and 3.6 ppm. RESULTS: The HRMAS spectra revealed significant metabolic differences between sensitive and resistant tissue samples. In particular choline metabolites were higher in resistant tumors by more than 50% with respect to creatine and by more than 30% with respect to all signals between 2.9 and 3.6 ppm. Shortly after treatment (1-2 days) the normalized choline metabolite levels were significantly increased by more than 30% in the sensitive group coinciding with the time of highest apoptotic activity induced by docetaxel. Thereafter, choline metabolites in these tumors returned towards pre-treatment levels. No change in choline compounds was observed in the resistant tumors over the whole time of investigation. CONCLUSIONS: Relative tissue concentrations of choline compounds are higher in docetaxel resistant than in sensitive BRCA1-mutated mouse mammary tumors, but in the first days after docetaxel treatment only in the sensitive tumors an increase of these compounds is observed. Thus both pre- and post-treatment tissue levels of choline compounds have potential to predict response to docetaxel treatment. PMID: 25890200 [PubMed - as supplied by publisher]

Fluxome study of Pseudomonas fluorescens reveals major reorganisation of carbon flux through central metabolic pathways in response to inactivation of the anti-sigma factor MucA. BMC Syst Biol. 2015;9(1):6 Authors: Lien SK, Niedenführ S, Sletta H, Nöh K, Bruheim P Abstract BACKGROUND: The bacterium Pseudomonas fluorescens switches to an alginate-producing phenotype when the pleiotropic anti-sigma factor MucA is inactivated. The inactivation is accompanied by an increased biomass yield on carbon sources when grown under nitrogen-limited chemostat conditions. A previous metabolome study showed significant changes in the intracellular metabolite concentrations, especially of the nucleotides, in mucA deletion mutants compared to the wild-type. In this study, the P. fluorescens SBW25 wild-type and an alginate non-producing mucA- ΔalgC double-knockout mutant are investigated through model-based (13)C-metabolic flux analysis ((13)C-MFA) to explore the physiological consequences of MucA inactivation at the metabolic flux level. Intracellular metabolite extracts from three carbon labelling experiments using fructose as the sole carbon source are analysed for (13)C-label incorporation in primary metabolites by gas and liquid chromatography tandem mass spectrometry. RESULTS: From mass isotopomer distribution datasets, absolute intracellular metabolic reaction rates for the wild type and the mutant are determined, revealing extensive reorganisation of carbon flux through central metabolic pathways in response to MucA inactivation. The carbon flux through the Entner-Doudoroff pathway was reduced in the mucA- ΔalgC mutant, while flux through the pentose phosphate pathway was increased. Our findings also indicated flexibility of the anaplerotic reactions through down-regulation of the pyruvate shunt in the mucA- ΔalgC mutant and up-regulation of the glyoxylate shunt. CONCLUSIONS: Absolute metabolic fluxes and metabolite levels give detailed, integrated insight into the physiology of this industrially, medically and agriculturally important bacterial species and suggest that the most efficient way of using a mucA- mutant as a cell factory for alginate production would be to use non-growing conditions and nitrogen deprivation. PMID: 25889900 [PubMed - as supplied by publisher]

EGFR/ERBB receptors differentially modulate sebaceous lipogenesis. FEBS Lett. 2015 Apr 15; Authors: Dahlhoff M, Camera E, Ludovici M, Picardo M, Müller U, Leonhardt H, Zouboulis CC, Schneider MR Abstract The roles of the epidermal growth factor receptor (EGFR) in sebaceous glands remain poorly explored. We show that human sebocytes express EGFR and lower levels of ERBB2 and ERBB3, all receptors being downregulated after the induction of lipid synthesis. Nile red staining showed that siRNA-mediated downregulation of EGFR or ERBB3 increases lipid accumulation, whereas ERBB2 downregulation has no effect. Spectrometry confirmed induction of triglycerides after EGFR or ERBB3 downregulation and revealed induction of cholesteryl esters after downregulation of EGFR, ERBB2 or ERBB3. Thus, EGFR/ERBB receptors differentially modulate sebaceous lipogenesis, a key feature of sebaceous gland physiology and of several skin diseases. PMID: 25889637 [PubMed - as supplied by publisher]

High-resolution metabolomics to discover potential parasite-specific biomarkers in a Plasmodium falciparum erythrocytic stage culture system. Malar J. 2015;14(1):122 Authors: Park YH, Shi YP, Liang B, Medriano CA, Jeon YH, Torres E, Uppal K, Slutsker L, Jones DP Abstract BACKGROUND: Current available malaria diagnostic methods each have some limitations to meet the need for real-time and large-scale screening of asymptomatic and low density malaria infection at community level. It was proposed that malaria parasite-specific low molecular-weight metabolites could be used as biomarkers for the development of a malaria diagnostic tool aimed to address this diagnostic challenge. In this study, high resolution metabolomics (HRM) was employed to identify malaria parasite-specific metabolites in Plasmodium falciparum in vitro culture samples. METHODS: Supernatants were collected at 12 hours interval from 3% haematocrit in vitro 48-hour time-course asynchronized culture system of P. falciparum. Liquid chromatography coupled with high resolution mass spectrometry was applied to discover potential parasite-specific metabolites in the cell culture supernatant. A metabolome-wide association study was performed to extract metabolites using Manhattan plot with false discovery rate (FDR) and hierarchical cluster analysis. The significant metabolites based on FDR cutoff were annotated using Metlin database. Standard curves were created using corresponding chemical compounds to accurately quantify potential Plasmodium-specific metabolites in culture supernatants. RESULTS: The number of significant metabolite features was 1025 in the supernatant of the Plasmodium infected culture based on Manhattan plot with FDR q=0.05. A two way hierarchical cluster analysis showed a clear segregation of the metabolic profile of parasite infected supernatant from non-infected supernatant at four time points during the 48 hour culture. Among the 1025 annotated metabolites, the intensities of four molecules were significantly increased with culture time suggesting a positive association between the quantity of these molecules and level of parasitaemia: i) 3-methylindole, a mosquito attractant, ii) succinylacetone, a haem biosynthesis inhibitor, iii) S-methyl-L-thiocitrulline, a nitric oxide synthase inhibitor, and iv) O-arachidonoyl glycidol, a fatty acid amide hydrolase inhibitor, The highest concentrations of 3-methylindole and succinylacetone were 178 ± 18.7 pmoles at 36 hours and 157±30.5 pmoles at 48 hours respectively in parasite infected supernatant. CONCLUSION: HRM with bioinformatics identified four potential parasite-specific metabolite biomarkers using in vitro culture supernatants. Further study in malaria infected human is needed to determine presence of the molecules and its relationship with parasite densities. PMID: 25889340 [PubMed - as supplied by publisher]

Helminth infections and type 2 diabetes: a cluster-randomized placebo controlled SUGARSPIN trial in Nangapanda, Flores, Indonesia. BMC Infect Dis. 2015;15(1):133 Authors: Tahapary DL, de Ruiter K, Martin I, van Lieshout L, Guigas B, Soewondo P, Djuardi Y, Wiria AE, Mayboroda OA, Houwing-Duistermaat JJ, Tasman H, Sartono E, Yazdanbakhsh M, Smit JW, Supali T Abstract BACKGROUND: Insulin resistance is a strong predictor of the development of type 2 diabetes mellitus. Chronic helminth infections might protect against insulin resistance via a caloric restriction state and indirectly via T-helper-2 polarization of the immune system. Therefore the elimination of helminths might remove this beneficial effect on insulin resistance. METHODS/DESIGN: To determine whether soil-transmitted helminth infections are associated with a better whole-body insulin sensitivity and whether this protection is reversible by anthelmintic treatment, a household-based cluster-randomized, double blind, placebo-controlled trial was conducted in the area of Nangapanda on Flores Island, Indonesia, an area endemic for soil-transmitted helminth infections. The trial incorporates three monthly treatment with albendazole or matching placebo for one year, whereby each treatment round consists of three consecutive days of supervised drug intake. The presence of soil-transmitted helminths will be evaluated in faeces using microscopy and/or PCR. The primary outcome of the study will be changes in insulin resistance as assessed by HOMA-IR, while the secondary outcomes will be changes in body mass index, waist circumference, fasting blood glucose, 2 h-glucose levels after oral glucose tolerance test, HbA1c, serum lipid levels, immunological parameters, and efficacy of anthelmintic treatment. DISCUSSION: The study will provide data on the effect of helminth infections on insulin resistance. It will assess the relationship between helminth infection status and immune responses as well as metabolic parameters, allowing the establishment of a link between inflammation and whole-body metabolic homeostasis. In addition, it will give information on anthelmintic treatment efficacy and effectiveness. TRIAL REGISTRATION: This study has been approved by the ethical committee of Faculty of Medicine Universitas Indonesia (ref: 549/H2.F1/ETIK/2013), and has been filed by the ethics committee of Leiden University Medical Center, clinical trial number: ISRCTN75636394 . The study is reported in accordance with the CONSORT guidelines for cluster-randomised trials. PMID: 25888525 [PubMed - as supplied by publisher]

IPO: a tool for automated optimization of XCMS parameters. BMC Bioinformatics. 2015 Apr 16;16(1):118 Authors: Libiseller G, Dvorzak M, Kleb U, Gander E, Eisenberg T, Madeo F, Neumann S, Trausinger G, Sinner F, Pieber T, Magnes C Abstract BACKGROUND: Untargeted metabolomics generates a huge amount of data. Software packages for automated data processing are crucial to successfully process these data. A variety of such software packages exist, but the outcome of data processing strongly depends on algorithm parameter settings. If they are not carefully chosen, suboptimal parameter settings can easily lead to biased results. Therefore, parameter settings also require optimization. Several parameter optimization approaches have already been proposed, but a software package for parameter optimization which is free of intricate experimental labeling steps, fast and widely applicable is still missing. RESULTS: We implemented the software package IPO ('Isotopologue Parameter Optimization') which is fast and free of labeling steps, and applicable to data from different kinds of samples and data from different methods of liquid chromatography - high resolution mass spectrometry and data from different instruments. IPO optimizes XCMS peak picking parameters by using natural, stable (13)C isotopic peaks to calculate a peak picking score. Retention time correction is optimized by minimizing relative retention time differences within peak groups. Grouping parameters are optimized by maximizing the number of peak groups that show one peak from each injection of a pooled sample. The different parameter settings are achieved by design of experiments, and the resulting scores are evaluated using response surface models. IPO was tested on three different data sets, each consisting of a training set and test set. IPO resulted in an increase of reliable groups (146% - 361%), a decrease of non-reliable groups (3% - 8%) and a decrease of the retention time deviation to one third. CONCLUSIONS: IPO was successfully applied to data derived from liquid chromatography coupled to high resolution mass spectrometry from three studies with different sample types and different chromatographic methods and devices. We were also able to show the potential of IPO to increase the reliability of metabolomics data. The source code is implemented in R, tested on Linux and Windows and it is freely available for download at https://github.com/glibiseller/IPO . The training sets and test sets can be downloaded from https://health.joanneum.at/IPO . PMID: 25888443 [PubMed - as supplied by publisher]

Metabolome searcher: a high throughput tool for metabolite identification and metabolic pathway mapping directly from mass spectrometry and using genome restriction. BMC Bioinformatics. 2015;16(1):62 Authors: Dhanasekaran AR, Pearson JL, Ganesan B, Weimer BC Abstract BACKGROUND: Mass spectrometric analysis of microbial metabolism provides a long list of possible compounds. Restricting the identification of the possible compounds to those produced by the specific organism would benefit the identification process. Currently, identification of mass spectrometry (MS) data is commonly done using empirically derived compound databases. Unfortunately, most databases contain relatively few compounds, leaving long lists of unidentified molecules. Incorporating genome-encoded metabolism enables MS output identification that may not be included in databases. Using an organism's genome as a database restricts metabolite identification to only those compounds that the organism can produce. RESULTS: To address the challenge of metabolomic analysis from MS data, a web-based application to directly search genome-constructed metabolic databases was developed. The user query returns a genome-restricted list of possible compound identifications along with the putative metabolic pathways based on the name, formula, SMILES structure, and the compound mass as defined by the user. Multiple queries can be done simultaneously by submitting a text file created by the user or obtained from the MS analysis software. The user can also provide parameters specific to the experiment's MS analysis conditions, such as mass deviation, adducts, and detection mode during the query so as to provide additional levels of evidence to produce the tentative identification. The query results are provided as an HTML page and downloadable text file of possible compounds that are restricted to a specific genome. Hyperlinks provided in the HTML file connect the user to the curated metabolic databases housed in ProCyc, a Pathway Tools platform, as well as the KEGG Pathway database for visualization and metabolic pathway analysis. CONCLUSIONS: Metabolome Searcher, a web-based tool, facilitates putative compound identification of MS output based on genome-restricted metabolic capability. This enables researchers to rapidly extend the possible identifications of large data sets for metabolites that are not in compound databases. Putative compound names with their associated metabolic pathways from metabolomics data sets are returned to the user for additional biological interpretation and visualization. This novel approach enables compound identification by restricting the possible masses to those encoded in the genome. PMID: 25887958 [PubMed - as supplied by publisher]

Human metabolic response to systemic inflammation: assessment of the concordance between experimental endotoxemia and clinical cases of sepsis/SIRS. Crit Care. 2015;19(1):71 Authors: Kamisoglu K, Haimovich B, Calvano SE, Coyle SM, Corbett SA, Langley RJ, Kingsmore SF, Androulakis IP Abstract INTRODUCTION: Two recent, independent, studies conducted novel metabolomics analyses relevant to human sepsis progression; one was a human model of endotoxin (lipopolysaccharide (LPS)) challenge (experimental endotoxemia) and the other was community acquired pneumonia and sepsis outcome diagnostic study (CAPSOD). The purpose of the present study was to assess the concordance of metabolic responses to LPS and community-acquired sepsis. METHODS: We tested the hypothesis that the patterns of metabolic response elicited by endotoxin would agree with those in clinical sepsis. Alterations in the plasma metabolome of the subjects challenged with LPS were compared with those of sepsis patients who had been stratified into two groups: sepsis patients with confirmed infection and non-infected patients who exhibited systemic inflammatory response syndrome (SIRS) criteria. Common metabolites between endotoxemia and both these groups were individually identified, together with their direction of change and functional classifications. RESULTS: Response to endotoxemia at the metabolome level elicited characteristics that agree well with those observed in sepsis patients despite the high degree of variability in the response of these patients. Moreover, some distinct features of SIRS have been identified. Upon stratification of sepsis patients based on 28-day survival, the direction of change in 21 of 23 metabolites was the same in endotoxemia and sepsis survival groups. CONCLUSIONS: The observed concordance in plasma metabolomes of LPS-treated subjects and sepsis survivors strengthens the relevance of endotoxemia to clinical research as a physiological model of community-acquired sepsis, and gives valuable insights into the metabolic changes that constitute a homeostatic response. Furthermore, recapitulation of metabolic differences between sepsis non-survivors and survivors in LPS-treated subjects can enable further research on the development and assessment of rational clinical therapies to prevent sepsis mortality. Compared with earlier studies which focused exclusively on comparing transcriptional dynamics, the distinct metabolomic responses to systemic inflammation with or without confirmed infection, suggest that the metabolome is much better at differentiating these pathophysiologies. Finally, the metabolic changes in the recovering patients shift towards the LPS-induced response pattern strengthening the notion that the metabolic, as well as transcriptional responses, characteristic to the endotoxemia model represent necessary and "healthy" responses to infectious stimuli. PMID: 25887472 [PubMed - as supplied by publisher]

Dysbiotic gut microbiota causes transmissible Crohn's disease-like ileitis independent of failure in antimicrobial defence. Gut. 2015 Apr 17; Authors: Schaubeck M, Clavel T, Calasan J, Lagkouvardos I, Haange SB, Jehmlich N, Basic M, Dupont A, Hornef M, Bergen MV, Bleich A, Haller D Abstract OBJECTIVES: Dysbiosis of the intestinal microbiota is associated with Crohn's disease (CD). Functional evidence for a causal role of bacteria in the development of chronic small intestinal inflammation is lacking. Similar to human pathology, TNF(deltaARE) mice develop a tumour necrosis factor (TNF)-driven CD-like transmural inflammation with predominant ileal involvement. DESIGN: Heterozygous TNF(deltaARE) mice and wildtype (WT) littermates were housed under conventional (CONV), specific pathogen-free (SPF) and germ-free (GF) conditions. Microbial communities were analysed by high-throughput 16S ribosomal RNA gene sequencing. Metaproteomes were measured using LC-MS. Temporal and spatial resolution of disease development was followed after antibiotic treatment and transfer of microbial communities into GF mice. Granulocyte infiltration and Paneth cell function was assessed by immunofluorescence and gene expression analysis. RESULTS: GF-TNF(deltaARE) mice were free of inflammation in the gut and antibiotic treatment of CONV-TNF(deltaARE) mice attenuated ileitis but not colitis, demonstrating that disease severity and location are microbiota-dependent. SPF-TNF(deltaARE) mice developed distinct ileitis-phenotypes associated with gradual loss of antimicrobial defence. 16S analysis and metaproteomics revealed specific compositional and functional alterations of bacterial communities in inflamed mice. Transplantation of disease-associated but not healthy microbiota transmitted CD-like ileitis to GF-TNF(deltaARE) recipients and triggered loss of lysozyme and cryptdin-2 expression. Monoassociation of GF-TNF(deltaARE) mice with the human CD-related Escherichia coli LF82 did not induce ileitis. CONCLUSIONS: We provide clear experimental evidence for the causal role of gut bacterial dysbiosis in the development of chronic ileal inflammation with subsequent failure of Paneth cell function. PMID: 25887379 [PubMed - as supplied by publisher]

Kernel approaches for differential expression analysis of mass spectrometry-based metabolomics data. BMC Bioinformatics. 2015;16(1):77 Authors: Zhan X, Patterson AD, Ghosh D Abstract BACKGROUND: Data generated from metabolomics experiments are different from other types of "-omics" data. For example, a common phenomenon in mass spectrometry (MS)-based metabolomics data is that the data matrix frequently contains missing values, which complicates some quantitative analyses. One way to tackle this problem is to treat them as absent. Hence there are two types of information that are available in metabolomics data: presence/absence of a metabolite and a quantitative value of the abundance level of a metabolite if it is present. Combining these two layers of information poses challenges to the application of traditional statistical approaches in differential expression analysis. RESULTS: In this article, we propose a novel kernel-based score test for the metabolomics differential expression analysis. In order to simultaneously capture both the continuous pattern and discrete pattern in metabolomics data, two new kinds of kernels are designed. One is the distance-based kernel and the other is the stratified kernel. While we initially describe the procedures in the case of single-metabolite analysis, we extend the methods to handle metabolite sets as well. CONCLUSIONS: Evaluation based on both simulated data and real data from a liver cancer metabolomics study indicates that our kernel method has a better performance than some existing alternatives. An implementation of the proposed kernel method in the R statistical computing environment is available at http://works.bepress.com/debashis_ghosh/60/ . PMID: 25887233 [PubMed - as supplied by publisher]