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  • 1.
    Angelcheva, Liudmila
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mishra, Yogesh
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kjellsen, Trygve D.
    Department of Biology, Norwegian University of Science and Technology.
    Funk, Christiane
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Strimbeck, Richard G.
    Department of Biology, Norwegian University of Science and Technology.
    Schröder, Wolfgang P.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Metabolomic analysis of extreme freezing tolerance in Siberian spruce (Picea obovata)2014In: New Phytologist, ISSN 0028-646X, E-ISSN 1469-8137, Vol. 204, no 3, 545-555 p.Article in journal (Refereed)
    Abstract [en]

    Siberian spruce (Picea obovata) is one of several boreal conifer species that can survive at extremely low temperatures (ELTs). When fully acclimated, its tissues can survive immersion in liquid nitrogen. Relatively little is known about the biochemical and biophysical strategies of ELT survival. We profiled needle metabolites using gas chromatography coupled with mass spectrometry (GC-MS) to explore the metabolic changes that occur during cold acclimation caused by natural temperature fluctuations. In total, 223 metabolites accumulated and 52 were depleted in fully acclimated needles compared with pre-acclimation needles. The metabolite profiles were found to develop in four distinct phases, which are referred to as pre-acclimation, early acclimation, late acclimation and fully acclimated. Metabolite changes associated with carbohydrate and lipid metabolism were observed, including changes associated with increased raffinose family oligosaccharide synthesis and accumulation, accumulation of sugar acids and sugar alcohols, desaturation of fatty acids, and accumulation of digalactosylglycerol. We also observed the accumulation of protein and nonprotein amino acids and polyamines that may act as compatible solutes or cryoprotectants. These results provide new insight into the mechanisms of freezing tolerance development at the metabolite level and highlight their importance in rapid acclimation to ELT in P.obovata.

  • 2.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Chemistry.
    Chemometric and bioinformatic methodologies in modeling and interpretation of metabolic and genomic data2004Conference paper (Other academic)
  • 3.
    Antti, Henrik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Alexandersson, Daniel
    Sjöström, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wallbäcks, Lars
    Detection of kappa number distributions in kraft pulps using nir spectroscopy and multivariate calibration2000In: TAPPI Journal, Vol. 83, no 3, 102-8 p.Article in journal (Refereed)
    Abstract [en]

    Chemical pulp is characterized by its average lignin content, commonly expressed as the pulp-kappa number. However, this average kappa number provides no information about the distribution of kappa number within the pulp . This study proposes a new method of pulp characterization using near-infrared reflectance (NIR) spectroscopy to measure distributions of kappa numbers within pulp samples. Pure pulps with different kappa numbers were mixed to create blended samples with a known nonuniformity of kappa number distribution. NIR spectroscopy-combined with multi-variate calibration methods was used to detect distributions of kappa numbers in the pulps. Models calculated from these data gave good predictions of the average kappa number as well as the standard deviation around the average. The results imply that NIR spectroscopy can provide information about the average kappa number as well as the distribution of kappa number within the pulp.

  • 4.
    Antti, Henrik
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Bollard, M E
    Ebbels, T
    Keun, H
    Lindon, J C
    Nicholson, J K
    Holmes, E
    Batch statistical processing of 1H NMR-derived urinary spectral data2002In: Journal of Chemometrics: Special Issue: Proceedings of the 7th Scandinavian Symposium on Chemometrics. Issue Edited by Lars Nørgaard, Vol. 16, no 8-10, 461-8 p.Article in journal (Refereed)
    Abstract [en]

    Multivariate statistical batch processing (BP) analysis of 1H nuclear magnetic resonance (NMR) urine spectra was employed to establish time-dependent metabolic variations in animals treated with the model hepatotoxin hydrazine. Hydrazine was administered orally to rats (at 90 mg kg-1), and urine samples were collected from dosed rats and matched control animals (n = 5 per group) at time points up to 168 h post-dose. Urine samples were analysed via 1H NMR spectroscopy and partial least squares-based batch processing analysis, treating each rat as an individual batch comprising a series of timed urine samples. A model defining the mean urine profile was established for the control group, and samples obtained from hydrazine-treated animals were assessed using this model. Time-dependent deviations from the control model were evident in all hydrazine-treated animals, and hepatotoxicity was manifested by increased urinary excretion of taurine, creatine, 2-aminoadipate, citrulline and -alanine together with depletion of urinary levels of citrate, succinate and hippurate. The experiment was repeated at six different pharmaceutical centres in order to assess the robustness of the technology and to establish the natural variability in the data. Results were consistent across the data for all centres. BP plots showed a characteristic pattern for each toxin, allowing the time points at which there were maximum metabolic differences to be determined and providing a means of visualizing the net toxin-induced metabolic movement of urinary metabolism. BP may prove to be a powerful metabonomic tool in defining time-dependent metabolic consequences of toxicity and is an efficient means of visualizing inter-animal variations in response as well as defining multivariate statistical limits of normality in terms of biofluid composition.

  • 5.
    Antti, Henrik
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Ebbels, Timothy M D
    Keun, Hector C
    Bollard, Mary E
    Beckonert, Olaf
    Lindon, John C
    Nicholson, Jeremy K
    Holmes, Elaine
    Statistical experimental design and partial least squares regression analysis of biofluid metabonomic NMR and clinical chemistry data for screening of adverse drug effects2004In: Chemometrics and Intelligent Laboratory Systems, Vol. 73, no 1, 139-49 p.Article in journal (Refereed)
    Abstract [en]

    Metabonomic analysis is increasingly recognised as a powerful approach for delineating the integrated metabolic changes in biofluids and tissues due to toxicity, disease processes or genetic modification in whole animal systems. When dealing with complex biological data sets, as generated within metabonomics, as well as related fields such as genomics and proteomics, reliability and significance of identified biomarkers associated with specific states related to toxicity or disease are crucial in order to gain detailed and relevant interpretations of the metabolic fluxes in the studied systems. Since various physiological factors, such as diet, state of health, age, diurnal cycles, stress, genetic drift, and strain differences, affect the metabolic composition of biological matrices, it is of great importance to create statistically reliable decision tools for distinguishing between physiological and pathological responses in animal models. In the screening for new biomarkers or patterns of pathological dysfunction, methods providing statistically valid measures of effect-related changes will become increasingly important as the data within areas such as genomics, proteomics and metabonomics continues to grow in size and complexity. 1H NMR spectroscopy and mass spectrometry are the principal analytical platforms used to derive the data and, because extensively large data sets are required, as much consideration has to be given to optimum design of experiments (DoE) as for subsequent data analysis. Thus, statistical experimental design combined with partial least squares (PLS) regression is proposed as an efficient approach for undertaking metabonomic studies and for analysis of the results. The method was applied to data from a liver toxicology study in the rat using hydrazine as a model toxin. 1D projections of 2D J-resolved (J-RES) 1H NMR spectra and the corresponding clinical chemistry parameters of blood serum samples from control and dosed rats (30 and 90 mg/kg) collected at 48 and 168 h post dose were analysed. Confidence intervals for the PLS regression coefficients were used to create a statistical means for screening of biomarkers in the two combined data blocks (NMR and clinical chemistry data). PLS analysis was also used to reveal the correlation pattern between the two blocks of data as well as the within the two blocks according to dose, time and the interaction dose×time.

  • 6.
    Antti, Henrik
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fahlgren, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Näsström, Elin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kouremenos, Konstantinos
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Sundén-Cullberg, Jonas
    Guo, Yongzhi
    Moritz, Thomas
    Wolf-Watz, Hans
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Fällman, Maria
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Metabolic profiling for detection of staphylococcus aureus infection and antibiotic resistance2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, e56971Article in journal (Refereed)
    Abstract [en]

    Due to slow diagnostics, physicians must optimize antibiotic therapies based on clinical evaluation of patients without specific information on causative bacteria. We have investigated metabolomic analysis of blood for the detection of acute bacterial infection and early differentiation between ineffective and effective antibiotic treatment. A vital and timely therapeutic difficulty was thereby addressed: the ability to rapidly detect treatment failures because of antibiotic-resistant bacteria. Methicillin-resistant (MRSA) and methicillin-sensitive (MSSA) were used and for infecting mice, while natural MSSA infection was studied in humans. Samples of bacterial growth media, the blood of infected mice and of humans were analyzed with combined Gas Chromatography/Mass Spectrometry. Multivariate data analysis was used to reveal the metabolic profiles of infection and the responses to different antibiotic treatments. experiments resulted in the detection of 256 putative metabolites and mice infection experiments resulted in the detection of 474 putative metabolites. Importantly, ineffective and effective antibiotic treatments were differentiated already two hours after treatment start in both experimental systems. That is, the ineffective treatment of MRSA using cloxacillin and untreated controls produced one metabolic profile while all effective treatment combinations using cloxacillin or vancomycin for MSSA or MRSA produced another profile. For further evaluation of the concept, blood samples of humans admitted to intensive care with severe sepsis were analyzed. One hundred thirty-three putative metabolites differentiated severe MSSA sepsis (n = 6) from severe sepsis (n = 10) and identified treatment responses over time. Combined analysis of human, , and mice samples identified 25 metabolites indicative of effective treatment of sepsis. Taken together, this study provides a proof of concept of the utility of analyzing metabolite patterns in blood for early differentiation between ineffective and effective antibiotic treatment in acute infections.

  • 7. Azmi, Jahanara
    et al.
    Griffin, Julian L
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Chemistry.
    Shore, Richard F
    Johansson, Erik
    Nicholson, Jeremy K
    Holmes, Elaine
    Metabolic trajectory characterisation of xenobiotic-induced hepatotoxic lesions using statistical batch processing of NMR data: Nicholson Jeremy K., Holmes Elaine2002In: Analyst, Vol. 127, 271-6 p.Article in journal (Refereed)
    Abstract [en]

    Multivariate statistical batch processing (BP) analysis of 1H NMR urine spectra was employed to establish time-dependent metabolic variations in animals treated with the model hepatotoxin, -naphthylisothiocyanate (ANIT). ANIT (100 mg kg-1) was administered orally to rats (n = 5) and urine samples were collected from dosed and matching control rats at time-points up to 168 h post-dose. Urine samples were measured via1H NMR spectroscopy and partial least squares (PLS) based batch processing analysis was used to interpret the spectral data, treating each rat as an individual batch comprising a series of timed urine samples. A model defining the mean urine profile over the 7 day study period was established, together with model confidence limits (±3 standard deviation), for the control group. Samples obtained from ANIT treated animals were evaluated using the control model. Time-dependent deviations from the control model were evident in all ANIT treated animals consisting of glycosuria, bile aciduria, an initial decrease in taurine levels followed by taurinuria and a reduction of tricarboxylic acid cycle intermediate excretion. BP provided an efficient means of visualising the biochemical response to ANIT in terms of both inter-animal variation and net variation in metabolite excretion profiles. BP also allowed multivariate statistical limits for normality to be established and provided a template for defining the sequence of time-dependent metabolic consequences of toxicity in NMR based metabonomic studies.

  • 8. Beckwith-Hall, BM
    et al.
    Brindle, JT
    Barton, RH
    Coen, M
    Holmes, E
    Nicholson, JK
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Chemistry.
    Application of orthogonal signal correction to minimise the effects of physical and biological variation in high resolution 1H NMR spectra of biofluids2002In: Analyst, Vol. 127, no 10, 1283-8 p.Article in journal (Refereed)
    Abstract [en]

    1H nuclear magnetic resonance (NMR)-based metabonomics is a well-established technique used to analyse and interpret complex multiparametric metabolic data, and has a wide number of applications in the development of pharmaceuticals. However, interpretation of biological data can be confounded by extraneous variation in the data such as fluctuations in either experimental conditions or in physiological status. Here we have shown the novel application of a data filtering method, orthogonal signal correction (OSC), to biofluid NMR data to minimise the influence of inter- and intra-spectrometer variation during data acquisition, and also to minimise innate physiological variation. The removal of orthogonal variation exposed features of interest in the NMR data and facilitated interpretation of the derived multivariate models. Furthermore, analysis of the orthogonal variation provided an explanation of the systematic analytical/biological changes responsible for confounding the original NMR data.

  • 9.
    Bergemalm, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonsson, P Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Changes in the spinal cord proteome of an amyotrophic lateral sclerosis murine model determined by differential in-gel electrophoresis2009In: Molecular and cellular proteomics, ISSN 1535-9484, Vol. 8, no 6, 1306-1317 p.Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons resulting in progressive paralysis. To date, more than 140 different mutations in the gene encoding CuZn-superoxide dismutase (SOD1) have been associated with ALS. Several transgenic murine models exist in which various mutant SOD1s are expressed. We have used differential in-gel electrophoresis (DIGE) to analyze the changes in the spinal cord proteome induced by expression of the unstable SOD1 truncation mutant G127insTGGG (G127X) in mice. Unlike mutants used in most other models, G127X lacks SOD activity and is present at low levels, thus reducing the risk of overexpression artifacts. The mice were analyzed at their peak body weights, just before onset of symptoms. Variable importance plot (VIP) analysis showed that 420 of 1,800 detected protein spots contributed significantly to the differences between the groups. By MALDI-TOF MS analysis, 54 proteins were identified. One spot was found to be a covalently linked mutant SOD1 dimer, apparently analogous to SOD1 immunoreactive bands migrating at double the molecular weight of SOD1 monomers previously detected in humans and mice carrying mutant SOD1s and in sporadic ALS cases. Analyses of affected functional pathways, and the subcellular representation of alterations suggest that the toxicity exerted by mutant SODs induces oxidative stress and affects mitochondria, cellular assembly/organization, and protein degradation.

  • 10.
    Björklund, Simon
    et al.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Uddestrand, Ida
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Moritz, Thomas
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Sundberg, Björn
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Cross-talk between gibberellin and auxin in development of Populus wood: gibberellin stimulates polar auxin transport and has a common transcriptome with auxin2007In: The Plant Journal, ISSN 0960-7412, E-ISSN 1365-313X, Vol. 52, no 3, 499-511 p.Article in journal (Refereed)
    Abstract [en]

    Both indole acetic acid (IAA) and gibberellins (GAs) stimulate cell and organ growth. We have examined GA/IAA cross-talk in cambial growth of hybrid aspen (Populus tremulaxtremuloides). Decapitated trees were fed with IAA and GA, alone and in combination. Endogenous hormone levels after feeding were measured, by mass spectrometry, in the stem tissues below the point of application. These stem tissues with defined hormone balances were also used for global transcriptome analysis, and the abundance of selected transcripts was measured by real-time reverse-transcription polymerase chain reaction. By feeding isotope-labeled IAA, we demonstrated that GA increases auxin levels in the stem by stimulating polar auxin transport. This finding adds a new dimension to the concept that the endogenous GA/IAA balance in plants is determined by cross-talk between the two hormones. We also show that GA has a common transcriptome with auxin, including many transcripts related to cell growth. This finding provides molecular support to physiological experiments demonstrating that either hormone can induce growth if the other hormone is absent/deficient because of mutations or experimental treatments. It also highlights the potential for extensive cross-talk between GA- and auxin-induced responses in vegetative growth of the intact plant. The role of endogenous IAA and GA in wood development is discussed.

  • 11. Bollard, Mary E
    et al.
    Keun, Hector C
    Beckonert, Olaf
    Ebbels, Tim M D
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Chemistry.
    Nicholls, Andrew W
    Shockcor, John P
    Cantor, Glenn H
    Stevens, Greg
    Lindon, John C
    Holmes, Elaine
    Nicholson, Jeremy K
    Comparative metabonomics of differential hydrazine toxicity in the rat and mouse2005In: Toxicology and Applied Pharmacology, Vol. 204, no 2, 135-51 p.Article in journal (Refereed)
    Abstract [en]

    Interspecies variation between rats and mice has been studied for hydrazine toxicity using a novel metabonomics approach. Hydrazine hydrochloride was administered to male Sprague–Dawley rats (30 mg/kg, n = 10 and 90 mg/kg, n = 10) and male B6C3F mice (100 mg/kg, n = 8 and 250 mg/kg, n = 8) by oral gavage. In each species, the high dose was selected to produce the major histopathologic effect, hepatocellular lipid accumulation. Urine samples were collected at sequential time points up to 168 h post dose and analyzed by 1H NMR spectroscopy. The metabolites of hydrazine, namely diacetyl hydrazine and 1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid (THOPC), were detected in both the rat and mouse urine samples. Monoacetyl hydrazine was detected only in urine samples from the rat and its absence in the urine of the mouse was attributed to a higher activity of N-acetyl transferases in the mouse compared with the rat. Differential metabolic effects observed between the two species included elevated urinary β-alanine, 3-d-hydroxybutyrate, citrulline, N-acetylcitrulline, and reduced trimethylamine-N-oxide excretion unique to the rat. Metabolic principal component (PC) trajectories highlighted the greater degree of toxic response in the rat. A data scaling method, scaled to maximum aligned and reduced trajectories (SMART) analysis, was used to remove the differences between the metabolic starting positions of the rat and mouse and varying magnitudes of effect, to facilitate comparison of the response geometries between the rat and mouse. Mice followed “biphasic” open PC trajectories, with incomplete recovery 7 days after dosing, whereas rats followed closed “hairpin” time profiles, indicating functional reversibility. The greater magnitude of metabolic effects observed in the rat was supported by the more pronounced effect on liver pathology in the rat when compared with the mouse.

  • 12.
    Boman, Niklas
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Burén, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Michael B.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Gene expression and fiber type variations in repeated vastus lateralis biopsies2015In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 52, no 2, 812-817 p.Article in journal (Refereed)
    Abstract [en]

    Introduction: Muscle sample collection can introduce variation in any measured variable due to inter- and intramuscle variation. We investigated the variation in gene expression and fiber type composition after repeated biopsy sampling from the vastus lateralis muscle. Methods: Six subjects donated 3 tissue samples each. One hour after baseline sampling from 1 vastus lateralis muscle, samples from both vastus lateralis muscles were obtained. Results: The fiber type composition differed between biopsies taken from the same leg. There were no within-subject differences in gene expression between the 3 biopsies. Multivariate analysis supports a model in which gene expression differs significantly between individuals but is not affected by repeated muscle biopsy sampling from the same subject. Conclusion: One vastus lateralis muscle sample per subject is sufficient to establish a reliable baseline for comparing gene expression representing selected pathways over time within the same individual.

  • 13. Brindle, Joanne T
    et al.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Chemistry.
    Holmes, Elaine
    Tranter, George
    Nicholson, Jeremy K
    Bethell, Hugh W L
    Clarke, Sarah
    Schofield, Peter M
    McKilligin, Elaine
    Mosedale, David E
    Grainger, David J
    Rapid and Nonivasive Diagnosis of the Presence and Severity of Coronary Heart Disease Using 1H-NMR-Based Metabonomics2002In: Nature Medicine, Vol. 8, 1439-45 p.Article in journal (Refereed)
    Abstract [en]

    Although a wide range of risk factors for coronary heart disease have been identified from population studies, these measures, singly or in combination, are insufficiently powerful to provide a reliable, noninvasive diagnosis of the presence of coronary heart disease. Here we show that pattern-recognition techniques applied to proton nuclear magnetic resonance (1H-NMR) spectra of human serum can correctly diagnose not only the presence, but also the severity, of coronary heart disease. Application of supervised partial least squares-discriminant analysis to orthogonal signal-corrected data sets allows >90% of subjects with stenosis of all three major coronary vessels to be distinguished from subjects with angiographically normal coronary arteries, with a specificity of >90%. Our studies show for the first time a technique capable of providing an accurate, noninvasive and rapid diagnosis of coronary heart disease that can be used clinically, either in population screening or to allow effective targeting of treatments such as statins.

  • 14.
    Bruce, Stephen J
    et al.
    Umeå Plant Science Center, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Cloarec, Olivier
    Technologie Servier, 45000 Orleans, France.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Moritz, Thomas
    Umeå Plant Science Center, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Evaluation of a protocol for metabolic profiling studies on human blood plasma by combined ultra-performance liquid chromatography/mass spectrometry: From extraction to data analysis2009In: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 372, no 2, 237-249 p.Article in journal (Refereed)
    Abstract [en]

    The investigation presented here describes a protocol designed to perform high-throughput metabolic profiling analysis on human blood plasma by ultra-performance liquid chromatography/mass spectrometry (UPLC/MS). To address whether a previous extraction protocol for gas chromatography (GC)/MS-based metabolic profiling of plasma could be used for UPLC/MS-based analysis, the original protocol was compared with similar methods for extraction of low-molecular-weight compounds from plasma via protein precipitation. Differences between extraction methods could be observed, but the previously published extraction method was considered the best. UPLC columns with three different stationary phases (C8, C18, and phenyl) were used in identical experimental runs consisting of a total of 60 injections of extracted male and female plasma samples. The C8 column was determined to be the best for metabolic profiling analysis on plasma. The acquired UPLC/MS data of extracted male and female plasma samples was subjected to principal component analysis (PCA) and orthogonal projections to latent structures discriminant analysis (OPLS–DA). Furthermore, a strategy for compound identification was applied here, demonstrating the strength of high-mass-accuracy time-of-flight (TOF)/MS analysis in metabolic profiling.

  • 15.
    Bylesjö, Max
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Eriksson, Daniel
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Sjödin, Andreas
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Sjöström, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    MASQOT: a method for cDNA microarray spot quality control.2005In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 6, 250- p.Article in journal (Refereed)
    Abstract [en]

    Background

    cDNA microarray technology has emerged as a major player in the parallel detection of biomolecules, but still suffers from fundamental technical problems. Identifying and removing unreliable data is crucial to prevent the risk of receiving illusive analysis results. Visual assessment of spot quality is still a common procedure, despite the time-consuming work of manually inspecting spots in the range of hundreds of thousands or more.

    Results

    A novel methodology for cDNA microarray spot quality control is outlined. Multivariate discriminant analysis was used to assess spot quality based on existing and novel descriptors. The presented methodology displays high reproducibility and was found superior in identifying unreliable data compared to other evaluated methodologies.

    Conclusion

    The proposed methodology for cDNA microarray spot quality control generates non-discrete values of spot quality which can be utilized as weights in subsequent analysis procedures as well as to discard spots of undesired quality using the suggested threshold values. The MASQOT approach provides a consistent assessment of spot quality and can be considered an alternative to the labor-intensive manual quality assessment process.

  • 16.
    Bylesjö, Max
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjödin, Andreas
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Eriksson, Daniel
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Moritz, Thomas
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Jansson, Stefan
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    MASQOT-GUI: spot quality assessment for the two-channel microarray platform2006In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 22, no 20, 2554-2555 p.Article in journal (Refereed)
    Abstract [en]

    MASQOT-GUI provides an open-source, platform-independent software pipeline for two-channel microarray spot quality control. This includes gridding, segmentation, quantification, quality assessment and data visualization. It hosts a set of independent applications, with interactions between the tools as well as import and export support for external software. The implementation of automated multivariate quality control assessment, which is a unique feature of MASQOT-GUI, is based on the previously documented and evaluated MASQOT methodology. Further abilities of the application are outlined and illustrated. AVAILABILITY: MASQOT-GUI is Java-based and licensed under the GNU LGPL. Source code and installation files are available for download at http://masqot-gui.sourceforge.net/

  • 17.
    Chermenina, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Henrik, Antti
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    A novel animal model for Parkinson's disease based on in vivo effects of small-molecule of alpha-synucleinManuscript (preprint) (Other academic)
    Abstract [en]

    Amyloid fibrils of alpha-synuclein are major constituents of Lewy bodies, the pathological hallmark of Parkinson’s disease. Monomeric α-synuclein is involved in synaptic vesicle trafficking and long-term maintenance of neurons. The underlying mechanisms of Parkinson’s disease are not known but it has been proposed that oligomers of α-synuclein, formed during the aggregation process, are toxic to neurons. To search for a new animal model of Parkinson’s disease, here we capitalized on the in vitro discovery of a small-molecule templator of α-synuclein fibrillization, the 2-pyridone, FN075. FN075 and MS382, another 2-pyridone variant that act as an inhibitor of amyloids in vitro, were injected into the striatum or substantia nigra of normal C57Bl/6 mice. No acute toxicity of the compounds was detected, as there was 100 % survival of the injected mice. At 6 months after the striatal injection, sensorimotor functions were impaired with no reduction in TH-positive neurons in the substantia nigra in mice injected with FN075, whereas mice injected with MS382 or vehicle had no dysfunctions. Injection of FN075 into the substantia nigra revealed a significant loss of TH-positive neurons already at 3 months and TH-negative inclusion-like structures were detected in substantia nigra neurons of these mice. Thus, the results suggest that injection of a templator of α-synuclein aggregation into the brain of normal mice can serve as a novel experimental design for an animal model of Parkinson’s disease.

  • 18.
    Chermenina, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pokrzywa, Malgorzata
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Almqvist, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Wittung-Stafshede, Pernilla
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Single injection of small-molecule amyloid accelerator results in cell death of nigral dopamine neurons in mice2015In: Parkinson's Disease, ISSN 2090-8083, E-ISSN 2042-0080, Vol. 1, 15024Article in journal (Refereed)
    Abstract [en]

    The assembly process of a-synuclein toward amyloid fibers is linked to neurodegeneration in Parkinson´s disease. In the present study, we capitalized on the in vitro discovery of a small-molecule accelerator of a-synuclein amyloid formation and assessed its effects when injected in brains of normal mice. An accelerator and an inhibitor of a-synuclein amyloid formation, as well as vehicle only, were injected into the striatum of normal mice and follwed by behavioral evaluation, immunohistochemistry, and metabolomics up to six months later. The effects of molecules injected into the substansia nigra of normal and a-synuclein knockout mice were also analyzed. When accelerator or inhibitor was injected into the brain of normal mice no acute compound toxicity was found. However, 6 months after single striatal injection of accelerator, mice sensorimotor functions were impaired, whereas mice injected with inhibitor had no dysfunctions. Injection of accelerator (but not inhibitor or vehicle) into the substantia nigra revealed singificant loss of tyrosine hydroxylase (TH)-positive neurons after 3 months. No loss of TH-positive neurons was found in a-synuclein knock-out mice injected with accelerator intor the substantia nigra. Metabolic serum profiles from accelerator-injected normal mice matched those of newly diagnosed Parkinson´s disease patients, whereas the profiles from inhibitor-injected normal mice matched controls. Single inoculation of a small-molecule amyloid accelerator may be a new approach for studies of early events during dopamine neurodegeneration in mice.

  • 19.
    Chorell, Elin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Karlsson, Frida
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    West, Christina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    The impact of feeding Lactobacillus F19 during weaning: a study of the plasma metabolomeManuscript (preprint) (Other academic)
  • 20.
    Chorell, Elin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Moritz, Thomas
    Branth, Stefan
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    A predictive metabolomics evaluation of nutrition-modulated metabolic stress responses in human blood serum during the early recovery phase of strenuous physical exercise2009In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 8, no 6, 2966-77 p.Article in journal (Refereed)
    Abstract [en]

    We have investigated whether postexercise ingestion of carbohydrates in combination with proteins generates a different systemic metabolic response, as compared to the sole ingestion of carbohydrate or water, in the early recovery phase following exercise. In addition, metabolic patterns related to fitness level were studied together with individual responses to nutritional modulation. Twenty-four male subjects were exposed to 90 min of ergometer-cycling. Each participant was subject to four identical test-sessions, including ingestion of one of four beverages (water, low-carbohydrate beverage, high-carbohydrate beverage, and low-carbohydrate−protein beverage (LCHO-P)) immediately after cycling. Blood was collected at six time points, one pre- and five postexercise. Extracted blood serum was subject to metabolomic characterization by gas chromatography/time-of-flight mass spectrometry (GC−TOF MS). Data was processed using hierarchical multivariate curve resolution (HMCR), and multivariate statistical analysis was carried out using orthogonal partial least-squares (OPLS). Predictive metabolomics, including predictive HMCR and OPLS classification, was applied to ensure efficient sample processing and validation of detected metabolic patterns. Separation of subjects in relation to ingested beverage was detected and interpreted. Pseudouridine was suggested as a novel marker for pro-anabolic effect following LCHO-P ingestion, which was supported by the detected decrease of the catabolic marker 3-methylhistidine. Separation of subjects according to fitness level was achieved, and nutritional modulation by LCHO-P was shown to improve the metabolic status of less fit subjects in the recovery phase. In addition, the potential of the methodology for detection of early signs of insulin resistance was also demonstrated.

  • 21.
    Chorell, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Norrlands University Hospital, Umeå University, Umeå, Sweden .
    Ryberg, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Larsson, Christel
    Department of Food and Nutrition and Sport Science, University of Gothenburg, Gothenburg, Sweden.
    Sandberg, Susanne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mellberg, Caroline
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindahl, Bernt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Plasma metabolomic response to postmenopausal weight loss induced by different diets2016In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 12, no 5, 85Article in journal (Refereed)
    Abstract [en]

    Background Menopause is associated with increased abdominal fat and increased risk of developing diabetes and cardiovascular disease. Objectives The present study evaluated the plasma metabolic response in relation to insulin sensitivity after weight loss via diet intervention. Methods This work includes two studies; i) Ten women on a 5 weeks Paleolithic-type diet (PD, 30 energy percent (E%) protein, 40 E% fat, 30 E% carbohydrates), ii) 55 women on 6 months of either PD or Nordic Nutrition Recommendations diet (NNR, 15 E% protein, 30 E% fat, and 55 E% carbohydrates). Plasma metabolic profiles were acquired at baseline and post diet using gas chromatography time-of-flight/mass spectrometry and investigated in relation to insulin sensitivity using multivariate bioinformatics. Results Both the PD and NNR diet resulted in significant weight loss, reduced waist circumference, improved serum lipid profiles, and improved insulin sensitivity. We detected a baseline metabolic profile that correlated significantly with insulin sensitivity, and of which components increased significantly in the PD group compared to NNR. Specifically, a significant increase in myo-inositol (MI), a second messenger of insulin action, and beta-hydroxybutyric acid (beta-HB)increased while dihomogamma-linoleic acid (DGLA) decreased in PD compared to NNR, which correlated with improved insulin sensitivity. We also detected a significant decrease in tyrosine and tryptophan, potential markers of insulin resistance when elevated in the circulation, with the PD but not the NNR. Conclusions Using metabolomics, we detected changes in the plasma metabolite profiles associated with weight loss in postmenopausal women by different diets. The metabolic profiles following 6 months of PD were linked to beneficial effects on insulin sensitivity compared to NNR.

  • 22.
    Chorell, Elin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Rydberg, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Larsson, Christel
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    A metabolomic evaluation of short and long term effects of different macronutrient intake in overweight and obese postmenopausal womenManuscript (preprint) (Other academic)
  • 23.
    Chorell, Elin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Moritz, Thomas
    Swedish University of Agricultural Sciences.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Physical fitness level is reflected by alterations in the human plasma metabolome2012In: Molecular BioSystems, ISSN 1742-206X, Vol. 8, no 4, 1187-1196 p.Article in journal (Refereed)
    Abstract [en]

    An excessive energy intake combined with a low level of physical activity induces detrimental processes involved in disease development, e.g. type 2 diabetes and cardiovascular disease. However the underlying mechanisms for regulation of metabolic capacity and fitness status remain unclear. Metabolomics involves global studies of the metabolic reactions in an organism or cell. Thus hypotheses regarding biochemical events can be generated to increase the understanding of disease development and thereby aid in the development of novel treatments or preventions. We present the first standardized intervention study focusing on characterizing the human metabolome in relation to moderate differences in cardiorespiratory fitness. Gas chromatography-time of flight/mass spectrometry (GC-TOF/MS) was used to characterize 460 plasma samples from 27 individuals divided into two groups based on physical fitness level (VO2max). Multi- and univariate between group comparisons based on 197 metabolites were carried out in samples collected at rest prior to any intervention, over time following a nutritional load or a standardized exercise scheme, with and without nutritional load. We detected decreased levels of gamma-tocopherol (GT), a vitamin E isomer, in response to a high fitness level, whereas the opposite was seen for the alpha isomer (AT). In addition, the high fitness level was associated with elevated ω3-PUFA (DHA, 22:6ω3) and a decrease in ω6-PUFA (18:2ω6) as well as in saturated (16:0, 18:0), monounsaturated (18:1) and trans (16:1) fatty acids. We thus hypothesize that high fitness status induces an increased cardiorespiratory inflammatory and antioxidant defense system, more prone to deal with the inflammatory response following exercise and nutrition intake.

  • 24.
    Chorell, Elin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thysell, Elin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Eklund, Caroline
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Silfver, Anders
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Carlsson, Inga-Britt
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Lundgren, Krister
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Moritz, Thomas
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Svensson, Michael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    A Multivariate Screening Strategy for Investigating Metabolic Effects of Strenuous Physical Exercise in Human Serum2007In: Journal of Proteome Research, ISSN 1535-3893, Vol. 6, no 6, 2113-2120 p.Article in journal (Refereed)
    Abstract [en]

    A novel hypothesis-free multivariate screening methodology for the study of human exercise metabolism in blood serum is presented. Serum gas chromatography/time-of-flight mass spectrometry (GC/TOFMS) data was processed using hierarchical multivariate curve resolution (H-MCR), and orthogonal partial least-squares discriminant analysis (OPLS-DA) was used to model the systematic variation related to the acute effect of strenuous exercise. Potential metabolic biomarkers were identified using data base comparisons. Extensive validation was carried out including predictive H-MCR, 7-fold full cross-validation, and predictions for the OPLS-DA model, variable permutation for highlighting interesting metabolites, and pairwise t tests for examining the significance of metabolites. The concentration changes of potential biomarkers were verified in the raw GC/TOFMS data. In total, 420 potential metabolites were resolved in the serum samples. On the basis of the relative concentrations of the 420 resolved metabolites, a valid multivariate model for the difference between pre- and post-exercise subjects was obtained. A total of 34 metabolites were highlighted as potential biomarkers, all statistically significant (p < 8.1E-05). As an example, two potential markers were identified as glycerol and asparagine. The concentration changes for these two metabolites were also verified in the raw GC/TOFMS data.The strategy was shown to facilitate interpretation and validation of metabolic interactions in human serum as well as revealing the identity of potential markers for known or novel mechanisms of human exercise physiology. The multivariate way of addressing metabolism studies can help to increase the understanding of the integrative biology behind, as well as unravel new mechanistic explanations in relation to, exercise physiology.

  • 25.
    Chorell, Elin
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thysell, Elin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindberg, Johan
    Schuppe-Koistinen, Ina
    Moritz, Thomas
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Statistical multivariate metabolite profiling for aiding biomarker pattern detection and mechanistic interpretations in GC/MS based metabolomics2006In: Metabolomics, Vol. 2, no 4, 257-68 p.Article in journal (Refereed)
    Abstract [en]

    A strategy for robust and reliable mechanistic statistical modelling of metabolic responses in relation to drug induced toxicity is presented. The suggested approach addresses two cases commonly occurring within metabonomic toxicology studies, namely; 1) A pre-defined hypothesis about the biological mechanism exists and 2) No such hypothesis exists. GC/MS data from a liver toxicity study consisting of rat urine from control rats and rats exposed to a proprietary AstraZeneca compound were resolved by means of hierarchical multivariate curve resolution (H-MCR) generating 287 resolved chromatographic profiles with corresponding mass spectra. Filtering according to significance in relation to drug exposure rendered in 210 compound profiles, which were subjected to further statistical analysis following correction to account for the control variation over time. These dose related metabolite traces were then used as new observations in the subsequent analyses. For case 1, a multivariate approach, named Target Batch Analysis, based on OPLS regression was applied to correlate all metabolite traces to one or more key metabolites involved in the pre-defined hypothesis. For case 2, principal component analysis (PCA) was combined with hierarchical cluster analysis (HCA) to create a robust and interpretable framework for unbiased mechanistic screening. Both the Target Batch Analysis and the unbiased approach were cross-verified using the other method to ensure that the results did match in terms of detected metabolite traces. This was also the case, implying that this is a working concept for clustering of metabolites in relation to their toxicity induced dynamic profiles regardless if there is a pre-existing hypothesis or not. For each of the methods the detected metabolites were subjected to identification by means of data base comparison as well as verification in the raw data. The proposed strategy should be seen as a general approach for facilitating mechanistic modelling and interpretations in metabolomic studies.

  • 26.
    Chorell, Elin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Videhult, Frida Karlsson
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    West, Christina E
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Impact of probiotic feeding during weaning on the serum lipid profile and plasma metabolome in infants2013In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 110, no 1, 116-126 p.Article in journal (Refereed)
    Abstract [en]

    The gut microbiome interacts with the host in the metabolic response to diet, and early microbial aberrancies may be linked to the development of obesity and metabolic disorders later in life. Probiotics have been proposed to affect metabolic programming and blood lipid levels, although studies are lacking in infants. Here, we report on the lipid profile and global metabolic response following daily feeding of probiotics during weaning. A total of 179 healthy, term infants were randomised to daily intake of cereals with (n 89) or without (n 90) the addition of Lactobacillus paracasei ssp. paracasei F19 (LF19) 108 colony-forming units per serving from 4 to 13 months of age. Weight, length and skinfold thickness were monitored. Venous blood was drawn at 5·5 and 13 months of age for analysis of the serum lipid profile. In a subsample, randomly selected from each group, GC-time-of-flight/MS was used to metabolically characterise plasma samples from thirty-seven infants. A combination of multi- and univariate analysis was applied to reveal differences related to LF19 treatment based on 228 putative metabolites, of which ninety-nine were identified or classified. We observed no effects of probiotic feeding on anthropometrics or the serum lipid profile. However, we detected significantly lower levels of palmitoleic acid (16 : 1) (P < 0·05) and significantly higher levels of putrescine (P < 0·01) in LF19-treated infants. Palmitoleic acid is a major MUFA strongly linked to visceral obesity, while putrescine is a polyamine with importance for gut integrity. Whether the observed differences will have long-term health consequences are being followed.

  • 27. Clayton, T. Andrew
    et al.
    Lindon, John C.
    Cloarec, Olivier
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Chemistry.
    Charuel, Claude
    Hanton, Gilles
    Provost, Jean-Pierre
    Le Net, Jean-Loic
    Baker, David
    Walley, Rosalind J.
    Everett, Jeremy R.
    Nicholson, Jeremy K.
    Pharmaco-metabonomic phenotyping and personalized drug treatment.2006In: Nature, ISSN 1476-4687, Vol. 440, no 7087, 1073-7 p.Article in journal (Refereed)
    Abstract [en]

    There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions. However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination. After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion. For instance, a major factor underlying inter-individual variation in drug effects is variation in metabolic phenotype, which is influenced not only by genotype but also by environmental factors such as nutritional status, the gut microbiota, age, disease and the co- or pre-administration of other drugs. Thus, although genetic variation is clearly important, it seems unlikely that personalized drug therapy will be enabled for a wide range of major diseases using genomic knowledge alone. Here we describe an alternative and conceptually new 'pharmaco-metabonomic' approach to personalizing drug treatment, which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. We provide proof-of-principle for this new approach, which is sensitive to both genetic and environmental influences, with a study of paracetamol (acetaminophen) administered to rats. We show pre-dose prediction of an aspect of the urinary drug metabolite profile and an association between pre-dose urinary composition and the extent of liver damage sustained after paracetamol administration.

  • 28. De Petris, L.
    et al.
    Forshed, J.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Branden, E.
    Koyi, H.
    Johnsson, A.
    Lewensohn, R.
    Lehtio, J.
    Plasma metabolomics in non-small-cell lung cancer2011Conference paper (Refereed)
  • 29.
    Edlund, Ulf
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wiklund, SusanneUmeå University, Faculty of Science and Technology, Department of Chemistry.Antti, HenrikUmeå University, Faculty of Science and Technology, Department of Chemistry.Karlsson, MWingsle, G
    Batch process strategy for analysing metabolic variation controlling the growth process of hybrid aspen2005Conference proceedings (editor) (Other (popular science, discussion, etc.))
    Abstract [en]

    High resolution magic angle spinning proton nuclear magnetic resonance spectroscopy, {1}H HR/MAS NMR, and multivariate data analysis using batch processing, BP, was applied for the analysis of two different genotypes of poplar tree (Populus tremula L. x tremuloides Michx.), containing an antisense construct of PttMYB76 and control (wild type). A gene encoding a MYB transcription factor, with unknown function, PttMYB76, was selected from a cambial EST library of poplar tree (Populus tremula L. x remuloides Michx.) for metabonomic characterisation. The PttMYB76 gene is believed to affect different paths of the phenyl propanoid synthetic pathway. This pathway leads to the formation of S- and G-lignin, flavonoids and sinapate esters. Milled poplar samples collected at the internodes of the tree were analysed using {1}H high resolution magic angle spinning NMR spectroscopy. The application of multivariate batch processing of the NMR results revealed a growth-related gradient in the plant internode direction as well as the discrimination between the trees with down regulated PttMYB76 expression and wild type populations. This paper is focused on the potential of a new analytical multivariate approach for analysing time-related plant metabonomic data. The techniques used could, with the aid of suitable model compounds, be of high relevance to the detection and understanding of the different lignification processes within the two types of poplar tree. Additionally, the findings are highlighting the importance of applying robust and organised multivariate data analysis approaches to facilitate modelling and interpretation of complex biological data sets.

  • 30. Eriksson, Lennart
    et al.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gottfries, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Holmes, Elaine
    Johansson, Erik
    Lindgren, Fredrik
    Long, Ingrid
    Lundstedt, Torbjörn
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wold, Svante
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Using chemometrics for navigating in the large data sets of genomics, proteomics, and metabonomics (gpm)2004In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642 (Print) 1618-2650 (Online), Vol. 380, no 3, 419-29 p.Article in journal (Refereed)
    Abstract [en]

    This article describes the applicability of multivariate projection techniques, such as principal-component analysis (PCA) and partial least-squares (PLS) projections to latent structures, to the large-volume high-density data structures obtained within genomics, proteomics, and metabonomics. PCA and PLS, and their extensions, derive their usefulness from their ability to analyze data with many, noisy, collinear, and even incomplete variables in both X and Y. Three examples are used as illustrations: the first example is a genomics data set and involves modeling of microarray data of cell cycle-regulated genes in the microorganism Saccharomyces cerevisiae. The second example contains NMR-metabonomics data, measured on urine samples of male rats treated with either of the drugs chloroquine or amiodarone. The third and last data set describes sequence-function classification studies in a set of G-protein-coupled receptors using hierarchical PCA.

  • 31.
    Hadrevi, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Sports medicine.
    Bjorklund, Martin
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Kosek, E.
    Hallgren, Solveig
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Professionell Development.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fahlstrom, Martin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Professionell Development.
    Hellstrom, F.
    Systemic differences in serum metabolome: a cross sectional comparison of women with localised and widespread pain and controls2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, 15925Article in journal (Refereed)
    Abstract [en]

    Chronic musculoskeletal pain exists either as localised to a single region or as widespread to multiple sites in several quadrants of the body. Prospective studies indicate that widespread pain could act as a far end of a continuum of musculoskeletal pain that started with chronic localised pain. The mechanism by which the transition from localised pain to widespread occurs is not clear, although many studies suggest it to be an altered metabolism. In this study, systemic metabolic differences between women with chronic localised neck-shoulder pain (NP), women with chronic widespread pain (CWP) and women who were healthy (CON) were assessed. Blood samples were analysed taking a metabolomics approach using gas chromatography mass spectrometry (GC-MS) and orthogonal partial least square discriminant analysis (OPLS-DA). The metabolomics analysis showed a clear systematic difference in the metabolic profiles between the subjects with NP and the CON but only a weak systematic difference between the subjects with CWP and the CON. This most likely reflects a difference in the portion of the metabolome influenced by the two pain conditions. In the NP group, the overall metabolic profile suggests that processes related to energy utilisation and lipid metabolism could be central aspects of mechanisms maintaining disorder.

  • 32.
    Hadrévi, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Ghafouri, Bijar
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden.
    Sjörs, Anna
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden; Institute of Stress Medicine, Carl Skottsbergs gata 22B, SE 41319 Gothenburg, Sweden.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Larsson, Britt
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden.
    Crenshaw, A. G.
    Centre for Musculoskeletal Research, Department of Occupational and Public Health Sciences, Faculty of Health and Occupational Studies , University of Gävle, Umeå, Sweden.
    Gerdle, Björn
    Rehabilitation Medicine, Department of Medicine and Health Sciences (IMH), Faculty of Health Sciences, Linköping University and Pain and Rehabilitation Centre, County Council of Östergötland, SE 581 85 Linköping, Sweden.
    Hellström, Fredrik
    Centre for Musculoskeletal Research, Department of Occupational and Public Health Sciences, Faculty of Health and Occupational Studies , University of Gävle, Umeå, Sweden.
    Comparative metabolomics of muscle interstitium fluid in human trapezius myalgia: an in vivo microdialysis study2013In: European Journal of Applied Physiology, ISSN 1439-6319, E-ISSN 1439-6327, Vol. 113, no 12, 2977-2989 p.Article in journal (Other academic)
    Abstract [en]

    The mechanisms behind trapezius myalgia are unclear. Many hypotheses have been presented suggesting an altered metabolism in the muscle. Here, muscle microdialysate from healthy and myalgic muscle is analysed using metabolomics. Metabolomics analyse a vast number of metabolites, enabling a comprehensive explorative screening of the cellular processes in the muscle.

    Microdialysate samples were obtained from the shoulder muscle of healthy and myalgic subjects that performed a work and stress test. Samples from the baseline period and from the recovery period were analysed using gas chromatography-mass spectrometry (GC-MS) together with multivariate analysis to detect differences in extracellular content of metabolites between groups. Systematic differences in metabolites between groups were identified using multivariate analysis and orthogonal partial least square discriminate analysis (OPLS-DA). A complementary Mann-Whitney U test of group difference in individual metabolites was also performed.

    A large number of metabolites were detected and identified in this screening study. At baseline, no systematic differences between groups were observed according to the OPLS-DA. However, two metabolites, l-leucine and pyroglutamic acid, were significantly more abundant in the myalgic muscle compared to the healthy muscle. In the recovery period, systematic difference in metabolites between the groups was observed according to the OPLS-DA. The groups differed in amino acids, fatty acids and carbohydrates. Myristic acid and putrescine were significantly more abundant and beta-d-glucopyranose was significantly less abundant in the myalgic muscle.

    This study provides important information regarding the metabolite content, thereby presenting new clues regarding the pathophysiology of the myalgic muscle.

  • 33. Hoffman, Daniel E
    et al.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bylesjö, Max
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Eriksson, Maria E
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Moritz, Thomas
    Changes in diurnal patterns within the Populus transcriptome and metabolome in response to photoperiod variation2010In: Plant, Cell and Environment, ISSN 0140-7791, E-ISSN 1365-3040, Vol. 33, no 8, 1298-1313 p.Article in journal (Refereed)
    Abstract [en]

    Changes in seasonal photoperiod provides an important environmental signal that affects the timing of winter dormancy in perennial, deciduous, temperate tree species, such as hybrid aspen (Populus tremula x Populus tremuloides). In this species, growth cessation, cold acclimation and dormancy are induced in the autumn by the detection of day-length shortening that occurs at a given critical day length. Important components in the detection of such day-length changes are photoreceptors and the circadian clock, and many plant responses at both the gene regulation and metabolite levels are expected to be diurnal. To directly examine this expectation and study components in these events, here we report transcriptomic and metabolomic responses to a change in photoperiod from long to short days in hybrid aspen. We found about 16% of genes represented on the arrays to be diurnally regulated, as assessed by our pre-defined criteria. Furthermore, several of these genes were involved in circadian-associated processes, including photosynthesis and primary and secondary metabolism. Metabolites affected by the change in photoperiod were mostly involved in carbon metabolism. Taken together, we have thus established a molecular catalog of events that precede a response to winter.

  • 34.
    Hörnberg, Emma
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bovinder Ylitalo, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 4, e19059- p.Article in journal (Refereed)
    Abstract [en]

    Background: Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote  the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival.

    Methodology/Principal Findings: Hormone-naı¨ve (n = 10) and CRPC bone metastases samples (n = 30) were obtained from  40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival.

    Conclusions/Significance: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.

  • 35.
    Jansson, Stina
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Chemistry.
    Marklund, Stellan
    Umeå University, Faculty of Science and Technology, Chemistry.
    Tysklind, Mats
    Umeå University, Faculty of Science and Technology, Chemistry.
    Correlations of PCDD/F isomer distribution patterns from MSW combustion with physicochemical variables and chlorine substitution descriptorsManuscript (preprint) (Other (popular science, discussion, etc.))
  • 36.
    Jansson, Stina
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Chemistry.
    Marklund, Stellan
    Umeå University, Faculty of Science and Technology, Chemistry.
    Tysklind, Mats
    Umeå University, Faculty of Science and Technology, Chemistry.
    Multivariate Relationships between Molecular Descriptors and Isomer Distribution Patterns of PCDD/Fs Formed during MSW Combustion2009In: Environmental Science & Technology, Vol. 43, no 18, 7032-8 p.Article in journal (Refereed)
    Abstract [en]

    The isomer distribution patterns of mono- to hepta-chlorinated dibenzo-p-dioxins (PC1−7DD) and dibenzofurans (PC1−7DF) in postcombustion zone flue gas during incineration of an artificial municipal solid waste in a laboratory-scale fluidized-bed reactor were evaluated. Bidirectional orthogonal projections to latent structures (O2PLS) was used to correlate a set of physicochemical properties and chlorine substitution descriptors with the objective to identify parameters correlated with postcombustion zone PCDD and PCDF formation. The most influential variable for the distribution of PCDD congeners was chlorine substitution in positions 1 and 3 (Cl1 + 3), and overall the chlorine substitution descriptors exerted a larger impact on PCDDs than on PCDFs. For the PCDF, chlorination of the 9-position was the most influential X-variable. Distinct clustering was observed and was most pronounced for PCDFs, dividing most of the homologues into two or three subgroups of congeners. These subgroups seemed to correspond to the probability of formation by chlorophenol condensation. The sterically crowded dibenzofuran bay-sites (1- and 9-positions) were found to negatively influence PCDF formation, with chlorination of the 9-position having the greatest impact. Since PCDD/F toxicity is related to the lateral positions, elucidating the factors governing chlorination may be of great importance for detoxification of incineration byproducts.

  • 37.
    Jernberg, Emma
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lundberg, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Molecular features of prostate cancer bone metastases harboring androgen receptor gene amplificationManuscript (preprint) (Other academic)
    Abstract [en]

    The relation between AR amplification and other mechanisms behind castration-resistance in prostate cancer, such as increased expression of AR splice variants and steroid-converting enzymes in CRPC metastases, has been poorly examined. Specific aims of this study were therefore to examine AR amplification in hormone-naïve and castration-resistant prostate cancer (CRPC) bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying molecular targets for treatment of CRPC bone metastases. AR amplification was assessed by fluorescence in situ hybridization and verified in 16 (53 %) of the CRPC bone metastases (n=30), and in none of the untreated bone metastases (n=10). AR amplification was associated with increased expression of AR and its constitutively active AR-V7 splice variant as well as with co-amplification of genes in the AR proximity at Xq12, such as of YIPF6. Furthermore, gene expression pattern pointed at decreased osteoclast activity, and consequently decreased bone resorption and increased bone mineral density in AR amplified metastases. In conclusion, our results indicated a sclerotic phenotype in CRPC bone metastases with AR amplification that may be of both biological and clinical relevance. This is a novel hypothesis that requires to be thoroughly examined.

  • 38.
    Jiye, A
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Granström, Micael
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan
    Johansson, Annika
    Stenlund, Hans
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Moritz, Thomas
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jiye, A
    Guangji, Wang
    Dynamic modification of blood erythrocytes metabolism based on GC/TOF-MS analysis2006Other (Other (popular science, discussion, etc.))
  • 39.
    Jiye, A
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Gullberg, Jonas
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Johansson, Annika I.
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Moritz, Thomas
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Extraction and GC/MS analysis of the human blood plasma metabolome2005In: ANALYTICAL CHEMISTRY, ISSN 0003-2700, Vol. 77, no 24, 8086-94 p.Article in journal (Refereed)
    Abstract [en]

    Analysis of the entire set of low molecular weight compounds (LMC), the metabolome, could provide deeper insights into mechanisms of disease and novel markers for diagnosis. In the investigation, we developed an extraction and derivatization protocol, using experimental design theory (design of experiment), for analyzing the human blood plasma metabolome by GC/MS. The protocol was optimized by evaluating the data for more than 500 resolved peaks using multivariate statistical tools including principal component analysis and partial least-squares projections to latent structures (PLS). The performance of five organic solvents (methanol, ethanol, acetonitrile, acetone, chloroform), singly and in combination, was investigated to optimize the LMC extraction. PLS analysis demonstrated that methanol extraction was particularly efficient and highly reproducible. The extraction and derivatization conditions were also optimized. Quantitative data for 32 endogenous compounds showed good precision and linearity. In addition, the determined amounts of eight selected compounds agreed well with analyses by independent methods in accredited laboratories, and most of the compounds could be detected at absolute levels of similar to 0.1 pmol injected, corresponding to plasma concentrations between 0.1 and 1 mu M. The results suggest that the method could be usefully integrated into metabolomic studies for various purposes, e.g., for identifying biological markers related to diseases.

  • 40.
    Jonsson, Pär
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bruce, Stephen J
    Moritz, Thomas
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjöström, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Plumb, Robert
    Granger, Jennifer
    Maibaum, Elaine
    Nicholson, Jeremy K
    Holmes, Elaine
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Extraction, interpretation and validation of information for comparing samples in metabolic LC/MS data sets2005In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 130, no 5, 701-707 p.Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    LC/MS is an analytical technique that, due to its high sensitivity, has become increasingly popular for the generation of metabolic signatures in biological samples and for the building of metabolic data bases. However, to be able to create robust and interpretable ( transparent) multivariate models for the comparison of many samples, the data must fulfil certain specific criteria: (i) that each sample is characterized by the same number of variables, (ii) that each of these variables is represented across all observations, and (iii) that a variable in one sample has the same biological meaning or represents the same metabolite in all other samples. In addition, the obtained models must have the ability to make predictions of, e. g. related and independent samples characterized accordingly to the model samples. This method involves the construction of a representative data set, including automatic peak detection, alignment, setting of retention time windows, summing in the chromatographic dimension and data compression by means of alternating regression, where the relevant metabolic variation is retained for further modelling using multivariate analysis. This approach has the advantage of allowing the comparison of large numbers of samples based on their LC/MS metabolic profiles, but also of creating a means for the interpretation of the investigated biological system. This includes finding relevant systematic patterns among samples, identifying influential variables, verifying the findings in the raw data, and finally using the models for predictions. The presented strategy was here applied to a population study using urine samples from two cohorts, Shanxi (People's Republic of China) and Honolulu ( USA). The results showed that the evaluation of the extracted information data using partial least square discriminant analysis (PLS-DA) provided a robust, predictive and transparent model for the metabolic differences between the two populations. The presented findings suggest that this is a general approach for data handling, analysis, and evaluation of large metabolic LC/MS data sets.

  • 41.
    Jonsson, Pär
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Johansson, Annika I.
    Gullberg, Jonas
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Jiye, A
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Grung, Björn
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Sjöström, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    High-throughput data analysis for detecting and identifying differences between samples in GC/MS-based metabolomic analyses2005In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 77, no 17, 5635-5642 p.Article in journal (Refereed)
    Abstract [en]

    In metabolomics, the objective is to identify differences in metabolite profiles between samples. A widely used tool in metabolomics investigations is gas chromatography-mass spectrometry (GC/MS). More than 400 compounds can be detected in a single analysis, if overlapping GC/ MS peaks are deconvoluted. However, the deconvolution process is time-consuming and difficult to automate, and additional processing is needed in order to compare samples. Therefore, there is a need to improve and automate the data processing strategy for data generated in GC/MS-based metabolomics; if not, the processing step will be a major bottleneck for high-throughput analyses. Here we describe a new semiautomated strategy using a hierarchical multivariate curve resolution approach that processes all samples simultaneously. The presented strategy generates (after appropriate treatment, e.g., multivariate analysis) tables of all the detected metabolites that differ in relative concentrations between samples. The processing of 70 samples took similar time to that of the GC/TOFMS analyses of the samples. The strategy has been validated using two different sets of samples: a complex mixture of standard compounds and Arabidopsis samples.

    KeyWords Plus: CHROMATOGRAPHY MASS-SPECTROMETRY; PRINCIPAL COMPONENT ANALYSIS; SYSTEMS BIOLOGY; ARABIDOPSIS-THALIANA; CHEMOMETRIC ANALYSIS; 2-WAY DATA; MS; REGRESSION; RESOLUTION; ALIGNMENT

  • 42.
    Jonsson, Pär
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjöström, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wallbäcks, Lars
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Strategies for implementation and validation of on-line models for multivariate monitoring and control of wood chip properties2004In: Journal of Chemometrics, Vol. 18, no 3-4, 203-7 p.Article in journal (Refereed)
    Abstract [en]

    Here we present an approach for on-line control and monitoring of pulpwood chip properties based on near infrared (NIR) spectroscopy and multivariate data analysis. In addition, this paper suggests how to deal with large multivariate data sets in order to extract information which can be used as a basis for changes in raw material or process conditions in the drive towards more optimal intermediate or end product properties within the pulp and paper industry. The pulpwood chips used as raw material in a pulp and paper making process were characterized at- and on-line using NIR spectroscopic measurements. Collected NIR spectra were used in multivariate calibration models for prediction of the moisture content as well as the between- and within-species variation in the studied raw material. Statistical experimental design was used to form a calibration data set including most of the variation occurring in a real on-line situation. NIR spectra for all designed samples were measured at-line and the estimated calibration models were used for carrying out predictions on-line. Predictions of the moisture content (% dry weight) as well as the percentage contents of pine and sawmill chips in the raw material were carried out using partial least squares projections to latent structures (PLS) methodology. NIR spectra were collected subsequently on-line once every minute, and, to reduce the problem with noise in the time series predictions, the measured signals were filtered using a moving average of 100 predicted values. This provided smoother predictions more suitable for process monitoring and control. To validate the quality of the predictions, wood chips from the studied process were sampled and analysed in the laboratory before being subjected to predictions in the on-line model. Comparison of the filtered on-line predictions with the results obtained from the laboratory measurements indicated that moisture and pine chip contents could be well predicted by the on-line model, while predictions of sawmill chip content showed less promising results.

  • 43.
    Jonsson, Pär
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjövik-Johansson, Elin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lindberg, Johan
    Schuppe-Koistinen, Ina
    Kusano, Miyako
    Sjöström, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Moritz, Thomas
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Predictive metabolite profiling applying hierarchical multivariate curve resolution to GC-MS data: a potential tool for multi-parametric diagnosis2006In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 5, no 6, 1407-1414 p.Article in journal (Refereed)
    Abstract [en]

    A method for predictive metabolite profiling based on resolution of GC-MS data followed by multivariate data analysis is presented and applied to three different biofluid data sets (rat urine, aspen leaf extracts, and human blood plasma). Hierarchical multivariate curve resolution (H-MCR) was used to simultaneously resolve the GC-MS data into pure profiles, describing the relative metabolite concentrations between samples, for multivariate analysis. Here, we present an extension of the H-MCR method allowing treatment of independent samples according to processing parameters estimated from a set of training samples. Predictions or inclusion of the new samples, based on their metabolite profiles, into an existing model could then be carried out, which is a requirement for a working application within, e.g., clinical diagnosis. Apart from allowing treatment and prediction of independent samples the proposed method also reduces the time for the curve resolution process since only a subset of representative samples have to be processed while the remaining samples can be treated according to the obtained processing parameters. The time required for resolving the 30 training samples in the rat urine example was approximately 13 h, while the treatment of the 30 test samples according to the training parameters required only approximately 30 s per sample (approximately 15 min in total). In addition, the presented results show that the suggested approach works for describing metabolic changes in different biofluids, indicating that this is a general approach for high-throughput predictive metabolite profiling, which could have important applications in areas such as plant functional genomics, drug toxicity, treatment efficacy and early disease diagnosis.

  • 44.
    Jonsson, Pär
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stenlund, Hans
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Moritz, Thomas
    Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjöström, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Verheij, Elwin R
    Lindberg, Johan
    Schuppe-Koistinen, Ina
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    A strategy for modelling dynamic responses in metabolic samples characterized by GC/MS2006In: Metabolomics, Vol. 2, no 3, 135-143 p.Article in journal (Refereed)
    Abstract [sv]

    A multivariate strategy for studying the metabolic response over time in urinary GC/MS data is presented and exemplified by a study of drug-induced liver toxicity in the rat. The strategy includes the generation of representative data through hierarchical multivariate curve resolution (H-MCR), highlighting the importance of obtaining resolved metabolite profiles for quantification and identification of exogenous (drug related) and endogenous compounds (potential biomarkers) and for allowing reliable comparisons of multiple samples through multivariate projections. Batch modelling was used to monitor and characterize the normal (control) metabolic variation over time as well as to map the dynamic response of the drug treated animals in relation to the control. In this way treatment related metabolic responses over time could be detected and classified as being drug related or being potential biomarkers. In summary the proposed strategy uses the relatively high sensitivity and reproducibility of GC/MS in combination with efficient multivariate curve resolution and data analysis to discover individual markers of drug metabolism and drug toxicity. The presented results imply that the strategy can be of great value in drug toxicity studies for classifying metabolic markers in relation to their dynamic responses as well as for biomarker identification.

  • 45.
    Jonsson, Pär
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stenlund, Hans
    Moritz, Thomas
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sjöström, Michael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Verheij, Elwin R
    Lindberg, Johan
    Schuppe-Koistinen, Ina
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Modeling of time dependent toxicological responses in urinary GC/MS dataArticle in journal (Refereed)
  • 46.
    Jonsson, Pär
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wuolikainen, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Chorell, Elin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Constrained randomization and multivariate effect projections improve information extraction and biomarker pattern discovery in metabolomics studies involving dependent samples2015In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 11, no 6, 1667-1678 p.Article in journal (Refereed)
    Abstract [en]

    Analytical drift is a major source of bias in mass spectrometry based metabolomics confounding interpretation and biomarker detection. So far, standard protocols for sample and data analysis have not been able to fully resolve this. We present a combined approach for minimizing the influence of analytical drift on multivariate comparisons of matched or dependent samples in mass spectrometry based metabolomics studies. The approach is building on a randomization procedure for sample run order, constrained to independent randomizations between and within dependent sample pairs (e.g. pre/post intervention). This is followed by a novel multivariate statistical analysis strategy allowing paired or dependent analyses of individual effects named OPLS-effect projections (OPLS-EP). We show, using simulated data that OPLS-EP gives improved interpretation over existing methods and that constrained randomization of sample run order in combination with an appropriate dependent statistical test increase the accuracy and sensitivity and decrease the false omission rate in biomarker detection. We verify these findings and prove the strength of the suggested approach in a clinical data set consisting of LC/MS data of blood plasma samples from patients before and after radical prostatectomy. Here OPLS-EP compared to traditional (independent) OPLS-discriminant analysis (OPLS-DA) on constrained randomized data gives a less complex model (3 versus 5 components) as well a higher predictive ability (Q2 = 0.80 versus Q2 = 0.55). We explain this by showing that paired statistical analysis detects 37 unique significant metabolites that were masked for the independent test due to bias, including analytical drift and inter-individual variation.

  • 47. Kouremenos, Konstantinos A.
    et al.
    Beale, David J.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Palombo, Enzo A.
    Liquid chromatography time of flight mass spectrometry based environmental metabolomics for the analysis of Pseudomonas putida Bacteria in potable water2014In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 966, 179-186 p.Article in journal (Refereed)
    Abstract [en]

    Water supply biofilms have the potential to harbour waterborne diseases, accelerate corrosion, and contribute to the formation of tuberculation in metallic pipes. One particular species of bacteria known to be found in the water supply networks is Pseudomonas sp., with the presence of Pseudomonas putida being isolated to iron pipe tubercles. Current methods for detecting and analysis pipe biofilms are time consuming and expensive. The application of metabolomics techniques could provide an alternative method for assessing biofilm risk more efficiently based on bacterial activity. As such, this paper investigates the application of metabolomic techniques and provides a proof-of-concept application using liquid chromatography coupled with time-of-flight mass spectrometry (LC-ToF-MS) to three biologically independent P. putida samples, across five different growth conditions exposed to solid and soluble iron (Fe). Analysis of the samples in +ESI and -ESI mode yielded 887 and 1789 metabolite features, respectively. Chemometric analysis of the +ESI and -ESI data identified 34 and 39 significant metabolite features, respectively, where features were considered significant if the fold change was greater than 2 and obtained a p-value less than 0.05. Metabolite features were subsequently identified according to the Metabolomics Standard Initiative (MSI) Chemical Analysis Workgroup using analytical standards and standard online LC-MS databases. Possible markers for P. putida growth, with and without being exposed to solid and soluble Fe, were identified from a diverse range of different chemical classes of metabolites including nucleobases, nucleosides, dipeptides, tripeptides, amino acids, fatty acids, sugars, and phospholipids.

  • 48. Langer, Julia
    et al.
    Elustondo, Fernando Abaitua
    Chan, Eric Chun Yong
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Want, Elizabeth
    ONeill, Kevin
    Syed, Nelofer
    Metabolomic analysis of glioblastoma multiforme upon arginine deprivation treatment2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, no 5Article in journal (Other academic)
  • 49.
    Lindahl, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Simonsson, Monika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Increased levels of macrophage-secreted Cathepsin S during Prostate Cancer progression in TRAMP mice and patients2009In: Cancer Genomics and Proteomics, ISSN ISSN 1109-6535, EISSN 1790-6245, Vol. 6, no 3, 149-159 p.Article in journal (Refereed)
    Abstract [en]

    Background: Protein expression during prostate tumour progression in transgenic TRAMP mice was studied, with the aim of identifying proteins associated with tumour progression and castration resistant tumour growth. Materials and Methods: Protein expression was compared between normal mouse prostate, primary TRAMP tumours and peripheral metastases in long-term castrated TRAMP mice using 2-dimensional differential in-gel electrophoresis and MALDI TOF/TOF analysis. Results were verified with Western blot analysis and immunohisto-chemistry in the TRAMP model and samples from patients. Results: The active form of cathepsin S (Cat S) was identified as being significantly up-regulated in poorly differentiated TRAMP tumours and in castration-resistant metastases compared to normal mouse prostate and well-differentiated tumours. Increased Cat S levels were also found in high Gleason grade tumour areas in patients. Cat S was primarily expressed by tumour-infiltrating macrophages, as shown by double staining of Cat S and CD68 expressing cells. A significantly higher number of Cat S expressing macrophages was found in castration-resistant than in hormone naïve high grade tumours in patients. No relation was found between Cat S levels and suggested Cat S regulated, matrix-derived fragments of collagen IV or laminin 5 γ2. Conclusion: Macrophage-secreted Cat S levels increase during prostate cancer progression and could be an interesting target for therapy.

  • 50.
    Lindberg, Ann-Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin. Winternet, Boden, Sweden.
    Oksa, Juha
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Malm, Christer
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Idrottsmedicin. Winternet, Boden, Sweden.
    Multivariate Statistical Assessment of Predictors of Firefighters' Muscular and Aerobic Work Capacity2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, e0118945Article in journal (Refereed)
    Abstract [en]

    Physical capacity has previously been deemed important for firefighters physical work capacity, and aerobic fitness, muscular strength, and muscular endurance are the most frequently investigated parameters of importance. Traditionally, bivariate and multivariate linear regression statistics have been used to study relationships between physical capacities and work capacities among firefighters. An alternative way to handle datasets consisting of numerous correlated variables is to use multivariate projection analyses, such as Orthogonal Projection to Latent Structures. The first aim of the present study was to evaluate the prediction and predictive power of field and laboratory tests, respectively, on firefighters' physical work capacity on selected work tasks. Also, to study if valid predictions could be achieved without anthropometric data. The second aim was to externally validate selected models. The third aim was to validate selected models on firefighters' and on civilians'. A total of 38 (26 men and 12 women) + 90 (38 men and 52 women) subjects were included in the models and the external validation, respectively. The best prediction (R-2) and predictive power (Q(2)) of Stairs, Pulling, Demolition, Terrain, and Rescue work capacities included field tests (R-2 = 0.73 to 0.84, Q(2) = 0.68 to 0.82). The best external validation was for Stairs work capacity (R-2 = 0.80) and worst for Demolition work capacity (R-2 = 0.40). In conclusion, field and laboratory tests could equally well predict physical work capacities for fire-fighting work tasks, and models excluding anthropometric data were valid. The predictive power was satisfactory for all included work tasks except Demolition.

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