Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    The interaction between genotype and maternal nutritional environments affects tomato seed and seedling quality
    Geshnizjani, Nafiseh ; Sarikhani Khorami, Saadat ; Willems, Leo A.J. ; Snoek, Basten L. ; Hilhorst, Henk W.M. ; Ligterink, Wilco - \ 2019
    Journal of Experimental Botany 70 (2019)10. - ISSN 0022-0957 - p. 2905 - 2918.
    Solanum lycopersicum - Solanum pimpinellifolium - Genotype by environment interaction (G×E) - maternal environment - metabolites - seed quality - seedling quality

    Seed and seedling traits are affected by the conditions of the maternal environment, such as light, temperature, and nutrient availability. In this study, we have investigated whether different maternally applied nitrate and phosphate concentrations affect the seed and seedling performance of two closely related tomato species: Solanum lycopersicum cv. Money maker and Solanum pimpinellifolium accession CGN14498. We observed large differences for seed and seedling traits between the two species. Additionally, we have shown that for nitrate most of the seed and seedling traits were significantly affected by genotype-environment interactions (G×E). The effect of the maternal environment was clearly visible in the primary metabolites of the dry seeds. For example, we could show that the amount of γ-aminobutyric acid (GABA) in Money maker seeds was affected by the differences in the maternal environments and was positively correlated with seed germination under high temperature. Overall, compared with phosphate, nitrate had a larger effect on seed and seedling performance in tomato. In general, the different responses to the maternal environments of the two tomato species showed a major role for G×E in shaping seed and seedling traits.

    Toll-Like Receptor-Dependent Immunomodulatory Activity of Pycnogenol®
    Verlaet, Annelies ; Bolt, Nieke van der; Meijer, Ben ; Breynaert, Annelies ; Naessens, Tania ; Konstanti, Prokopis ; Smidt, Hauke ; Hermans, Nina ; Savelkoul, Huub F.J. ; Teodorowicz, Malgorzata - \ 2019
    Nutrients 11 (2019)2. - ISSN 2072-6643
    catechin - gastrointestinal metabolism - immunomodulation - metabolites - partial agonist - Pycnogenol® - Toll-like receptors

    BACKGROUND: Pycnogenol® (PYC), an extract of French maritime pine bark, is widely used as a dietary supplement. PYC has been shown to exert anti-inflammatory actions via inhibiting the Toll-like receptor 4 (TLR4) pathway. However, the role of the other receptors from the TLR family in the immunomodulatory activity of PYC has not been described so far. AIM: The aim of this study was to investigate whether PYC might exert its immunomodulatory properties through cell membrane TLRs (TLR1/2, TLR5, and TLR2/6) other than TLR4. Moreover, the effect of gastrointestinal metabolism on the immunomodulatory effects of PYC was investigated. FINDINGS: We showed that intact non-metabolized PYC dose-dependently acts as an agonist of TLR1/2 and TLR2/6 and as a partial agonist of TLR5. PYC on its own does not agonize or antagonize TLR4. However, after the formation of complexes with lipopolysaccharides (LPS), it is a potent activator of TLR4 signaling. Gastrointestinal metabolism of PYC revealed the immunosuppressive potential of the retentate fraction against TLR1/2 and TLR2/6 when compared to the control fraction containing microbiota and enzymes only. The dialyzed fraction containing PYC metabolites revealed the capacity to induce anti-inflammatory IL-10 secretion. Finally, microbially metabolized PYC affected the colonic microbiota composition during in vitro gastrointestinal digestion. CONCLUSIONS: This study showed that gastrointestinal metabolism of PYC reveals its biological activity as a potential inhibitor of TLRs signaling. The results suggest that metabolized PYC acts as a partial agonist of TLR1/2 and TLR2/6 in the presence of the microbiota-derived TLR agonists (retentate fraction) and that it possesses anti-inflammatory potential reflected by the induction of IL-10 from THP-1 macrophages (dialysate fraction).

    Identification of metabolites involved in heat stress response in different tomato genotypes
    Paupière, Marine J. - \ 2017
    Wageningen University. Promotor(en): R.G.F. Visser, co-promotor(en): A.G. Bovy; Y.M. Tikunov. - Wageningen : Wageningen University - ISBN 9789463431842 - 168
    solanum lycopersicum - tomatoes - genotypes - heat stress - heat tolerance - pollen - metabolomes - metabolites - metabolomics - solanum lycopersicum - tomaten - genotypen - warmtestress - hittetolerantie - stuifmeel - metabolomen - metabolieten - metabolomica

    Tomato production is threatened by climate change. High temperatures lead to a decrease of fruit set which correlates with a decrease of pollen fertility. The low viability of tomato pollen under heat stress was previously shown to be associated with alterations in specific metabolites. In this thesis, we used untargeted metabolomics approaches to broaden the identification of metabolites affected by heat stress. We assessed the suitability of pollen isolation methods for metabolomics analysis and considered the pitfalls for our further analysis. We explored the developmental metabolomes of pollen and anthers of different tomato genotypes under control and high temperature conditions and identified that microsporogenesis is a critical developmental stage for the production of mature and fertile pollen grain under heat stress. Several metabolites were putatively associated with tolerance to high temperature such as specific flavonoids, polyamines and alkaloids. These metabolites can be further used as markers in breeding programs to develop new genotypes tolerant to high temperatures.

    Physiologically based kinetic modelling based prediction of oral systemic bioavailability of flavonoids, their metabolites, and their biological effects
    Boonpawa, Rungnapa - \ 2017
    Wageningen University. Promotor(en): Ivonne Rietjens, co-promotor(en): Arjen Punt. - Wageningen : Wageningen University - ISBN 9789463430371 - 180
    flavonoids - bioavailability - modeling - metabolites - quercetin - physiology - hesperidin - flavonoïden - biologische beschikbaarheid - modelleren - metabolieten - quercetine - fysiologie - hesperidine

    Flavonoids, abundantly present in fruits and vegetables, have been reported to exert various positive health effects based on in vitro bioassays. However, effects detected in in vitro models cannot be directly correlated to human health as most in vitro studies have been performed using flavonoid aglycones at high concentration ignoring extensive metabolism of flavonoids in the human body. To better understand positive health effects of flavonoids in humans, it is of importance to gain insight in at which form and concentration flavonoids are present in the systemic circulation after consumption. This insight can be obtained using physiologically based kinetic (PBK) computer modeling. The results obtained show that PBK modeling provides a useful additional research tool for studies on the fate of flavonoids in the human body and can reveal at what oral dose levels of flavonoids in vitro positive health effects can be expected to occur in vivo, presenting opportunities that are not easily provided by other methods.

    Metabolites contributing to taste in Agaricus bisporus
    Baars, J.J.P. ; Sonnenberg, A.S.M. ; Mumm, R. ; Stijger, I. ; Wehrens, H.R.M.J. - \ 2016
    Plant Research International (PPO/PRI-report 2016-1) - 19
    mushrooms - edible fungi - metabolites - taste - agaricus bisporus - taste panels - postharvest quality - paddestoelen - eetbare paddestoelen - metabolieten - smaak - agaricus bisporus - smaakpanels - kwaliteit na de oogst
    During the last 35 years, hardly any breeding has been done in the button mushrooms (Agaricus bisporus). The fact that no new varieties are generated directed to trends in the food market has caused a slowly decrease in mushroom consumption in the Netherlands and in Europe. The hurdles for generating new varieties are difficulties in breeding and protection of new varieties. These hurdles are now nearly tackled and it is time to generate new varieties. One issue that has never been addressed is taste. The collection of Plant Breeding Wageningen UR contains a large number of strains of the button mushroom with a large genetic variation. In previous research this collection has been genotyped and a small selection of genetically different strains has been made. In 2014 these strains were cultivated along two different methods that were likely to cause differences in taste. Atempts were made to link the results from the taste panel to the metabolite concentrations. Even though it is a relatively small dataset, some correlations can be found for the taste attributes Firmness, Gummi and Boiled Egg and for the metabolites Alanine, Arginine and Proline.
    The assessment of selectivity in different quadrupole-orbitrap mass spectrometry acquisition
    Berendsen, B.J.A. ; Wegh, R.S. ; Meijer, T. ; Nielen, M.W.F. - \ 2015
    Journal of the American Society for Mass Spectrometry 26 (2015)2. - ISSN 1044-0305 - p. 337 - 346.
    performance liquid-chromatography - veterinary drugs - confirmation - metabolites - residues - plasma - food - meat
    Selectivity of the confirmation of identity in liquid chromatography (tandem) mass spectrometry using Q-Orbitrap instrumentation was assessed using different acquisition modes based on a representative experimental data set constructed from 108 samples, including six different matrix extracts and containing over 100 analytes each. Single stage full scan, all ion fragmentation, and product ion scanning were applied. By generating reconstructed ion chromatograms using unit mass window in targeted MS(2), selected reaction monitoring (SRM), regularly applied using triple-quadrupole instruments, was mimicked. This facilitated the comparison of single stage full scan, all ion fragmentation, (mimicked) SRM, and product ion scanning applying a mass window down to 1 ppm. Single factor Analysis of Variance was carried out on the variance (s(2)) of the mass error to determine which factors and interactions are significant parameters with respect to selectivity. We conclude that selectivity is related to the target compound (mainly the mass defect), the matrix, sample clean-up, concentration, and mass resolution. Selectivity of the different instrumental configurations was quantified by counting the number of interfering peaks observed in the chromatograms. We conclude that precursor ion selection significantly contributes to selectivity: monitoring of a single product ion at high mass accuracy with a 1 Da precursor ion window proved to be equally selective or better to monitoring two transition products in mimicked SRM. In contrast, monitoring a single fragment in all ion fragmentation mode results in significantly lower selectivity versus mimicked SRM. After a thorough inter-laboratory evaluation study, the results of this study can be used for a critical reassessment of the current identification points system and contribute to the next generation of evidence-based and robust performance criteria in residue analysis and sports doping.
    Testing of a cumulative and aggregate exposure model using biomonitoring studies and dietary records for Italian vineyard spray operators.
    Kennedy, M.C. ; Glass, C.R. ; Fustinoni, S. ; Moretto, A. ; Mandic-Rajcevic, S. ; Riso, P. ; Turrini, A. ; Voet, H. van der; Hetmanski, M.T. ; Fussel, R.J. ; Klaveren, J.D. van - \ 2015
    Food and Chemical Toxicology 79 (2015). - ISSN 0278-6915 - p. 45 - 53.
    pesticide-residues - urinary concentrations - metabolites - food - tebuconazole - health
    The need for improved tools to estimate the cumulative and aggregate exposure to compounds such as plant protection products (PPPs) is recognised in the EU Regulation 1107/2009. A new model has been developed to estimate the exposure within a population to single compounds or compounds within a Cumulative Action Group, considering dietary and non-dietary sources and multiple exposure routes. To test the model a field study was carried out in Italy with operators applying tebuconazole fungicides, with measurements of dermal exposure collected. Whole urine samples were collected and analysed to provide values for the absorbed dose of tebuconazole, with duplicate diet samples collected and analysed as a measure of dietary exposures. The model provided predicted values of exposure for combined dietary and non-dietary routes of exposures which were compared to the measured absorbed dose values based on urinary analysis. The model outputs provided mean daily exposure values of 1.77 (±1.96) µg a.s./kg BW which are comparable to measured mean values from the biomonitoring field study of 1.73 (±1.31) µg a.s./kg BW. To supplement the limited measurement data available, comparisons against other models were also made and found to be comparable.
    Volatile-mediated interactions between phylogenetically different soil bacteria
    Garbeva, P. ; Hordijk, C. ; Gerards, S. ; Boer, W. de - \ 2014
    Frontiers in Microbiology 5 (2014). - ISSN 1664-302X
    organic-compounds - pseudomonas-fluorescens - rhizosphere - microorganisms - communication - metabolites - regulators - collimonas - signals - systems
    There is increasing evidence that organic volatiles play an important role in interactions between micro-organisms in the porous soil matrix. Here we report that volatile compounds emitted by different soil bacteria can affect the growth, antibiotic production and gene expression of the soil bacterium Pseudomonas fluorescens Pf0-1. We applied a novel cultivation approach that mimics the natural nutritional heterogeneity in soil in which P fluorescens grown on nutrient-limited agar was exposed to volatiles produced by 4 phylogenetically different bacterial isolates (Collimonas pratensis, Serratia plymuthica, Paenibacillus sp., and Pedobacter sp.) growing in sand containing artificial root exudates. Contrary to our expectation, the produced volatiles stimulated rather than inhibited the growth of P fluorescens. A genome-wide, microarray-based analysis revealed that volatiles of all four bacterial strains affected gene expression of P fluorescens, but with a different pattern of gene expression for each strain. Based on the annotation of the differently expressed genes, bacterial volatiles appear to induce a chemotactic motility response in P fluorescens, but also an oxidative stress response. A more detailed study revealed that volatiles produced by C. pratensis triggered, antimicrobial secondary metabolite production in P fluorescens. Our results indicate that bacterial volatiles can have an important role in communication, trophic - and antagonistic interactions within the soil bacterial community.
    Use of electron ionization and atmospheric pressure chemical ionization in gas chromatography coupled to time-of-flight mass spetrometry for screening and identification of organic pollutants in waters
    Portoles, T. ; Mol, J.G.J. ; Sancho, J.V. ; Hernandez, F. - \ 2014
    Journal of Chromatography. A, Including electrophoresis and other separation methods 1339 (2014). - ISSN 0021-9673 - p. 145 - 153.
    urban waste-water - pesticide-residues - ms analysis - qtof-ms - tof-ms - contaminants - metabolites - quantification - elucidation - vegetables
    A new approach has been developed for multiclass screening of organic contaminants in water based on the use of gas chromatography coupled to hybrid quadrupole high-resolution time-of-flight mass spectrometry with atmospheric pressure chemical ionization (GC–(APCI)QTOF MS). The soft ionization promoted by the APCI source allows effective and wide-scope screening based on the investigation of the molecular ion and/or protonated molecule. This is in contrast to electron ionization (EI) where ionization typically results in extensive fragmentation, and diagnostic ions and/or spectra need to be known a priori to facilitate detection of the analytes in the raw data. Around 170 organic contaminants from different chemical families were initially investigated by both approaches, i.e. GC-(EI)TOF and GC-(APCI)QTOF, including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and a notable number of pesticides and relevant metabolites. The new GC–(APCI)QTOF MS approach easily allowed widening the number of compounds investigated (85 additional compounds), with more pesticides, personal care products (UV filters, musks), polychloronaphthalenes (PCNs), antimicrobials, insect repellents, etc., most of them considered as emerging contaminants. Both GC-(EI)TOF and GC-(APCI)QTOF methodologies have been applied, evaluating their potential for a wide-scope screening in the environmental field.
    Active pharmaceutical ingredients detected in herbal food supplements for weight loss samples on the Dutch market
    Reeuwijk, N.M. ; Venhuis, B.J. ; Kaste, D. de; Hoogenboom, L.A.P. ; Rietjens, I. ; Martena, M.J. - \ 2014
    Food Additives & Contaminants. Pt. A, Chemistry, Analysis, Control, Exposure & Risk Assessment 31 (2014)11. - ISSN 1944-0049 - p. 1783 - 1793.
    dietary-supplements - liquid-chromatography - loss products - case series - mass-spectrometry - slimming products - sibutramine - internet - adulteration - metabolites
    Herbal food supplements claiming to reduce weight may contain active pharmacological ingredients (APIs) that can be used for the treatment of overweight and obesity. The aim of this study was to determine whether herbal food supplements for weight loss on the Dutch market contain APIs with weight loss properties. Herbal food supplements intended for weight loss (n = 50) were sampled from August 2004 to May 2013. An HPLC-DAD-MS/MS method was used to screen for the presence of the APIs in herbal supplements. In 24 samples the APIs sibutramine, desmethylsibutramine (DMS), didesmethylsibutramine (DDMS), rimonabant, sildenafil and/or the laxative phenolphthalein were identified 41 times. The presence of these APIs was, however, not stated on the label. The potential pharmacological effects of the detected APIs were estimated using data from reported effective doses of approved drugs. Use of 20 of the 24 herbal food supplements may result in potential pharmacological effects. Furthermore, risk assessment of phenolphthalein, a suspected carcinogen and found to be present in 10 supplements, based on the margin of exposure (MOE) approach, resulted in MOE values of 96–30 000. MOE values lower than 10 000 (96–220) were calculated for the daily intake levels of four out of these 10 supplements in which phenolphthalein was found. However, taking into account that weight loss preparations may be used for only a few weeks or months rather than during a lifetime, MOE values may be two to three orders of magnitude higher. The current study shows that the use of food supplements with sibutramine, DMS, DDMS and/or phenolphthalein could result in pharmacological effects.
    Faox enzymes inhibited Maillard reaction development during storage both in protein glucose model system and low lactose UHT milk
    Troise, A.D. ; Dathan, N.A. ; Fiore, A. ; Roviello, G. ; Fiore, A. Di; Caira, S. ; Cuollo, M. ; Simone, G. De; Fogliano, V. ; Monti, S.M. - \ 2014
    Amino Acids 46 (2014)2. - ISSN 0939-4451 - p. 279 - 288.
    glycation end-products - aspergillus-fumigatus - liquid-chromatography - amadoriase-i - ec 1.5.3 - oxidoreductase - complications - purification - metabolites - dysfunction
    Fructosamines, also known asAmadori products, are formed by the condensation of glucose with the amino group of amino acids or proteins. These compounds are precursors of advanced glycation end products (AGEs) that can be formed either endogenously during aging and diabetes, and exogenously in heat-processed food. The negative effects of dietary AGEs on human health as well as their negative impact on the quality of dairy products have been widely described, therefore specific tools able to prevent the formation of glycation products are needed. Two fructosamine oxidase enzymes isolated fromAspergillus sp. namely, Faox I and Faox II catalyze the oxidative deglycation of Amadori products representing a potential tool for inhibiting the Maillard reaction in dairy products. In this paper, the ability of recombinant Faox I and II in limiting the formation of carboxy-methyl lysine (CML) and protein-bound hydroxymethyl furfurol (b-HMF) in a commercial UHT low lactose milk and a beta-lactoglobulin (b-LG) glucose model system was investigated. Results show a consistent reduction of CML and b-HMF under all conditions. Faox effects were particularly evident on b-HMF formation in low lactose commercial milk. Peptide analysis of the b-LG glucose system identified some peptides, derived from cyanogen bromide hydrolysis, as suitable candidates to monitor Faox action in milk-based products. All in all data suggested that non-enzymatic reactions in dairy products might be strongly reduced by implementing Faox enzymes.
    Rapid and sustained systemic circulation of conjugated gut microbiol catabolites after single-dose black tea extract consumption
    Duynhoven, J.P.M. van; Hooft, J.J.J. van der; Dorsten, F.A. van; Peters, S. ; Foltz, M. ; Gomez-Roldan, V. ; Vervoort, J.J.M. ; Vos, R.C.H. de - \ 2014
    Journal of Proteome Research 13 (2014)5. - ISSN 1535-3893 - p. 2668 - 2678.
    randomized controlled-trial - red wine/grape juice - green tea - mass-spectrometry - in-vitro - dietary polyphenols - blood-pressure - catechins - metabolites - humans
    Gut microbial catabolites of black tea polyphenols (BTPs) have been proposed to exert beneficial cardiovascular bioactivity. This hypothesis is difficult to verify because the conjugation patterns and pharmacokinetics of these catabolites are largely unknown. The objective of our study was to identify, quantify, and assess the pharmacokinetics of conjugated BTP metabolites in plasma of healthy humans by means of an a priori untargeted LC–MS-based metabolomics approach. In a randomized, open, placebo-controlled, crossover study, 12 healthy men consumed a single bolus of black tea extract (BTE) or a placebo. The relative and, in several cases, absolute concentrations of a wide range of metabolites were determined using U(H)PLC-LTQ-Orbitrap-FTMS. Following BTE consumption, a kinetic response in plasma was observed for 59 BTP metabolites, 11 of these in a quantitative manner. Conjugated and unconjugated catechins appeared in plasma without delay, at 2–4 h, followed by a range of microbial catabolites. Interindividual variation in response was greater for gut microbial catabolites than for directly absorbed BTPs. The rapid and sustained circulation of conjugated catabolites suggests that these compounds may be particularly relevant to proposed health benefits of BTE. Their presence and effects may depend on individual variation in catabolic capacity of the gut microbiota.
    Simultaneous growth and metabolite production by yoghurt starters and probiotics: a metabolomics approach
    Settachaimongkon, S. - \ 2014
    Wageningen University. Promotor(en): Toon van Hooijdonk; Marcel Zwietering, co-promotor(en): Eddy Smid. - Wageningen : Wageningen University - ISBN 9789462570115 - 213
    yoghurt - melk starterculturen - probiotica - co-vergisting - metabolieten - yoghurt - cultured milk starters - probiotics - co-fermentation - metabolites

    The main objective of this research was to investigate the simultaneous growth and metabolite production by yoghurt starters and different probiotic strains, i.e. Lactobacillus rhamnosus GG, Bifidobacterium animalis subsp. lactis BB12 and Lactobacillus plantarum WCFS1, during set-yoghurt fermentation and refrigerated storage. In this context, the microbial activity was evaluated in terms of bacterial population dynamics, milk acidification and formation of volatile and non-volatile metabolites in set-yoghurt. A complementary metabolomics approach using headspace SPME-GC/MS and 1H-NMR was applied for characterization of biochemical changes associated with the microbial metabolism during fermentation and storage. The results revealed that incorporation of the three probiotic strains did not significantly influence the acidity and concentrations of key-aroma volatile compounds of set-yoghurt. Still, the presence of probiotics substantially contributed to the formation of a large number of volatile and non-volatile metabolites detected at low concentration. Because many probiotic strains are not able to survive well in fermented milk, a strategy to enhance their survival was additionally applied by preculturing the three probiotic strains under sublethal salt and low pH stress conditions prior to inoculation in milk. The results revealed an improved survival of L. rhamnosus GG and B. animalis subsp. lactis BB12, specifically by preculturing at relatively low pH conditions. Moreover, incorporation of sublethally precultured L. plantarum WCFS1 significantly impaired the survival of L. delbrueckii subsp. bulgaricus, which consequently reduced the post-acidification of yoghurt. Metabolomics analyses revealed that the presence of stress-adapted probiotics induced significant changes in the overall metabolite profile of yoghurt. This finding is important, since variations in the relative abundance of various organic acids, aroma volatiles and proteolytic-derived compounds may directly influence the organoleptic quality of product. Finally, multivariate analysis enabled to distinguish yoghurts fermented by different types of starter combinations and different durations of storage according to their metabolite profiles. This research provides new information regarding the impact of probiotics on the metabolome of yoghurt and potential application of stress-adapted probiotics in an actual food-carrier environment.

    De Kas als Apotheek voor mens, dier en plant : "Er zit zoveel meer in planten"
    Poot, Eric - \ 2014
    greenhouse horticulture - plant composition - plant products - metabolites - drug development - product development - biobased economy - plant breeding
    Text mining for metabolic reaction extraction from scientific literature
    Risse, J.E. - \ 2014
    Wageningen University. Promotor(en): Ton Bisseling; Jack Leunissen, co-promotor(en): P.E. van der Vet. - Wageningen : Wageningen University - ISBN 9789461739001 - 138
    metabolomica - gegevensanalyse - databanken - text mining - publicaties - wetenschappelijk onderzoek - moleculaire biologie - thesauri - enzymen - metabolieten - metabolomics - data analysis - databases - text mining - publications - scientific research - molecular biology - thesauri - enzymes - metabolites

    Science relies on data in all its different forms. In molecular biology and bioinformatics in particular large scale data generation has taken centre stage in the form of high-throughput experiments. In line with this exponential increase of experimental data has been the near exponential growth of scientific publications. Yet where classical data mining techniques are still capable of coping with this deluge in structured data (Chapter 2), access of information found in scientific literature is still limited to search engines allowing searches on the level keywords, titles and abstracts. However, large amounts of knowledge about biological entities and their relations are held within the body of articles. When extracted, this data can be used as evidence for existing knowledge or hypothesis generation making scientific literature a valuable scientific resource. To unlock the information inside the articles requires a dedicated set of techniques and approaches tailored to the unstructured nature of free text. Analogous to the field of data mining for the analysis of structured data, the field of text mining has emerged for unstructured text and a number of applications has been developed in that field.

    This thesis is about text mining in the field of metabolomics. The work focusses on strategies for accessing large collections of scientific text and on the text mining steps required to extract metabolic reactions and their constituents, enzymes and metabolites, from scientific text. Metabolic reactions are important for our understanding of metabolic processes within cells and that information provides an important link between genotype phenotype. Furthermore information about metabolic reactions stored in databases is far from complete making it an excellent target for our text mining application.

    In order to access the scientific publications for further analysis they can be used as flat text or loaded into database systems. In Chapter 2we assessed and discussed the capabilities and performance of XML-type database systems to store and access very large collections of XML-type documents in the form of the Medline corpus, a collection of more than 20 million of scientific abstracts. XML data formats are common in the field of bioinformatics and are also at the core of most web services. With the increasing amount of data stored in XML comes the need for storing and accessing the data. The database systems were evaluated on a number of aspects broadly ranging from technical requirements to ease-of-use and performance. The performance of the different XML-type database systems was measured Medline abstract collections of increasing size and with a number of different queries. One of the queries assessed the capabilities of each database system to search the full-text of each abstract, which would allow access to the information within the text without further text analysis. The results show that all database systems cope well with the small and medium dataset, but that the full dataset remains a challenge. Also the query possibilities varied greatly across all studied databases. This led us to conclude that the performances and possibilities of the different database types vary greatly, also depending on the type of research question. There is no single system that outperforms the others; instead different circumstances can lead to a different optimal solution. Some of these scenarios are presented in the chapter.

    Among the conclusions of Chapter 2is that conventional data mining techniques do not work for the natural language part of a publication beyond simple retrieval queries based on pattern matching. The natural language used in written text is too unstructured for that purpose and requires dedicated text mining approaches, the main research topic of this thesis. Two major tasks of text mining are named entity recognition, the identification of relevant entities in the text, and relation extraction, the identification of relations between those named entities. For both text mining tasks many different techniques and approaches have been developed. For the named entity recognition of enzymes and metabolites we used a dictionary-based approach (Chapter 3) and for metabolic reaction extraction a full grammar approach (Chapter 4).

    In Chapter 3we describe the creation of two thesauri, one for enzymes and one for metabolites with the specific goal of allowing named entity identification, the mapping of identified synonyms to a common identifier, for metabolic reaction extraction. In the case of the enzyme thesaurus these identifiers are Enzyme Nomenclature numbers (EC number), in the case of the metabolite thesaurus KEGG metabolite identifiers. These thesauri are applied to the identification of enzymes and metabolites in the text mining approach of Chapter 4. Both were created from existing data sources by a series of automated steps followed by manual curation. Compared to a previously published chemical thesaurus, created entirely with automated steps, our much smaller metabolite thesaurus performed on the same level for F-measure with a slightly higher precision. The enzyme thesaurus produced results equal to our metabolite thesaurus. The compactness of our thesauri permits the manual curation step important in guaranteeing accuracy of the thesaurus contents, whereas creation from existing resources by automated means limits the effort required for creation. We concluded that our thesauri are compact and of high quality, and that this compactness does not greatly impact recall.

    In Chapter 4we studied the applicability and performance of a full parsing approach using the two thesauri described in Chapter 3 for the extraction of metabolic reactions from scientific full-text articles. For this we developed a text mining pipeline built around a modified dependency parser from the AGFL grammar lab using a pattern-based approach to extract metabolic reactions from the parsing output. Results of a comparison to a modified rule-based approach by Czarnecki et al.using three previously described metabolic pathways from the EcoCyc database show a slightly lower recall compared to the rule-based approach, but higher precision. We concluded that despite its current recall our full parsing approach to metabolic reaction extraction has high precision and potential to be used to (re-)construct metabolic pathways in an automated setting. Future improvements to the grammar and relation extraction rules should allow reactions to be extracted with even higher specificity.

    To identify potential improvements to the recall, the effect of a number of text pre-processing steps on the performance was tested in a number of experiments. The one experiment that had the most effect on performance was the conversion of schematic chemical formulas to syntactic complete sentences allowing them to be analysed by the parser. In addition to the improvements to the text mining approach described in Chapter 4I make suggestions in Chapter 5 for potential improvements and extensions to our full parsing approach for metabolic reaction extraction. Core focus here is the increase of recall by optimising each of the steps required for the final goal of extracting metabolic reactions from the text. Some of the discussed improvements are to increase the coverage of the used thesauri, possibly with specialist thesauri depending on the analysed literature. Another potential target is the grammar, where there is still room to increase parsing success by taking into account the characteristics of biomedical language. On a different level are suggestions to include some form of anaphora resolution and across sentence boundary search to increase the amount of information extracted from literature.

    In the second part of Chapter 5I make suggestions as to how to maximise the information gained from the text mining results. One of the first steps should be integration with other biomedical databases to allow integration with existing knowledge about metabolic reactions and other biological entities. Another aspect is some form of ranking or weighting of the results to be able to distinguish between high quality results useful for automated analyses and lower quality results still useful for manual approaches. Furthermore I provide a perspective on the necessity of computational literature analysis in the form of text mining. The main reasoning here is that human annotators cannot keep up with the amount of publications so that some form of automated analysis is unavoidable. Lastly I discuss the role of text mining in bioinformatics and with that also the accessibility of both text mining results and the literature resources necessary to create them. An important requirement for the future of text mining is that the barriers around high-throughput access to literature for text mining applications have to be removed. With regards to accessing text mining results, there is a long way to go for many applications, including ours, before they can be used directly by biologists. A major factor is that these applications rarely feature a suitable user interface and easy to use setup.

    To conclude, I see the main role of a text mining system like ours mainly in gathering evidence for existing knowledge and giving insights into the nuances of the research landscape of a given topic. When using the results of our reaction extraction system for the identification of ‘new’ reactions it is important to go back to the actual evidence presented for extra validations and to cross-validate the predictions with other resources or experiments. Ideally text mining will be used for generation of hypotheses, in which the researcher uses text mining findings to get ideas on, in our case, new connections between metabolites and enzymes; subsequently the researcher needs to go back to the original texts for further study. In this role text mining is an essential tool on the workbench of the molecular biologist.

    Rapid analysis of Delta-9-tetrahydrocannabinol in hair using direct analysis in real time ambient ionization orbitrap mass spectrometry
    Duvivier, W.F. ; Beek, T.A. van; Pennings, E.J.M. ; Nielen, M.W.F. - \ 2014
    Rapid Communications in Mass Spectrometry 28 (2014)7. - ISSN 0951-4198 - p. 682 - 690.
    synthetic cannabinoids - cocaine - drugs - identification - capabilities - metabolites - validation - samples - abuse
    RATIONALE - Forensic hair analysis methods are laborious, time-consuming and provide only a rough retrospective estimate of the time of drug intake. Recently, hair imaging methods using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) were reported, but these methods require the application of MALDI matrix and are performed under vacuum. Direct analysis of entire locks of hair without any sample pretreatment and with improved spatial resolution would thus address a need. METHODS - Hair samples were attached to stainless steel mesh screens and scanned in the X-direction using direct analysis in real time (DART) ambient ionization orbitrap MS. The DART gas temperature and the accuracy of the probed hair zone were optimized using ¿-9-tetrahydrocannabinol (THC) as a model compound. Since external contamination is a major issue in forensic hair analysis, sub-samples were measured before and after dichloromethane decontamination. RESULTS - The relative intensity of the THC signal in spiked blank hair versus that of quinine as the internal standard showed good reproducibility (26% RSD) and linearity of the method (R2¿=¿0.991). With the DART hair scan THC could be detected in hair samples from different chronic cannabis users. The presence of THC was confirmed by quantitative liquid chromatography/tandem mass spectrometry. Zones with different THC content could be clearly distinguished, indicating that the method might be used for retrospective timeline assessments. Detection of THC in decontaminated drug user hair showed that the DART hair scan not only probes THC on the surface of hair, but penetrates deeply enough to measure incorporated THC. CONCLUSIONS - A new approach in forensic hair analysis has been developed by probing complete locks of hair using DART-MS. Longitudinal scanning enables detection of incorporated compounds and can be used as pre-screening for THC without sample preparation. The method could also be adjusted for the analysis of other drugs of abuse.
    Investigation of the presence of prednisolone in bovine urine
    Rijke, E. de; Zoontjes, P.W. ; Samson, D. ; Oostra, S. ; Sterk, S.S. ; Ginkel, L.A. van - \ 2014
    Food Additives & Contaminants. Pt. A, Chemistry, Analysis, Control, Exposure & Risk Assessment 31 (2014)4. - ISSN 1944-0049 - p. 605 - 613.
    performance liquid-chromatography - synthetic corticosteroids - domestic livestock - mass-spectrometry - feces - metabolites - liver
    Over the past 2 years low levels of prednisolone have been reported in bovine urine by a number of laboratories in EU member states. Concentrations vary, but are reported to be below approximately 3 g/l. In 40% of bovine urine samples from the Dutch national control plan had concentrations of prednisolone between 0.112.04 g/l. In this study the mechanism of formation of prednisolone was investigated. In-vitro conversion of cortisol by bacteria from faeces and soil, bovine liver enzymes and stability at elevated temperatures were studied. In-vitro bovine liver S9 incubation experiments showed a significant 20% decrease of cortisol within 6 hours, and formation of prednisolone was observed from 0.2 g/l at t = 0 to 0.5 g/l at t = 6. Under the influence of faeces, the stability of cortisol in urine is reduced and cortisol breaks down within 50 h. Prednisolone is formed up to 4 g/l at 70C after 15 h. However, this decreases again to 0 after 50 h. With soil bacteria, a slower decrease of cortisol was observed, but slightly higher overall formation of prednisolone, up to 7 g/l at 20C. As opposed to incurred urine, in fortified urine incubated with faeces or soil bacteria no prednisolone was detected. This difference may be explained by the presence of natural corticosteroids in the incurred sample. With UPLC-QToF-MS experiments, in urine and water samples incubated with faeces, metabolites known from the literature could be (tentatively) identified as 20ß-hydroxy-prednisolone, cortisol-21-sulfate, oxydianiline, tetrahydrocortisone-3-glucuronide and cortexolone, but for all compounds except 20ß-hydroxy-prednisolone no standards were available for confirmation. Based on the results of this study and literature data, for regulatory purposes a threshold of 5 g/l for prednisolone in bovine urine is proposed. Findings of prednisolone in concentrations up to 5 g/l in bovine urine can, most likely, originate from other sources than illegal treatment with growth promoters.
    Evidence for a hydrogen-sink mechanism of (+)catechin-mediated emission reduction of the ruminant greenhouse gas methane
    Becker, P.M. ; Wikselaar, P.G. van; Franssen, M.C.R. ; Vos, C.H. de; Hall, R.D. ; Beekwilder, M.J. - \ 2014
    Metabolomics 10 (2014)2. - ISSN 1573-3882 - p. 179 - 189.
    rumen bacteria - fermentation - methanogenesis - perspective - metabolites - tannins - growth - acids
    Methane formation in the rumen is a major cause of greenhouse gas emission. Plant secondary compounds in ruminant diets, such as essential oils, saponins and tannins, are known to affect methane production. However, their methane-lowering properties have generally been associated with undesired side effects such as impaired feed digestibility. Here we show that microbial methane formation in diluted and buffered rumen fluid was significantly lowered in the presence of (+)-catechin, a natural polyphenol. This flavan-3-ol, a tannin precursor, decreased the production of methane in a dose-dependent manner, where 1.0 mol catechin prevented the emission of 1.2 mol methane. During methane mitigation, (+)-catechin was step-wise degraded via C- and A-ring cleavage and reductive dehydroxylation reactions, as indicated by LC-QToF-MS based metabolomic profiling and NMR-based metabolite identification. This accounted for the acceptance of six hydrogen atoms per catechin molecule. Consequently, catechin functions as an extensive hydrogen sink, thereby competing with methane production by rumen methanogens (TeX). Catechin therefore acts as an antireductant under the anaerobic test conditions, in contrast to its well-known antioxidant role during oxidative stress. The reductive degradation of catechin had no impact on the formation of ruminal fermentation products such as short-chain fatty acids in this model system. These results highlight the potential of plant secondary compounds to replace methane precursors as hydrogen sinks, and justify future scientific screening programs for similar, potentially more effective organic compounds
    Effect of reduced food intake on toxicokinetics of halogenated organic contaminants in herring gull (Larus argentatus) chicks
    Routti, H. ; Helgason, L.B. ; Arukwe, A. ; Wolkers, J. ; Heimstad, E.S. ; Harju, M. ; Berg, V. ; Gabrielsen, G.W. - \ 2013
    Environmental Toxicology and Chemistry 32 (2013)1. - ISSN 0730-7268 - p. 156 - 164.
    arctic seabirds - polychlorinated-biphenyls - organochlorine contaminants - o-dealkylation - rat-liver - biotransformation - blood - bioaccumulation - metabolites - pcbs
    The aim of the present study was to investigate how contaminant exposure and reduced food intake affect tissue distribution and biotransformation of halogenated organic contaminants (HOCs) in Arctic seabirds using herring gull (Larus argentatus) as a model species. Herring gull chicks were exposed for 44 d to cod liver oil containing a typical mixture of contaminants. Following exposure, food intake was reduced for a one-week period in a subgroup of the chicks. Polyclorinated biphenyls, organochlorine pesticides, and brominated flame retardants, as well as a wide range of hydroxy, methyl sulfone, and methoxy compounds were measured in liver, brain, and plasma samples. Additionally, phase I biotransformation enzyme activities and phase I and II messenger ribonucleic acid (mRNA) expression were investigated in the liver, brain, or both. Both contaminant exposure and reduced food intake had an increasing effect on the concentrations of HOCs and their metabolites. The HOC exposure and reduced food intake also led to increased 7-ethoxyresorufin-O-deethylation (EROD) activity, whereas mRNA expression of the biotransformation enzymes increased only following the reduced food intake. Tissue distribution of HOCs and their metabolites was not affected by either contaminant exposure or reduced food intake. In conclusion, the results indicate that biotransformation capacity and formation of HOC metabolites increase during reduced food intake. This finding supports the hypothesis that reduced food intake increases the susceptibility of Arctic animals to the effects of lipophilic HOCs. Environ. Toxicol. Chem. 2013;32:156164. (c) 2012 SETAC
    Microbial Removal of the Pharmaceutical Compounds Ibuprofen and Diclofenac from Wastewater
    Langenhoff, A.A.M. ; Inderfurth, N.S. ; Veuskens, T. ; Schraa, G. ; Blokland, M. ; Kujawa-Roeleveld, K. ; Rijnaarts, H.H.M. - \ 2013
    BioMed Research International 2013 (2013). - ISSN 2314-6133 - 9
    biodegradatie - geneesmiddelen - afvalwater - afvalwaterbehandeling - bioremediëring - afvalwaterbehandelingsinstallaties - verwijdering - oppervlaktewater - geneesmiddelenresiduen - biodegradation - drugs - waste water - waste water treatment - bioremediation - waste water treatment plants - removal - surface water - drug residues - personal care products - activated carbon - batch experiments - aquatic environment - metabolites - systems - sludge - acid - transformation
    Studies on the occurrence of pharmaceuticals show that the widely used pharmaceuticals ibuprofen and diclofenac are present in relevant concentrations in the environment. A pilot plant treating hospital wastewater with relevant concentrations of these pharmaceuticals was evaluated for its performance to reduce the concentration of the pharmaceuticals. Ibuprofen was completely removed, whereas diclofenac yielded a residual concentration, showing the necessity of posttreatment to remove diclofenac, for example, activated carbon. Successively, detailed laboratory experiments with activated sludge from the same wastewater treatment plant showed bioremediation potential in the treatment plant. The biological degradation pathway was studied and showed a mineralisation of ibuprofen and degradation of diclofenac. The present microbes were further studied in laboratory experiments, and DGGE analyses showed the enrichment and isolation of highly purified cultures that degraded either ibuprofen or diclofenac. This research illuminates the importance of the involved bacteria for the effectiveness of the removal of pharmaceuticals in a wastewater treatment plant. A complete removal of pharmaceuticals from wastewater will stimulate water reuse, addressing the worldwide increasing demand for clean and safe fresh water.
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