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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    Lifestyle-Intervention-Induced Reduction of Abdominal Fat Is Reflected by a Decreased Circulating Glycerol Level and an Increased HDL Diameter
    Beekman, Marian ; Schutte, Bianca A.M. ; Akker, Erik B. van den; Noordam, Raymond ; Dibbets-Schneider, Petra ; Geus-Oei, Lioe Fee de; Deelen, Joris ; Rest, Ondine van de; Heemst, Diana van; Feskens, Edith J.M. ; Slagboom, P.E. - \ 2020
    Molecular Nutrition & Food Research 64 (2020)10. - ISSN 1613-4125
    abdominal fat - biomarkers - lifestyle interventions - metabolomics

    Scope: Abdominal obesity is one of the main modifiable risk factors of age-related cardiometabolic disease. Cardiometabolic disease risk and its associated high abdominal fat mass, cholesterol, and glucose concentrations can be reduced by a healthier lifestyle. Hence, the aim is to understand the relation between lifestyle-induced changes in body composition, and specifically abdominal fat, and accompanying changes in circulating metabolic biomarkers. Methods and results: Data from the Growing Old Together (GOTO) study was used, which is a single arm lifestyle intervention in which 164 older adults (mean age 63 years, BMI 23–35 kg/m2) changed their lifestyle during 13 weeks by 12.5% caloric restriction plus 12.5% increase in energy expenditure. It is shown here that levels of circulating metabolic biomarkers, even after adjustment for body mass index, specifically associate with abdominal fat mass. The applied lifestyle intervention mainly reduces abdominal fat mass (−2.6%, SD = 3.0) and this reduction, when adjusted for general weight loss, is highly associated with decreased circulating glycerol concentrations and increased HDL diameter. Conclusion: The lifestyle-induced reduction of abdominal fat mass is particularly associated, independent of body mass index or general weight loss, with decreased circulating glycerol concentrations and increased HDL diameter.

    Metabolomics should be deployed in the identification and characterization of gene-edited crops
    Fraser, Paul D. ; Aharoni, Asaph ; Hall, Robert D. ; Huang, Sanwen ; Giovannoni, James J. ; Sonnewald, Uwe ; Fernie, Alisdair R. - \ 2020
    The Plant Journal 102 (2020)5. - ISSN 0960-7412 - p. 897 - 902.
    crop regulation - food system - genome-editing - metabolomics - substantial equivalence

    Gene-editing techniques are currently revolutionizing biology, allowing far greater precision than previous mutagenic and transgenic approaches. They are becoming applicable to a wide range of plant species and biological processes. Gene editing can rapidly improve a range of crop traits, including disease resistance, abiotic stress tolerance, yield, nutritional quality and additional consumer traits. Unlike transgenic approaches, however, it is not facile to forensically detect gene-editing events at the molecular level, as no foreign DNA exists in the elite line. These limitations in molecular detection approaches are likely to focus more attention on the products generated from the technology than on the process in itself. Rapid advances in sequencing and genome assembly increasingly facilitate genome sequencing as a means of characterizing new varieties generated by gene-editing techniques. Nevertheless, subtle edits such as single base changes or small deletions may be difficult to distinguish from normal variation within a genotype. Given these emerging scenarios, downstream ‘omics’ technologies reflective of edited affects, such as metabolomics, need to be used in a more prominent manner to fully assess compositional changes in novel foodstuffs. To achieve this goal, metabolomics or ‘non-targeted metabolite analysis’ needs to make significant advances to deliver greater representation across the metabolome. With the emergence of new edited crop varieties, we advocate: (i) concerted efforts in the advancement of ‘omics’ technologies, such as metabolomics, and (ii) an effort to redress the use of the technology in the regulatory assessment for metabolically engineered biotech crops.

    Relationship between energy balance and metabolic profiles in plasma and milk of dairy cows in early lactation
    Xu, Wei ; Vervoort, Jacques ; Saccenti, Edoardo ; Kemp, Bas ; Hoeij, Renny J. van; Knegsel, Ariette T.M. van - \ 2020
    Journal of Dairy Science 103 (2020). - ISSN 0022-0302 - p. 4795 - 4805.
    liquid chromatography–mass spectrometry - mammary gland - metabolomics - nuclear magnetic resonance

    Negative energy balance in dairy cows in early lactation is related to alteration of metabolic status. However, the relationships among energy balance, metabolic profile in plasma, and metabolic profile in milk have not been reported. In this study our aims were: (1) to reveal the metabolic profiles of plasma and milk by integrating results from nuclear magnetic resonance (NMR) with data from liquid chromatography triple quadrupole mass spectrometry (LC-MS); and (2) to investigate the relationship between energy balance and the metabolic profiles of plasma and milk. For this study 24 individual dairy cows (parity 2.5 ± 0.5; mean ± standard deviation) were studied in lactation wk 2. Body weight (mean ± standard deviation; 627.4 ± 56.4 kg) and milk yield (28.1 ± 6.7 kg/d; mean ± standard deviation) were monitored daily. Milk composition (fat, protein, and lactose) and net energy balance were calculated. Plasma and milk samples were collected and analyzed using LC-MS and NMR. From all plasma metabolites measured, 27 were correlated with energy balance. These plasma metabolites were related to body reserve mobilization from body fat, muscle, and bone; increased blood flow; and gluconeogenesis. From all milk metabolites measured, 30 were correlated with energy balance. These milk metabolites were related to cell apoptosis and cell proliferation. Nine metabolites detected in both plasma and milk were correlated with each other and with energy balance. These metabolites were mainly related to hyperketonemia; β-oxidation of fatty acids; and one-carbon metabolism. The metabolic profiles of plasma and milk provide an in-depth insight into the physiological pathways of dairy cows in negative energy balance in early lactation. In addition to the classical indicators for energy balance (e.g., β-hydroxybutyrate, acetone, and glucose), the current study presents some new metabolites (e.g., glycine in plasma and milk; kynurenine, panthothenate, or arginine in plasma) in lactating dairy cows that are related to energy balance and may be of interest as new indicators for energy balance.

    Biomarker Research in ADHD: the Impact of Nutrition (BRAIN) – Metabolomics data
    Stobernack, Tim ; Frankena, Klaas ; Rodrigues Pereira, Rob ; Schrama, Rosan P.H. ; Baarlen, Peter van; Kleerebezem, Michiel ; Pelsser, Lidy ; Hontelez, Saartje - \ 2020
    Wageningen University & Research
    ADHD - few-foods diet - biomarker - metabolomics
    Small-molecule profiling data for 79 children included in the Biomarker Research in ADHD: the Impact of Nutrition (BRAIN) study, an open-label trial during which children with ADHD followed a few-foods diet (FFD). Sampling was done before the FFD (t1) and after 5 weeks of FFD (t2).
    Differential Network Analysis Reveals Metabolic Determinants Associated with Mortality in Acute Myocardial Infarction Patients and Suggests Potential Mechanisms Underlying Different Clinical Scores Used To Predict Death
    Vignoli, Alessia ; Tenori, Leonardo ; Giusti, Betti ; Valente, Serafina ; Carrabba, Nazario ; Balzi, Daniela ; Barchielli, Alessandro ; Marchionni, Niccolò ; Gensini, Gian Franco ; Marcucci, Rossella ; Gori, Anna Maria ; Luchinat, Claudio ; Saccenti, Edoardo - \ 2020
    Journal of Proteome Research 19 (2020)2. - ISSN 1535-3893 - p. 949 - 961.
    acute myocardial infarction - metabolite−metabolite association networks - metabolomics - network inference - nuclear magnetic resonance

    We present here the differential analysis of metabolite-metabolite association networks constructed from an array of 24 serum metabolites identified and quantified via nuclear magnetic resonance spectroscopy in a cohort of 825 patients of which 123 died within 2 years from acute myocardial infarction (AMI). We investigated differences in metabolite connectivity of patients who survived, at 2 years, the AMI event, and we characterized metabolite-metabolite association networks specific to high and low risks of death according to four different risk parameters, namely, acute coronary syndrome classification, Killip, Global Registry of Acute Coronary Events risk score, and metabolomics NOESY RF risk score. We show significant differences in the connectivity patterns of several low-molecular-weight molecules, implying variations in the regulation of several metabolic pathways regarding branched-chain amino acids, alanine, creatinine, mannose, ketone bodies, and energetic metabolism. Our results demonstrate that the characterization of metabolite-metabolite association networks is a promising and powerful tool to investigate AMI patients according to their outcomes at a molecular level.

    Integrated Univariate, Multivariate, and Correlation-Based Network Analyses Reveal Metabolite-Specific Effects on Bacterial Growth and Biofilm Formation in Necrotizing Soft Tissue Infections
    Afzal, Muhammad ; Saccenti, Edoardo ; Madsen, Martin Bruun ; Hansen, Marco Bo ; Hyldegaard, Ole ; Skrede, Steinar ; Martins Dos Santos, Vitor A.P. ; Norrby-Teglund, Anna ; Svensson, Mattias - \ 2020
    Journal of Proteome Research 19 (2020)2. - ISSN 1535-3893 - p. 688 - 698.
    bacterial infection - differential network analysis - metabolomics - necrotizing fasciitis - necrotizing soft-tissue infections - streptococcus

    Necrotizing soft-tissue infections (NSTIs) have multiple causes, risk factors, anatomical locations, and pathogenic mechanisms. In patients with NSTI, circulating metabolites may serve as a substrate having impact on bacterial adaptation at the site of infection. Metabolic signatures associated with NSTI may reveal the potential to be useful as diagnostic and prognostic markers and novel targets for therapy. This study used untargeted metabolomics analyses of plasma from NSTI patients (n = 34) and healthy (noninfected) controls (n = 24) to identify the metabolic signatures and connectivity patterns among metabolites associated with NSTI. Metabolite-metabolite association networks were employed to compare the metabolic profiles of NSTI patients and noninfected surgical controls. Out of 97 metabolites detected, the abundance of 33 was significantly altered in NSTI patients. Analysis of metabolite-metabolite association networks showed a more densely connected network: Specifically, 20 metabolites differentially connected between NSTI and controls. A selected set of significantly altered metabolites was tested in vitro to investigate potential influence on NSTI group A streptococcal strain growth and biofilm formation. Using chemically defined media supplemented with the selected metabolites, ornithine, ribose, urea, and glucuronic acid, revealed metabolite-specific effects on both bacterial growth and biofilm formation. This study identifies for the first time an NSTI-specific metabolic signature with implications for optimized diagnostics and therapies.

    Plasma metabolites associated with colorectal cancer stage: Findings from an international consortium
    Geijsen, Anne J.M.R. ; Roekel, Eline H. van; Duijnhoven, Fränzel J.B. van; Achaintre, David ; Bachleitner-Hofmann, Thomas ; Baierl, Andreas ; Bergmann, Michael M. ; Boehm, Jürgen ; Bours, Martijn J.L. ; Brenner, Hermann ; Breukink, Stéphanie O. ; Brezina, Stefanie ; Chang-Claude, Jenny ; Herpel, Esther ; Wilt, Johannes H.W. de; Gicquiau, Audrey ; Gigic, Biljana ; Gumpenberger, Tanja ; Hansson, Bibi M.E. ; Hoffmeister, Michael ; Holowatyj, Andreana N. ; Karner-Hanusch, Judith ; Keski-Rahkonen, Pekka ; Keulen, Eric T.P. ; Koole, Janna L. ; Leeb, Gernot ; Ose, Jennifer ; Schirmacher, Peter ; Schneider, Martin A. ; Schrotz-King, Petra ; Stift, Anton ; Ulvik, Arve ; Vogelaar, Jeroen F. ; Wesselink, Evertine ; Zutphen, Moniek van; Gsur, Andrea ; Habermann, Nina ; Kampman, Ellen ; Scalbert, Augustin ; Ueland, Per M. ; Ulrich, Alexis B. ; Ulrich, Cornelia M. ; Weijenberg, Matty P. ; Kok, Dieuwertje E. - \ 2020
    International Journal of Cancer 146 (2020)12. - ISSN 0020-7136 - p. 3256 - 3266.
    colorectal cancer - disease stage - epidemiology - metabolomics - plasma metabolites

    Colorectal cancer is the second most common cause of cancer-related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I–IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography-mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I–IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (pFDR < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl-alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (pFDR < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression.

    Breeding Has Increased the Diversity of Cultivated Tomato in The Netherlands
    Schouten, Henk J. ; Tikunov, Yury ; Verkerke, Wouter ; Finkers, Richard ; Bovy, Arnaud ; Bai, Yuling ; Visser, Richard G.F. - \ 2019
    Frontiers in Plant Science 10 (2019). - ISSN 1664-462X
    breeding - diversity - introgressions - metabolomics - tomato varieties

    It is generally believed that domestication and breeding of plants has led to genetic erosion, including loss of nutritional value and resistances to diseases, especially in tomato. We studied the diversity dynamics of greenhouse tomato varieties in NW Europe, especially The Netherlands, over the last seven decades. According to the used SNP array, the genetic diversity was indeed very low during the 1960s, but is now eight times higher when compared to that dip. The pressure since the 1970s to apply less pesticides led to the introgression of many disease resistances from wild relatives, representing the first boost of genetic diversity. In Europe a second boost ensued, largely driven by German popular media who named poor tasting tomatoes Wasserbomben (water bombs). The subsequent collapse of Dutch tomato exports to Germany fueled breeding for fruit flavor, further increasing diversity since the 1990s. The increased diversity in composition of aroma volatiles observed starting from 1990s may reflect the efforts of breeders to improve fruit quality. Specific groups of aroma compounds showed different quantitative trend over the decades studied. Our study provides compelling evidence that breeding has increased the diversity of tomato varieties considerably since the 1970s.

    The Synchytrium endobioticum AvrSen1 triggers a Hypersensitive Response in Sen1 potatoes while natural variants evade detection
    Vossenberg, Bart van de; Prodhomme, Charlotte ; Arkel, G. van; Gent-Pelzer, M.P.E. van; Bergervoet-van Deelen, J.E.M. ; Brankovics, Balázs ; Przetakiewicz, J. ; Visser, R.G.F. ; Lee, T.A.J. van der; Vossen, J.H. - \ 2019
    Molecular Plant-Microbe Interactions 32 (2019)11. - ISSN 0894-0282 - p. 1536 - 1546.
    avirulence factors - cell death - chytridiomycota - effector - fungus-plant interactions - Genomics - hypersensitive response - metabolomics - plant-pathogen interactions - population genetics - proteomics - resistance genes
    Synchytrium endobioticum is an obligate biotrophic fungus of the phylum Chytridiomycota. It causes potato wart disease, has a world-wide quarantine status and is included on the HHS and USDA Select Agent list. S. endobioticum isolates are grouped in pathotypes based on their ability to evade host-resistance in a set of differential potato varieties. So far, thirty-nine pathotypes are reported. A single dominant gene (Sen1) governs pathotype 1 resistance and we anticipated that the underlying molecular model would involve a pathogen effector (AvrSen1) that is recognized by the host. The S. endobioticum specific secretome of fourteen isolates representing six different pathotypes was screened for effectors specifically present in pathotype 1(D1) isolates but absent in others. We identified a single AvrSen1 candidate. Expression of this candidate in potato Sen1 plants showed a specific hypersensitive response, which co-segregated with the Sen1 resistance in potato populations. No HR was obtained with truncated genes found in pathotypes that evaded recognition by Sen1. These findings established that our candidate gene was indeed Avrsen1. The S. endobioticum AvrSen1 is a single copy gene and encodes a 376 amino acid protein without predicted function or functional domains, and is the first effector gene identified in Chytridiomycota, an extremely diverse yet underrepresented basal lineage of fungi.
    Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis
    Salic, Kanita ; Gart, Eveline ; Seidel, Florine ; Verschuren, Lars ; Caspers, Martien ; Duyvenvoorde, Wim van; Wong, Kari E. ; Keijer, Jaap ; Bobeldijk-Pastorova, Ivana ; Wielinga, Peter Y. ; Kleemann, Robert - \ 2019
    International Journal of Molecular Sciences 20 (2019)18. - ISSN 1661-6596
    acylcarnitines - lipid peroxidation - metabolomics - mitochondria - non-alcoholic fatty liver disease - obesity - transcriptomics - β-oxidation

    Obesity characterized by adiposity and ectopic fat accumulation is associated with the development of non-alcoholic fatty liver disease (NAFLD). Treatments that stimulate lipid utilization may prevent the development of obesity and comorbidities. This study evaluated the potential anti-obesogenic hepatoprotective effects of combined treatment with L-carnitine and nicotinamide riboside, i.e., components that can enhance fatty acid transfer across the inner mitochondrial membrane and increase nicotinamide adenine nucleotide (NAD+) levels, which are necessary for β-oxidation and the TCA cycle, respectively. Ldlr -/-.Leiden mice were treated with high-fat diet (HFD) supplemented with L-carnitine (LC; 0.4% w/w), nicotinamide riboside (NR; 0.3% w/w) or both (COMBI) for 21 weeks. L-carnitine plasma levels were reduced by HFD and normalized by LC. NR supplementation raised its plasma metabolite levels demonstrating effective delivery. Although food intake and ambulatory activity were comparable in all groups, COMBI treatment significantly attenuated HFD-induced body weight gain, fat mass gain (-17%) and hepatic steatosis (-22%). Also, NR and COMBI reduced hepatic 4-hydroxynonenal adducts. Upstream-regulator gene analysis demonstrated that COMBI reversed detrimental effects of HFD on liver metabolism pathways and associated regulators, e.g., ACOX, SCAP, SREBF, PPARGC1B, and INSR. Combination treatment with LC and NR exerts protective effects on metabolic pathways and constitutes a new approach to attenuate HFD-induced obesity and NAFLD.

    Plasma metabolites associated with colorectal cancer: A discovery-replication strategy
    Geijsen, Anne J.M.R. ; Brezina, Stefanie ; Keski-Rahkonen, Pekka ; Baierl, Andreas ; Bachleitner-Hofmann, Thomas ; Bergmann, Michael M. ; Boehm, Juergen ; Brenner, Hermann ; Chang-Claude, Jenny ; Duijnhoven, Fränzel J.B. van; Gigic, Biljana ; Gumpenberger, Tanja ; Hofer, Philipp ; Hoffmeister, Michael ; Holowatyj, Andreana N. ; Karner-Hanusch, Judith ; Kok, Dieuwertje E. ; Leeb, Gernot ; Ulvik, Arve ; Robinot, Nivonirina ; Ose, Jennifer ; Stift, Anton ; Schrotz-King, Petra ; Ulrich, Alexis B. ; Ueland, Per Magne ; Kampman, Ellen ; Scalbert, Augustin ; Habermann, Nina ; Gsur, Andrea ; Ulrich, Cornelia M. - \ 2019
    International Journal of Cancer 145 (2019)5. - ISSN 0020-7136 - p. 1221 - 1231.
    colorectal cancer - discovery-replication approach - metabolomics - UHPLC-QTOF-MS

    Colorectal cancer is known to arise from multiple tumorigenic pathways; however, the underlying mechanisms remain not completely understood. Metabolomics is becoming an increasingly popular tool in assessing biological processes. Previous metabolomics research focusing on colorectal cancer is limited by sample size and did not replicate findings in independent study populations to verify robustness of reported findings. Here, we performed a ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) screening on EDTA plasma from 268 colorectal cancer patients and 353 controls using independent discovery and replication sets from two European cohorts (ColoCare Study: n = 180 patients/n = 153 controls; the Colorectal Cancer Study of Austria (CORSA) n = 88 patients/n = 200 controls), aiming to identify circulating plasma metabolites associated with colorectal cancer and to improve knowledge regarding colorectal cancer etiology. Multiple logistic regression models were used to test the association between disease state and metabolic features. Statistically significant associated features in the discovery set were taken forward and tested in the replication set to assure robustness of our findings. All models were adjusted for sex, age, BMI and smoking status and corrected for multiple testing using False Discovery Rate. Demographic and clinical data were abstracted from questionnaires and medical records.

    Nutrimetabolomics: An Integrative Action for Metabolomic Analyses in Human Nutritional Studies
    Ulaszewska, Marynka M. ; Weinert, Christoph H. ; Trimigno, Alessia ; Portmann, Reto ; Andres Lacueva, Cristina ; Badertscher, René ; Brennan, Lorraine ; Brunius, Carl ; Bub, Achim ; Capozzi, Francesco ; Cialiè Rosso, Marta ; Cordero, Chiara E. ; Daniel, Hannelore ; Durand, Stéphanie ; Egert, Bjoern ; Ferrario, Paola G. ; Feskens, Edith J.M. ; Franceschi, Pietro ; Garcia-Aloy, Mar ; Giacomoni, Franck ; Giesbertz, Pieter ; González-Domínguez, Raúl ; Hanhineva, Kati ; Hemeryck, Lieselot Y. ; Kopka, Joachim ; Kulling, Sabine E. ; Llorach, Rafael ; Manach, Claudine ; Mattivi, Fulvio ; Migné, Carole ; Münger, Linda H. ; Ott, Beate ; Picone, Gianfranco ; Pimentel, Grégory ; Pujos-Guillot, Estelle ; Riccadonna, Samantha ; Rist, Manuela J. ; Rombouts, Caroline ; Rubert, Josep ; Skurk, Thomas ; Sri Harsha, Pedapati S.C. ; Meulebroek, Lieven Van; Vanhaecke, Lynn ; Vázquez-Fresno, Rosa ; Wishart, David ; Vergères, Guy - \ 2018
    Molecular Nutrition & Food Research 63 (2018)1. - ISSN 1613-4125
    GC–MS - LC–MS - metabolomics - NMR - nutrition
    The life sciences are currently being transformed by an unprecedented wave of developments in molecular analysis, which include important advances in instrumental analysis as well as biocomputing. In light of the central role played by metabolism in nutrition, metabolomics is rapidly being established as a key analytical tool in human nutritional studies. Consequently, an increasing number of nutritionists integrate metabolomics into their study designs. Within this dynamic landscape, the potential of nutritional metabolomics (nutrimetabolomics) to be translated into a science, which can impact on health policies, still needs to be realized. A key element to reach this goal is the ability of the research community to join, to collectively make the best use of the potential offered by nutritional metabolomics. This article, therefore, provides a methodological description of nutritional metabolomics that reflects on the state-of-the-art techniques used in the laboratories of the Food Biomarker Alliance (funded by the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL)) as well as points of reflections to harmonize this field. It is not intended to be exhaustive but rather to present a pragmatic guidance on metabolomic methodologies, providing readers with useful “tips and tricks” along the analytical workflow.
    Age and Sex Effects on Plasma Metabolite Association Networks in Healthy Subjects
    Vignoli, Alessia ; Tenori, Leonardo ; Luchinat, Claudio ; Saccenti, Edoardo - \ 2018
    Journal of Proteome Research 17 (2018)1. - ISSN 1535-3893 - p. 97 - 107.
    differential network analysis - metabolism - metabolomics - network inference - NMR
    In the era of precision medicine, the analysis of simple information like sex and age can increase the potential to better diagnose and treat conditions that occur more frequently in one of the two sexes, present sex-specific symptoms and outcomes, or are characteristic of a specific age group. We present here a study of the association networks constructed from an array of 22 plasma metabolites measured on a cohort of 844 healthy blood donors. Through differential network analysis we show that specific association networks can be associated with sex and age: Different connectivity patterns were observed, suggesting sex-related variability in several metabolic pathways (branched-chain amino acids, ketone bodies, and propanoate metabolism). Reduction in metabolite hub connectivity was also found to be associated with age in both sex groups. Network analysis was complemented with standard univariate and multivariate statistical analysis that revealed age- and sex-specific metabolic signatures. Our results demonstrate that the characterization of metabolite-metabolite association networks is a promising and powerful tool to investigate the human phenotype at a molecular level.
    Disentangling hexaploid genetics : towards DNA-informed breeding for postharvest performance in chrysanthemum
    Geest, Geert van - \ 2017
    Wageningen University. Promotor(en): R.G.F. Visser, co-promotor(en): U. van Meeteren; P.F.P. Arens. - Wageningen : Wageningen University - ISBN 9789463436427 - 142
    chrysanthemum - plant breeding - postharvest quality - hexaploidy - polyploidy - quantitative trait loci - phenotypes - linkage mapping - metabolomics - polymorphism - dna - chrysanthemum - plantenveredeling - kwaliteit na de oogst - hexaploïdie - polyploïdie - loci voor kwantitatief kenmerk - fenotypen - koppelingskartering - metabolomica - polymorfisme - dna

    DNA-informed selection can strongly improve the process of plant breeding. It requires the detection of DNA polymorphisms, calculation of genetic linkage, access to reliable phenotypes and methods to detect genetic loci associated with phenotypic traits of interest. Cultivated chrysanthemum is an outcrossing hexaploid with an unknown mode of inheritance. This complicates the development of resources and methods that enable the detection of trait loci. Postharvest performance is an essential trait in chrysanthemum, but is difficult to measure. This makes it an interesting but challenging trait to phenotype and detect associated genetic loci. In this thesis I describe the development of resources and methods to enable phenotyping for postharvest performance, genetic linkage map construction and detection of quantitative trait loci in hexaploid chrysanthemum.

    Postharvest performance is a complicated trait because it is related to many different disorders that reduce quality. One of these disorders in chrysanthemum is disk floret degreening, which occurs after long storage. In chapter 2, we show that degreening can be prevented by feeding the flower heads with sucrose, suggesting carbohydrate starvation plays a role in the degreening process. To investigate the response to carbohydrate starvation of genotypes with different sensitivity to disk floret degreening, we investigated the metabolome of sugar-fed and carbohydrate-starved disk florets by 1H-NMR and HPAEC. We show that the metabolome is severely altered at carbohydrate starvation. In general, starvation results in an upregulation of amino acid and secondary metabolism. Underlying causes of genotypic differences explaining variation in disk floret degreening in the three investigated genotypes remained to be elucidated, but roles of regulation of respiration rate and camphor metabolism were posed as possible candidates.

    In chapter 3, disk floret degreening was found to be the most important postharvest disorder after 3 weeks of storage among 44 white chrysanthemum cultivars. To investigate the inheritance of disk floret degreening, we crossed two genotypes with opposite phenotypic values of both disk floret degreening and carbohydrate content to obtain a population segregating for disk floret degreening. To phenotype the cultivar panel and the bi-parental population precisely and in a high throughput manner, we developed a method that quantified colour of detached capitula over time. This method was validated with visual observations of disk floret degreening during vase life tests. In a subset of the bi-parental population we measured carbohydrate content of the disk florets at harvest. The amount of total carbohydrates co-segregated with sensitivity to degreening, which shows that the difference in disk floret degreening sensitivity between the parents could be explained by their difference in carbohydrate content. However, the correlation was rather weak, indicating carbohydrate content is not the only factor playing a role.

    In order to develop resources for DNA-informed breeding, one needs to be able to characterize DNA polymorphisms. In chapter 4, we describe the development of a genotyping array containing 183,000 single nucleotide polymorphisms (SNPs). These SNPs were acquired by sequencing the transcriptome of 13 chrysanthemum cultivars. By comparing the genomic dosage based on the SNP assay and the dosage as estimated by the read depth from the transcriptome sequencing data, we show that alleles are expressed conform the genomic dosage, which contradicts to what is often found in disomic polyploids. In line with this finding, we conclusively show that cultivated chrysanthemum exhibits genome-wide hexasomic inheritance, based on the segregation ratios of large numbers of different types of markers in two different populations.

    Tools for genetic analysis in diploids are widely available, but these have limited use for polyploids. In chapter 5, we present a modular software package that enables genetic linkage map construction in tetraploids and hexaploids. Because of the modularity, functionality for other ploidy levels can be easily added. The software is written in the programming language R and we named it polymapR. It can generate genetic linkage maps from marker dosage scores in an F1 population, while taking the following steps: data inspection and filtering, linkage analysis, linkage group assignment and marker ordering. It is the first software package that can handle polysomic hexaploid and partial polysomic tetraploid data, and has advantages over other polyploid mapping software because of its scalability and cross-platform applicability.

    With the marker dosage scores of the bi-parental F1 population from the genotyping array and the developed methods to perform linkage analysis we constructed an integrated genetic linkage map for the hexaploid bi-parental population described in chapter 3 and 4. We describe this process in chapter 6. With this integrated linkage map, we reconstructed the inheritance of parental haplotypes for each individual, and expressed this as identity-by-descent (IBD) probabilities. The phenotypic data on disk floret degreening sensitivity that was acquired as described in chapter 3, was used in addition to three other traits to detect quantitative trait loci (QTL). These QTL were detected based on the IBD probabilities of 1 centiMorgan intervals of each parental homologue. This enabled us to study genetic architecture by estimating the effects of each separate allele within a QTL on the trait. We showed that for many QTL the trait was affected by more than two alleles.

    In chapter 7, the findings in this thesis are discussed in the context of breeding for heterogeneous traits, the implications of the mode of inheritance for breeding and the advantages and disadvantages of polyploidy in crop breeding. In conclusion, this thesis provides in general a significant step for DNA-informed breeding in polysomic hexaploids, and for postharvest performance in chrysanthemum in particular.

    Dual herbivore attack and herbivore density affect metabolic profiles of Brassica nigra leaves
    Ponzio, Camille ; Papazian, Stefano ; Albrectsen, Benedicte R. ; Dicke, Marcel ; Gols, Rieta - \ 2017
    Plant, Cell & Environment 40 (2017)8. - ISSN 0140-7791 - p. 1356 - 1367.
    Brevicoryne brassicae - dual herbivory - induced defence - metabolomics - Pieris brassicae - 017-4026

    Plant responses to dual herbivore attack are increasingly studied, but effects on the metabolome have largely been restricted to volatile metabolites and defence-related non-volatile metabolites. However, plants subjected to stress, such as herbivory, undergo major changes in both primary and secondary metabolism. Using a naturally occurring system, we investigated metabolome-wide effects of single or dual herbivory on Brassica nigra plants by Brevicoryne brassicae aphids and Pieris brassicae caterpillars, while also considering the effect of aphid density. Metabolomic analysis of leaf material showed that single and dual herbivory had strong effects on the plant metabolome, with caterpillar feeding having the strongest influence. Additionally, aphid-density-dependent effects were found in both the single and dual infestation scenarios. Multivariate analysis revealed treatment-specific metabolomic profiles, and effects were largely driven by alterations in the glucosinolate and sugar pools. Our work shows that analysing the plant metabolome as a single entity rather than as individual metabolites provides new insights into the subcellular processes underlying plant defence against multiple herbivore attackers. These processes appear to be importantly influenced by insect density.

    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.

    Entropy-Based Network Representation of the Individual Metabolic Phenotype
    Saccenti, Edoardo ; Menichetti, Giulia ; Ghini, Veronica ; Remondini, Daniel ; Tenori, Leonardo ; Luchinat, Claudio - \ 2016
    Journal of Proteome Research 15 (2016)9. - ISSN 1535-3893 - p. 3298 - 3307.
    metabolite modules - metabolite-metabolite association networks - metabolomics - network multiplex

    We approach here the problem of defining and estimating the nature of the metabolite-metabolite association network underlying the human individual metabolic phenotype in healthy subjects. We retrieved significant associations using an entropy-based approach and a multiplex network formalism. We defined a significantly over-represented network formed by biologically interpretable metabolite modules. The entropy of the individual metabolic phenotype is also introduced and discussed.

    Metabolomics meets functional assays: coupling LC-MS and microfluidic cell-based receptor-ligand analyses
    Henquet, M.G.L. ; Roelse, M. ; Vos, R.C.H. de; Schipper, A. ; Polder, G. ; Ruijter, N.C.A. de; Hall, R.D. ; Jongsma, M.A. - \ 2016
    Metabolomics 12 (2016). - ISSN 1573-3882

    Metabolomics has become a valuable tool in many research areas. However, generating metabolomics-based biochemical profiles without any related bioactivity is only of indirect value in understanding a biological process. Therefore, metabolomics research could greatly benefit from tools that directly determine the bioactivity of the detected compounds.


    We aimed to combine LC–MS metabolomics with a cell based receptor assay. This combination could increase the understanding of biological processes and may provide novel opportunities for functional metabolomics.


    We developed a flow through biosensor with human cells expressing both the TRPV1, a calcium ion channel which responds to capsaicin, and the fluorescent intracellular calcium ion reporter, YC3.6. We have analysed three contrasting Capsicum varieties. Two were selected with contrasting degrees of spiciness for characterization by HPLC coupled to high mass resolution MS. Subsequently, the biosensor was then used to link individual pepper compounds with TRPV1 activity.


    Among the compounds in the crude pepper fruit extracts, we confirmed capsaicin and also identified both nordihydrocapsaicin and dihydrocapsaicin as true agonists of the TRPV1 receptor. Furthermore, the biosensor was able to detect receptor activity in extracts of both Capsicum fruits as well as a commercial product. Sensitivity of the biosensor to this commercial product was similar to the sensory threshold of a human sensory panel.


    Our results demonstrate that the TRPV1 biosensor is suitable for detecting bioactive metabolites. Novel opportunities may lie in the development of a continuous functional assay, where the biosensor is directly coupled to the LC–MS.
    Regulation of cucumber (Cucumis sativus) induced defence against the two-spotted spider mite (Tetranychus urticae
    He, J. - \ 2016
    Wageningen University. Promotor(en): Harro Bouwmeester; Marcel Dicke, co-promotor(en): Iris Kappers. - Wageningen : Wageningen University - ISBN 9789462576810 - 211
    cucumis sativus - cucumbers - induced resistance - plant pests - tetranychus urticae - mites - defence mechanisms - herbivore induced plant volatiles - herbivory - metabolomics - terpenoids - genomics - cucumis sativus - komkommers - geïnduceerde resistentie - plantenplagen - tetranychus urticae - mijten - verdedigingsmechanismen - herbivoor-geinduceerde plantengeuren - herbivorie - metabolomica - terpenen - genomica

    Plants have evolved mechanisms to combat herbivory. These mechanisms can be classified as direct defences which have a negative influence on the herbivores and indirect defence that attracts natural enemies of the attacking herbivores. Both direct and indirect defences can be constantly present or induced upon attack. This study, using cucumber (Cucumis sativus) and the two-spotted spider mite (Tetranychus urticae) as model, aimed to reveal the molecular mechanisms underlying the induced defence during herbivory, with emphasis on transcriptional changes and the involved TFs, the enzymatic function of the genes associated with volatile biosynthesis, and their promoters which regulate their expression.

    Big data dringen door in de tuinbouw. Naar een volledig begrip van plantgedrag en productkwaliteit
    Kierkels, T. ; Zedde, H.J. van de - \ 2015
    Onder Glas 12 (2015)11. - p. 24 - 25.
    tuinbouw - glastuinbouw - innovaties - landbouwkundig onderzoek - kunstmatige intelligentie - gewaskwaliteit - plantenveredeling - sorteren - kwaliteit - teeltsystemen - 3d analyse - metabolomica - genomica - transcriptomica - horticulture - greenhouse horticulture - innovations - agricultural research - artificial intelligence - crop quality - plant breeding - sorting - quality - cropping systems - 3d analysis - metabolomics - genomics - transcriptomics
    Vijftien onderzoeksgroepen van Wageningen UR hebben de handen ineengeslagen om te komen tot het beter meten, begrijpen en voorspellen van plantgedrag en productkwaliteit. Het vakgebied heet ‘Plant phenomics’ en maakt gebruik van innovatieve technieken en sensoren. Het doel is een betere beheersing van teelt- en veredelingsproces en productkwaliteit. Toepassingen voor de praktijk liggen nog vooral op het terrein van sorteren en automatische kwaliteitsbeoordeling.
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