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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Loss of transglutaminase 2 sensitizes for diet-induced obesity-related inflammation and insulin resistance due to enhanced macrophage c-Src signaling
Sághy, Tibor ; Köröskényi, Krisztina ; Hegedűs, Krisztina ; Antal, Miklós ; Bankó, Csaba ; Bacsó, Zsolt ; Papp, Attila ; Stienstra, Rinke ; Szondy, Zsuzsa - \ 2019
Cell Death & Disease 10 (2019)6. - ISSN 2041-4889

Transglutaminase 2 (TG2) is a multifunctional protein that promotes clearance of apoptotic cells (efferocytosis) acting as integrin β3 coreceptor. Accumulating evidence indicates that defective efferocytosis contributes to the development of chronic inflammatory diseases. Obesity is characterized by the accumulation of dead adipocytes and inflammatory macrophages in the adipose tissue leading to obesity-related metabolic syndrome. Here, we report that loss of TG2 from bone marrow-derived cells sensitizes for high fat diet (HFD)-induced pathologies. We find that metabolically activated TG2 null macrophages express more phospho-Src and integrin β3, unexpectedly clear dying adipocytes more efficiently via lysosomal exocytosis, but produce more pro-inflammatory cytokines than the wild type ones. Anti-inflammatory treatment with an LXR agonist reverts the HFD-induced phenotype in mice lacking TG2 in bone marrow-derived cells with less hepatic steatosis than in wild type mice proving enhanced lipid clearance. Thus it is interesting to speculate whether LXR agonist treatment together with enhancing lysosomal exocytosis could be a beneficial therapeutic strategy in obesity.

Enzyme promiscuity shapes adaptation to novel growth substrates
Guzmán, Gabriela I. ; Sandberg, Troy E. ; LaCroix, Ryan A. ; Nyerges, Ákos ; Papp, Henrietta ; Raad, Markus de; King, Zachary A. ; Hefner, Ying ; Northen, Trent R. ; Notebaart, Richard A. ; Pál, Csaba ; Palsson, Bernhard O. ; Papp, Balázs ; Feist, Adam M. - \ 2019
Molecular Systems Biology 15 (2019)4. - ISSN 1744-4292 - p. e8462 - e8462.
adaptive evolution - enzyme promiscuity - genome‐scale modeling - systems biology

Evidence suggests that novel enzyme functions evolved from low-level promiscuous activities in ancestral enzymes. Yet, the evolutionary dynamics and physiological mechanisms of how such side activities contribute to systems-level adaptations are not well characterized. Furthermore, it remains untested whether knowledge of an organism's promiscuous reaction set, or underground metabolism, can aid in forecasting the genetic basis of metabolic adaptations. Here, we employ a computational model of underground metabolism and laboratory evolution experiments to examine the role of enzyme promiscuity in the acquisition and optimization of growth on predicted non-native substrates in Escherichia coli K-12 MG1655. After as few as approximately 20 generations, evolved populations repeatedly acquired the capacity to grow on five predicted non-native substrates-D-lyxose, D-2-deoxyribose, D-arabinose, m-tartrate, and monomethyl succinate. Altered promiscuous activities were shown to be directly involved in establishing high-efficiency pathways. Structural mutations shifted enzyme substrate turnover rates toward the new substrate while retaining a preference for the primary substrate. Finally, genes underlying the phenotypic innovations were accurately predicted by genome-scale model simulations of metabolism with enzyme promiscuity.

Alternative developmental toxicity models for assessing the in vivo embryotoxicity of azoles
Dimopoulou, Myrto - \ 2018
Wageningen University. Promotor(en): B. van Ravenzwaay; A.H. Piersma, co-promotor(en): I.M.C.M. Rietjens. - Wageningen : Wageningen University - ISBN 9789463437318 - 198

The implementation of regulations for protecting both humans and the environment from potential chemical health hazards, as well as the increase of global pressure for reducing, refining and replacing animal experiments promote the development and application of alternatives to in vivo developmental toxicity studies. Due to the complexity of the reproductive cycle, combined in vitro approaches, focusing on morphological, molecular and toxicokinetic parameters, could better define the developmental toxicity of chemicals. In this thesis, azoles, which are a group of chemicals with antifungal activity, are under investigation. These compounds show marked differences in developmental toxicity potency and similarities with retinoic acid (RA)- related teratogenicity.

Chapter 1 of this thesis introduced information regarding the background of reproductive and developmental toxicology, including scientific concerns and the impact of past teratogenic outcomes on the society. For screening developmental teratogens, in vitro approaches have been proposed and successfully applied. Their combination may better mimic the in vivo embryo and, therefore, increase the accuracy in predicting possible developmental toxicants. Additional co-implementation of molecular approaches may give an insight in the mode of action underlying the observed effects. Azoles were selected in the present thesis due to evidence for possibly increasing developmental toxicity through dysregulating the balance of the RA pathways in the mammalian system. The chapter also described the objectives and outline of the research.

In chapter 2, we examined the time- dependent developmental effects in rat embryos exposed in vitro to flusilazole (FLU), and their link to RA mediated pathways. To this end, we assessed the effects of 4-hour exposure of whole embryo culture (WEC) embryos to 300μM FLU during four developmental time windows (0-4, 4-8, 24-28 and 44-48 h), evaluated morphological parameters, as well as expression and localization of five genes directly or indirectly linked with the RA pathway. A stage- specific gene expression response of cultured rat embryos exposed to FLU was detected, which preceded the development of morphologically observable malformations. During all the tested time windows, the most pronounced effect was observed in the regulation of RA-related genes. Therefore, it was concluded that such biomarkers can be employed as useful tools for early detection of possible teratogenic properties of compounds that belong to the triazole- group or of compounds with a similar teratogenic mode of action.

Chapter 3 provides mechanistic insight into the embryotoxicity of six azoles tested in the rat WEC. Here, we evaluated dose-dependent embryotoxicity of azoles in the rat WEC, calculating the concentration at which the total morphological score (TMS) is 10% decreased (ID10). For the azoles tested we compared the in vitro ID10 for embryotoxicity to the in vivo effective doses, while we also performed a comparative analysis for understanding the toxicological and pharmacological mode of action of azoles in the rat WEC at the level of the transcriptome. Functional analysis of differential gene expression after 4 hours exposure at the ID10 revealed regulation of the sterol biosynthesis pathway and embryonic development genes, dominated by genes in the RA pathway, albeit in a differential way. FLU, ketoconazole and triadimefon were the most potent compounds affecting the RA pathway, while in terms of regulation of sterol function, difenoconazole and ketoconazole showed the most pronounced effects. A similar analysis at the 24-hour time point indicated an additional time-dependent difference in the aforementioned pathways regulated by FLU. Strong in vivo embryotoxic azoles showed also an increased regulation of the RA pathway when tested in vitro. On the other hand, weak or non- embryotoxic azoles showed a non-significant effect on genes that belong in the RA pathway. These observations led us to the conclusion that the toxicological mode of action of azoles was mediated through the RA pathway. In summary, the rat WEC assay in combination with transcriptomics could add mechanistic insight into the embryotoxic potency ranking and functional efficacy of the tested compounds, showing Cyp26a1 and Cyp51 as leader biomarkers of the off- and on- target effects, respectively.

Similarly to the previous chapter, in chapter 4, the potency ranking of the majority of the twelve tested azoles obtained based on the TMS in the WEC assay was in agreement with the in vivo potency ranking. Additionally, our expanded transcriptomics data, including gene specific responses of twelve azoles tested at their ID10 in the rat WEC for 4 hours, confirmed the observations of chapter 3 with another set of azoles. Potent embryotoxicants in both in vivo and in vitro assays caused more pronounced effects on the dysregulation of RA- mediated genes. Furthermore, azoles with more pronounced effects on the sterol biosynthesis mediated pathway were tested at a higher concentration, but with the same level of effect (ID10). Due to the increased concentration needed for reaching the same level of morphological effects and the absence of RA-mediated pathway regulation, these azoles were considered as more favourable candidates for clinical and agricultural use. Focusing on monitoring the fungicidal activity of azoles, we also detected an increased sensitivity of the expression of Msmo1, which is an enzyme participating in converting lanosterol for synthesizing cholesterol in the mammalian sterol biosynthesis, together with Cyp51and Nsdhl. This observation led us to the conclusion that Msmo1 could be a better biomarker of effect on the sterol biosynthesis pathway compared to the classical biomarker of this pathway, Cyp51, and this may be of use for further improvement of the assessment of fungicidal activity of azoles or chemicals with similar mode of action.

Chapter 5 shows the value of combining toxico-dynamic and -kinetic in vitro approaches for embryotoxicity testing of azoles. We also report on the alterations in gene expression induced by azoles. Both the WEC assay and the embryonic stem cells test (EST) predicted the in vivo potency ranking of the twelve tested azoles with moderate accuracy. Combining these results with relative placental transfer rates (Papp values) as determined in the BeWo cell culture model, increased the predictability of both WEC and EST, with R2 values increasing from 0.51 to 0.87 and from 0.35 to 0.60, respectively. The comparison of these in vitro systems correlated well (R2 = 0.67), correctly identifying the strong and weak embryotoxicants. Evaluating specific gene responses related with the toxicological and fungicidal mode of action of the tested azoles in WEC and EST, we observed that the differential regulation of Dhrs3 and Msmo1 reached higher magnitudes in both systems compared to Cyp26a1 and Cyp51. Establishing sensitive biomarkers across all the in vitro systems for studying the underlying mechanism of action of chemicals, such as azoles, is valuable for comparing alternative in vitro models and for improving insight in the mechanism of developmental toxicity of chemicals.

Chapter 6 of this thesis presented the general discussion and future perspectives on different topics raised based on the results obtained in the previously described experimental chapters. The results suggested that the combination of in vitro assays for screening the developmental toxicity of azoles may lead to predictions that are more accurate and in agreement with the in vivo observations. The addition of toxico-kinetics, which the BeWo placental transfer model offered, notably improved the correlations of in vivo and in vitro data. Furthermore, the co- implementation of transcriptomics and the identification of gene biomarkers revealed that despite the tested azoles were classified in the same chemical group, they might have a different mode of toxicological action. In conclusion, future combination of in vitro and in silico alternative approaches appear to be of advantage for screening and prioritizing chemical testing, in the process of assessing the consequences of chemical exposure for human health and the environment.

A comparison of the embryonic stem cell test and whole embryo culture assay combined with the BeWo placental passage model for predicting the embryotoxicity of azoles
Dimopoulou, Myrto ; Verhoef, Aart ; Gomes, Caroline A. ; Dongen, Catharina W. van; Rietjens, Ivonne M.C.M. ; Piersma, Aldert H. ; Ravenzwaay, Bennard van - \ 2018
Toxicology Letters 286 (2018). - ISSN 0378-4274 - p. 10 - 21.
Azoles - Biomarkers - Embryotoxicity - Placental transfer - Stem cell test - Whole embryo culture
In the present study, we show the value of combining toxico-dynamic and -kinetic in vitro approaches for embryotoxicity testing of azoles. Both the whole embryo culture (WEC) and the embryonic stem cells test (EST) predicted the in vivo potency ranking of twelve tested azoles with moderate accuracy. Combining these results with relative placental transfer rates (Papp values) as determined in the BeWo cell culture model, increased the predictability of both WEC and EST, with R2 values increasing from 0.51 to 0.87 and from 0.35 to 0.60, respectively. The comparison of these in vitro systems correlated well (R2 = 0.67), correctly identifying the in vivo strong and weak embryotoxicants. Evaluating also specific gene responses related with the retinoic acid and sterol biosynthesis pathways, which represent the toxicological and fungicidal mode of action of azoles respectively in the WEC and EST, we observed that the differential regulation of Dhrs3 and Msmo1 reached higher magnitudes in both systems compared to Cyp26a1 and Cyp51. Establishing sensitive biomarkers across the in vitro systems for studying the underlying mechanism of action of chemicals, such as azoles, is valuable for comparing alternative in vitro models and for improving insight in the mechanism of developmental toxicity of chemicals.
Underground metabolism : network-level perspective and biotechnological potential
Notebaart, Richard A. ; Kintses, Bálint ; Feist, Adam M. ; Papp, Balázs - \ 2018
Current Opinion in Biotechnology 49 (2018). - ISSN 0958-1669 - p. 108 - 114.
A key challenge in molecular systems biology is understanding how new pathways arise during evolution and how to exploit them for biotechnological applications. New pathways in metabolic networks often evolve by recruiting weak promiscuous activities of pre-existing enzymes. Here we describe recent systems biology advances to map such ‘underground’ activities and to predict and analyze their contribution to new metabolic functions. Underground activities are prevalent in cellular metabolism and can form novel pathways that either enable evolutionary adaptation to new environments or provide bypass to genetic lesions. We also illustrate the potential of integrating computational models of underground metabolism and experimental approaches to study the evolution of novel metabolic phenotypes and advance the field of biotechnology.
Finding needles in haystacks: linking scientific names, reference specimens and molecular data for Fungi
Schoch, C.L. ; Robbertse, B. ; Robert, V. ; Vu, D. ; Cardinali, G. ; Irinyi, L. ; Meyer, W. ; Nilsson, R.H. ; Hughes, K. ; Miller, A.N. ; Kirk, P.M. ; Abarenkov, K. ; Aime, M.C. ; Ariyawansa, H.A. ; Bidartondo, M. ; Boekhout, T. ; Buyck, B. ; Cai, Q. ; Chen, J. ; Crespo, A. ; Crous, P.W. ; Damm, U. ; Beer, Z.W. de; Dentinger, B.T.M. ; Divakar, P.K. ; Duenas, M. ; Feau, N. ; Fliegerova, K. ; Garcia, M.A. ; Ge, Z.W. ; Griffith, G.W. ; Groenewald, J.Z. ; Groenewald, M. ; Grube, M. ; Gryzenhout, M. ; Gueidan, C. ; Guo, L. ; Hambleton, S. ; Hamelin, R. ; Hansen, K. ; Hofstetter, V. ; Hong, S.B. ; Houbraken, J. ; Hyde, K.D. ; Inderbitzin, P. ; Johnston, P.A. ; Karunarathna, S.C. ; Koljalg, U. ; Kovacs, G.M. ; Kraichak, E. ; Krizsan, K. ; Kurtzman, C.P. ; Larsson, K.H. ; Leavitt, S. ; Letcher, P.M. ; Liimatainen, K. ; Liu, J.K. ; Lodge, D.J. ; Luangsa-ard, J.J. ; Lumbsch, H.T. ; Maharachchikumbura, S.S.N. ; Manamgoda, D. ; Martin, M.P. ; Minnis, A.M. ; Moncalvo, J.M. ; Mule, G. ; Nakasone, K.K. ; Niskanen, T. ; Olariaga, I. ; Papp, T. ; Petkovits, T. ; Pino-Bodas, R. ; Powell, M.J. ; Raja, H.A. ; Redecker, D. ; Sarmiento-Ramirez, J.M. ; Seifert, K.A. ; Shrestha, B. ; Stenroos, S. ; Stielow, B. ; Suh, S.O. ; Tanaka, K. ; Tedersoo, L. ; Telleria, M.T. ; Udayanga, D. ; Untereiner, W.A. ; Dieguez Uribeondo, J. ; Subbarao, K.V. ; Vagvolgyi, C. ; Visagie, C. ; Voigt, K. ; Walker, D.M. ; Weir, B.S. ; Weiss, M. ; Wijayawardene, N.N. ; Wingfield, M.J. ; Xu, J.P. ; Yang, Z.L. ; Zhang, N. ; Zhuang, W.Y. ; Federhen, S. - \ 2014
Database : the Journal of Biological Databases and Curation 2014 (2014). - ISSN 1758-0463 - 21 p.
internal transcribed spacer - arbuscular mycorrhizal fungi - ribosomal dna - interspecific hybridization - sequence analyses - species complex - identification - evolution - barcode - life
DNA phylogenetic comparisons have shown that morphology-based species recognition often underestimates fungal diversity. Therefore, the need for accurate DNA sequence data, tied to both correct taxonomic names and clearly annotated specimen data, has never been greater. Furthermore, the growing number of molecular ecology and microbiome projects using high-throughput sequencing require fast and effective methods for en masse species assignments. In this article, we focus on selecting and re-annotating a set of marker reference sequences that represent each currently accepted order of Fungi. The particular focus is on sequences from the internal transcribed spacer region in the nuclear ribosomal cistron, derived from type specimens and/or ex-type cultures. Re-annotated and verified sequences were deposited in a curated public database at the National Center for Biotechnology Information (NCBI), namely the RefSeq Targeted Loci (RTL) database, and will be visible during routine sequence similarity searches with NR_prefixed accession numbers. A set of standards and protocols is proposed to improve the data quality of new sequences, and we suggest how type and other reference sequences can be used to improve identification of Fungi.
Control of the pattern-recognition receptor EFR by an ER protein complex in plant immunity
Nekrasov, V. ; Li, J. ; Batoux, M. ; Roux, M. ; Chu, Z.H. ; Lacombe, S. ; Rougon, A. ; Bittel, P. ; Kiss-Papp, M. ; Chinchilla, D. ; Esse, H.P. van; Jorda, L. ; Schwessinger, B. ; Nicaise, V. ; Thomma, B.P.H.J. ; Molina, A. ; Jones, J.D.G. ; Zipfel, C. - \ 2009
The EMBO Journal 28 (2009)21. - ISSN 0261-4189 - p. 3428 - 3438.
agrobacterium-mediated transformation - defective brassinosteroid receptor - endoplasmic-reticulum - innate immunity - quality-control - pseudomonas-syringae - arabidopsis-thaliana - disease resistance - secretory pathway - flagellin perception
In plant innate immunity, the surface-exposed leucine-rich repeat receptor kinases EFR and FLS2 mediate recognition of the bacterial pathogen-associated molecular patterns EF-Tu and flagellin, respectively. We identified the Arabidopsis stromal-derived factor-2 (SDF2) as being required for EFR function, and to a lesser extent FLS2 function. SDF2 resides in an endoplasmic reticulum (ER) protein complex with the Hsp40 ERdj3B and the Hsp70 BiP, which are components of the ER-quality control (ER-QC). Loss of SDF2 results in ER retention and degradation of EFR. The differential requirement for ER-QC components by EFR and FLS2 could be linked to N-glycosylation mediated by STT3a, a catalytic subunit of the oligosaccharyltransferase complex involved in co-translational N-glycosylation. Our results show that the plasma membrane EFR requires the ER complex SDF2-ERdj3B-BiP for its proper accumulation, and provide a demonstration of a physiological requirement for ER-QC in transmembrane receptor function in plants. They also provide an unexpected differential requirement for ER-QC and N-glycosylation components by two closely related receptors
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