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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    Versnellen in de beroepskolom : Onderzoek naar de versnelde doorlopende leerroutes Talentontwikkeling Techniek en het Groene Lyceum
    Meijden, A. van der; Biemans, H.J.A. ; Mariën, H. ; Klatter, Ellen ; Harbers, J. ; Oprel, Carla ; Kreutz, Frank ; Margereij, Linda ; Schooten, Erik van; Boogaard, Marianne ; Diggelen, Wouter van - \ 2020
    Amsterdam : Kohnstamm Instituut - ISBN 9789463211208
    Machine learning for large-scale crop yield forecasting
    Paudel, D.R. ; Boogaard, H.L. ; Wit, A.J.W. de; Janssen, S.J.C. ; Osinga, S.A. ; Pylianidis, C. ; Athanasiadis, I.N. - \ 2020
    Agricultural Systems 187 (2020). - ISSN 0308-521X
    Crop yield prediction - Machine learning - Modularity - Reusability - Large-scale crop yield forecasting
    Many studies have applied machine learning to crop yield prediction with a focus on specific case studies. The data and methods they used may not be transferable to other crops and locations. On the other hand, operational large-scale systems, such as the European Commission's MARS Crop Yield Forecasting System (MCYFS), do not use machine learning. Machine learning is a promising method especially when large amounts of data are being collected and published. We combined agronomic principles of crop modeling with machine learning to build a machine learning baseline for large-scale crop yield forecasting. The baseline is a workflow emphasizing correctness, modularity and reusability. For correctness, we focused on designing explainable predictors or features (in relation to crop growth and development) and applying machine learning without information leakage. We created features using crop simulation outputs and weather, remote sensing and soil data from the MCYFS database. We emphasized a modular and reusable workflow to support different crops and countries with small configuration changes. The workflow can be used to run repeatable experiments (e.g. early season or end of season predictions) using standard input data to obtain reproducible results. The results serve as a starting point for further optimizations. In our case studies, we predicted yield at regional level for five crops (soft wheat, spring barley, sunflower, sugar beet, potatoes) and three countries (the Netherlands (NL), Germany (DE), France (FR)). We compared the performance with a simple method with no prediction skill, which either predicted a linear yield trend or the average of the training set. We also aggregated the predictions to the national level and compared with past MCYFS forecasts. The normalized RMSE (NRMSE) for early season predictions (30 days after planting) were comparable for NL (all crops), DE (all except soft wheat) and FR (soft wheat, spring barley, sunflower). For example, NRMSE was 7.87 for soft wheat (NL) (6.32 for MCYFS) and 8.21 for sugar beet (DE) (8.79 for MCYFS). In contrast, NRMSEs for soft wheat (DE), sugar beet (FR) and potatoes (FR) were twice as much compared to MCYFS. NRMSEs for end of season were still comparable to MCYFS for NL, but worse for DE and FR. The baseline can be improved by adding new data sources, designing more predictive features and evaluating different machine learning algorithms. The baseline will motivate the use of machine learning in large-scale crop yield forecasting.
    A High Glycemic Burden Relates to Functional and Metabolic Alterations of Human Monocytes in Patients with Type 1 Diabetes
    Thiem, Kathrin ; Dierendonck, Xanthe A.M.H. van; Janssen, Anna W.M. ; Boogaard, Joline P. ; Riksen, Niels P. ; Tack, Cees J. ; Stienstra, Rinke - \ 2020
    Diabetes 69 (2020)12. - ISSN 0012-1797 - p. 2735 - 2746.
    Diabetes mellitus is associated with increased cardiovascular risk and higher occurrence of infections. These complications suggest altered responses of the innate immune system. Recent studies have shown that energy metabolism of monocytes is crucial in determining their functionality. Here we investigate whether monocyte metabolism and function are changed in patients with diabetes and aim to identify diabetes-associated factors driving these alterations. Patients with type 1 diabetes (T1D) (n=41) and healthy age-, sex- and BMI-matched controls (n=20) were recruited. Monocytes were isolated from peripheral blood to determine immune functionality, metabolic responses and transcriptome profile. Upon ex vivo stimulation with TLR-4 or TLR-2 agonists, monocytes of patients with T1D secreted lower levels of various cytokines and showed lower glycolytic rates in comparison to monocytes isolated from matched controls. Stratification based on HbA1c levels revealed that lower cytokine secretion was coupled to higher glycolytic rate of monocytes in patients with higher glycemic burden. Circulating monocytes displayed an enhanced inflammatory gene expression profile associated with high glycemic burden. These results suggest that a high glycemic burden in patients with T1D is related to expression of inflammatory genes of monocytes and is associated with an impaired relationship between metabolism and inflammatory function upon activation.
    Functional analysis of the baculovirus per os infectivity factors 3 and 9 by imaging the interaction between fluorescently labelled virions and isolated midgut cells
    Boogaard, Bob ; Lent, Jan W.M. van; Oers, Monique M. van - \ 2020
    Journal of General Virology 101 (2020)7. - ISSN 0022-1317 - p. 778 - 784.
    AcMNPV - baculovirus - life imaging - membrane fusion - occlusion derived virus - Per os infectivity

    Baculovirus occlusion-derived viruses (ODVs) contain ten known per os infectivity factors (PIFs). These PIFs are crucial for midgut infection of insect larvae and form, with the exception of PIF5, an ODV entry complex. Previously, R18-dequenching assays have shown that PIF3 is dispensable for binding and fusion with midgut epithelial cells. Oral infection nevertheless fails in the absence of PIF3. PIF9 has not been analysed in much depth yet. Here, the biological role of these two PIFs in midgut infection was examined by monitoring the fate of fluorescently labelled ODVs when incubated with isolated midgut cells from Spodoptera exigua larvae. Confocal microscopy showed that in the absence of either PIF3 or PIF9, the ODVs bound to the brush borders, but the nucleocapsids failed to enter the cells. Finally, we discuss how the results obtained for PIF3 with dequenching assays and confocal microscopy can be explained by a two-phase fusion process.

    An African perspective on African problems
    Boogaard, Birgit - \ 2020
    The C-Termini of the baculovirus per os infectivity factors 1 and 2 mediate ODV oral infectivity by facilitating the binding of PIF0 and PIF8 to the core of the entry complex
    Boogaard, Bob ; Ortega Murillo, Fabiola D. ; Sminia, Alexander L. ; Theilmann, David A. ; Lent, Jan W.M. Van; Oers, Monique M. Van - \ 2020
    Journal of General Virology 101 (2020)5. - ISSN 0022-1317 - p. 553 - 564.
    AcMNPV. - Baculovirus - Oral Infectivity - PIF - PIF complex

    Oral infection of caterpillars by baculoviruses is initiated by occlusion-derived virus particles (ODVs) that infect midgut epithelium cells. The ODV envelope therefore contains at least ten different proteins, which are called per os infectivity factors (PIFs). Nine of these PIFs form the so-called ODV entry complex that consists of a stable core formed by PIF1, 2, 3 and 4, to which the other PIFs [PIF0, 6, 7, 8 and 9 (ac108)] bind with lower affinity. PIF1 and 2 are not only essential for complex formation, but also mediate ODV-binding to the epithelial brush border, probably via the C-Termini. To study the involvement of these PIFs during midgut infection in greater detail, we assessed the oral infectivity and the ability to form the complex of a series of PIF1 and PIF2 C-Terminal truncation mutants of Autographa californica multiple nucleopolyhedrovirus (AcMNPV), which were constructed in this study. Limited truncation of either PIF1 or 2 already severely impaired the ODV oral infectivity, but did not affect the formation of the core complex. However, the entry complex as a whole was not assembled in these mutants as PIF0 and 8 failed to bind to the core. This suggests that the interactions between the core and the loosely associated PIFs are important for the ODV infectivity and that complex formation complicates the determination of the exact roles of PIF1 and 2 during midgut infection. We also showed that the presence of PIF0, 6 and the ZF-domain of PIF8 are crucial for complex formation.

    System description of the WOFOST 7.2, cropping systems model
    Wit, A.J.W. de; Boogaard, H.L. ; Supit, I. ; Berg, M. van den - \ 2020
    Wageningen Environmental Research - 112 p.
    Robust node detection and tracking in fruit-vegetable crops using deep learning and multi-view imaging
    Boogaard, Frans P. ; Rongen, Kamiel S.A.H. ; Kootstra, Gert W. - \ 2020
    Biosystems Engineering 192 (2020). - ISSN 1537-5110 - p. 117 - 132.
    Deep learning - Digital plant phenotyping - Internode length - Multi-view imaging - Tracking node development

    Obtaining high-quality phenotypic data that can be used to study the relationship between genotype, phenotype and environment is still labour-intensive. Digital plant phenotyping can assist in collecting these data by replacing human vision by computer vision. However, for complex traits, such as plant architecture, robust and generic digital phenotyping methods have not yet been developed. This study focusses on internode length in cucumber plants. A method for estimating internode length and internode development over time is proposed. The proposed method firstly applies a robust node-detection algorithm based on a deep convolutional neural network. In tests, the algorithm had a precision of 0.95 and a recall of 0.92. The nodes are detected in images from multiple viewpoints around the plant in order to deal with the complex and cluttered plant environment and to solve the occlusion of nodes by other plant parts. The nodes detected in the multiple viewpoint images are then clustered using affinity propagation. The predicted clusters had a homogeneity of 0.98 and a completeness of 0.99. Finally, a linear function is fitted, which allows to study internode development over time. The presented method was able to measure internode length in cucumber plants with a higher accuracy and a larger temporal resolution than other methods proposed in literature and without the time investment needed to obtain the measurements manually. The relative error of our complete method was 5.8%. The proposed method provides many opportunities for robust phenotyping of fruit-vegetable crops grown under greenhouse conditions.

    WISS a Java Continuous Simulation Framework for Agro-Ecological Modelling
    Kraalingen, D.W.G. van; Knapen, Rob M.J. ; Wit, A. de; Boogaard, H.L. - \ 2020
    In: International Symposium on Environmental Software Systems (ISESS 2020) In: International Symposium on Environmental Software Systems (ISESS 2020). - Wageningen : Springer (IFIP Advances in Information and Communication Technology ) - ISBN 9783030398149 - p. 242 - 248.
    A simulation framework is presented (WISS, Wageningen Integrated Systems Simulator) which targets the agro-ecological modelling domain. Especially simulation for a large number of locations, such as in detailed regional and global simulation studies. The framework strengths are in modularization, control, speed, robustness and computational protection (multiple system checks during simulation). The WOFOST model is currently implemented in WISS, through which it is used in a number of Wageningen University and Research projects. WISS is written in Java and the framework code is freely available.
    In vitro metabolism of naphthalene and its alkylated congeners by human and rat liver microsomes via alkyl side chain or aromatic oxidation
    Wang, Danlei ; Bruyneel, Ben ; Kamelia, Lenny ; Wesseling, Sebastiaan ; Rietjens, Ivonne M.C.M. ; Boogaard, Peter J. - \ 2020
    Chemico-Biological Interactions 315 (2020). - ISSN 0009-2797
    Alkylated naphthalene - Human - Michaelis-menten kinetics - Microsomes - Rat

    Mineral oils are wide applied in food production and processing and may contain polycyclic aromatic hydrocarbons (PAHs). The PAHs that may be present in mineral oils are typically alkylated, and have been barely studied. Metabolic oxidation of the aromatic ring is a key step to form DNA-reactive PAH metabolites, but may be less prominent for alkylated PAHs since alkyl substituents would facilitate side chain oxidation as an alternative. The current study investigates this hypothesis of preferential side chain oxidation at the cost of aromatic oxidation using naphthalene and a series of its alkyl substituted analogues as model compounds. The metabolism was assessed by measuring metabolite formation in rat and human liver microsomal incubations using UPLC and GC-MS/MS. The presence of an alkyl side chain markedly reduced aromatic oxidation for all alkyl-substituted naphthalenes that were converted. 1-n-Dodecyl-naphthalene was not metabolized under the experimental conditions applied. With rat liver microsomes for 1-methyl-, 2-methyl-, 1-ethyl-, and 2-ethyl- naphthalene, alkyl side chain oxidation was preferred over aromatic oxidation. With human liver microsomes this was the case for 2-methyl-, and 2-ethyl-naphthalene. It is concluded that addition of an alkyl substituent in naphthalene shifts metabolism in favor of alkyl side chain oxidation at the cost of aromatic ring oxidation. Furthermore, alkyl side chains of 6 or more carbon atoms appeared to seriously hamper and reduce overall metabolism, metabolic conversion being no longer observed with the C12 alkyl side chain. In summary, alkylation of PAHs likely reduces their chances of aromatic oxidation and bioactivation.

    Baculovirus per os infectivity : a complex matter
    Boogaard, Bob - \ 2020
    Wageningen University. Promotor(en): M.M. van Oers, co-promotor(en): J.W.M. van Lent. - Wageningen : Wageningen University - ISBN 9789463952132 - 159

    Insect larvae are infected by baculoviruses when they consume plant material that is contaminated with occlusion bodies (OBs). OBs are polyhedral shaped particles of crystallized protein (polyhedrin or granulin), in which the occlusion derived viruses (ODVs) are embedded. Upon ingestion of the OBs, the ODVs are released in the alkaline lumen of the midgut and infect the midgut epithelial cells. To be infectious for these cells under alkaline conditions, the ODV envelope contains a set of proteins, which are called per os infectivity factors or PIFs. Eight different PIFs had been identified at the start of this research, of which six were known to participate in the formation of a large complex: the ODV entry complex. Presently, ten different PIFs are known, of which nine form the entry complex. This complex has a stable core that is formed by PIF1 to 4, which even resists treatment with denaturing and reducing agents (SDS and β-mercaptoethanol), and five additional PIFs (PIF0 and PIF6 to 9), which are associated to the complex more loosely. All these individual components are essential for complex formation. PIF5 is the only PIF-protein that is not a constituent of the entry complex.  

    Our initial studies with pif deletion mutant viruses were hampered by the disappearance of not only the targeted, but also non-targeted PIFs, when the OBs were produced in insect larvae, while the various PIFs were all detectable for  the wild type virus. However, those remaining PIFs were found again in these mutant viruses when the larval derived OBs were treated with heat prior to ODV isolation, or when the OBs were produced in cultured insect cells. These observations showed that proteases from the host, which had been reported to be co-occluded in the OBs, are able to degrade PIF proteins when complex formation is disrupted, as was the case in the various pif deletion mutant viruses. These observations provided a first clue on why the PIFs form a complex, which might be important to resist proteolytic degradation by proteases in the gut of the host.

    Previous research in our laboratory had identified viral protein AC108 as a PIF1 interaction partner in a co-immunoprecipitation study, indicating that this protein might be involved in oral infectivity as well. The research presented in this thesis demonstrated that mutation of the ac108 gene from the viral genome completely abolished the oral infectivity of ODVs, which was recovered when this gene was repaired. Further protein analyses revealed that AC108 is a loosely associated but nevertheless an essential component of the ODV entry complex. This protein was therefore designated as PIF9.

    The biological function of PIF9 was further investigated by the generation of fluorescently labelled ODVs of the pif9 mutant. These virus particles were then combined with isolated midgut cells of Spodoptera exigua larvae and monitored by confocal microscopy in a time lapse experiment. It was observed that in absence of PIF9, the ODVs still bind to the midgut cell brush border, but that the nucleocapsids failed to enter the cell, in contrast to fluorescent ODVs that have all PIFs. Fluorescent ODVs were also generated for a pif3 deletion mutant as it had been shown previously by others that this (complex deficient) mutant is able to bind and fuse with the host cell plasma membrane as the wild type virus, but nevertheless fails to establish a midgut infection. Our analysis with the confocal microscope showed that this mutant displays the same phenotype as the pif9 deletion mutant virus: ODV binding, but no entry of the nucleocapsids. We therefore proposed a two-step fusion process, in which first the outer leaflets of the lipid bilayers fuse and subsequently the inner leaflets. PIF3 might be important to complete the fusion process by aiding fusion of the inner leaflets of the lipid bilayers.  

    PIF1 and 2 had been reported to be important for ODV binding and were later also shown to be crucial for the formation of the ODV entry complex. Furthermore, ODV binding had been shown to be one of the viral host range determinants and as most baculoviruses have a narrow host range, we hypothesized that the more variable C-terminal parts of PIF1 and 2 are important for host interaction, while the highly conserved N-terminal parts are needed for complex formation. However, limited C-terminal truncation of either PIF1 or 2 abolished formation of the entry complex as PIF0 and 8 failed to bind the stable core in the truncation mutants. The lost ability to form the entry complex in the truncation mutants was accompanied by a severely hampered oral infectivity in S. exigua larvae. Some larvae incidentally got infected by one of the truncation mutants despite abolished complex formation. It was therefore speculated that although the ODV entry complex is the main determinant for the infectivity of ODVs, additional factors are present in the ODV that is able to incidentally cause infections in absence of the entry complex.

    To determine the context in which the PIFs function, the interaction partners were mapped of three loosely associated components of the entry complex (PIF6, 8 and 9) and the single solitary PIF, PIF5. These analyses revealed that the PIFs interact with a plethora of viral proteins with a wide variety of functions, from nucleocapsid assembly to OB formation. PIF5 also interacted with two components of the entry complex, PIF0 and 1. This indicated that PIF0 and 1 are not only present in the ODV envelope as part of the entry complex, but also occur outside the complex where these proteins interact with PIF5. This study shows that the PIFs not only interact with each other to form the entry complex, but are part of a network of protein interactions in ODVs. The biological significance of these interactions for midgut infection remains enigmatic.

    The role of metabolism in the developmental toxicity of polycyclic aromatic hydrocarbon-containing extracts of petroleum substances
    Kamelia, Lenny ; Haan, Laura de; Spenkelink, Bert ; Bruyneel, Ben ; Ketelslegers, Hans B. ; Boogaard, Peter J. ; Rietjens, Ivonne M.C.M. - \ 2020
    Journal of Applied Toxicology 40 (2020)3. - ISSN 0260-437X - p. 330 - 341.
    biotransformation - embryonic stem cell test - petroleum substances - polycyclic aromatic hydrocarbons - prenatal developmental toxicity - UVCBs

    In vitro assays presently used for prenatal developmental toxicity (PDT) testing only assess the embryotoxic potential of parent substances and not that of potentially embryotoxic metabolites. Here we combined a biotransformation system, using hamster liver microsomes, with the ES-D3 cell differentiation assay of the embryonic stem cell test (EST) to compare the in vitro PDT potency of two 5-ring polycyclic aromatic hydrocarbons (PAHs), benzo[a]pyrene (BaP) and dibenz[a,h]anthracene (DBA), and dimethyl sulfoxide extracts from five PAH-containing petroleum substances (PS) and a gas-to-liquid base oil (GTLb), with and without bioactivation. In the absence of bioactivation, DBA, but not BaP, inhibited the differentiation of ES-D3 cells into beating cardiomyocytes in a concentration-dependent manner. Upon bioactivation, BaP induced in vitro PDT, while its major metabolite 3-hydroxybenzo[a]pyrene was shown to be active in the EST as well. This means BaP needs biotransformation to exert its embryotoxic effects. GTLb extracts tested negative in the EST, with and without bioactivation. The PS-induced PDT in the EST was not substantially changed following bioactivation, implying that metabolism may not play a crucial role for the PS extracts under study to exert the in vitro PDT effects. Altogether, these results indicate that although some PAH require bioactivation to induce PDT, some do not and this latter appears to hold for the (majority of) the PS constituents responsible for the in vitro PDT of these complex substances.

    Minimum emission pathways to triple Africa’s cereal production by 2050
    Ittersum, M.K. van; Hijbeek, R. ; Berge, H.F.M. ten; Loon, M.P. van; Boogaard, H.L. ; Tesfaye, Kindie - \ 2019
    CCAFS - 5 p.
    This info note summarizes results of three recent studies that assessed whether SSA can be self-sufficient in cereals by 2050 under different scenarios of intensification on existing cereal area. For each scenario,yield increases and area expansion to meet cereal demand by 2050 were assessed. Increased demands for fertiliser use and associated GHG emissions were quantified.
    Vulnerability and adaptation options to climate change for rural livelihoods - a country-wide analysis for Uganda
    Ittersum, M.K. van; Hijbeek, R. ; Berge, H.F.M. ten; Loon, M.P. van; Boogaard, H.L. ; Tesfaye, Kindie - \ 2019
    Wageningen : Farming Systems Ecology, Wageningen UR / CIMMYT - 5 p.
    Monitoring SDG2 with Global Yield Gap Atlas
    Ittersum, M.K. van; Boogaard, H.L. - \ 2019
    Sustainable Development Solutions Network (SDSN)
    The relevance of connecting sustainable agricultural development with African philosophy
    Boogaard, Birgit K. - \ 2019
    South African Journal of Philosophy 38 (2019)3. - ISSN 0258-0136 - p. 273 - 286.
    Our global food system is complex and philosophers can – or should – pose critical questions about it. One question that deserves particular attention is Western interference in agricultural development in Africa. To today, the Western scientific paradigm forms the basis for mainstream agricultural research and development – with a firm belief in technological solutions and economic progress. It is concerning that African philosophy is a largely unknown field among agricultural scientists and practitioners. The aim of this philosophical essay is therefore to explore the relevance of connecting sustainable agricultural development with African philosophy. The article explores Eurocentric thinking in agricultural research and development and why such thinking can be problematic. In a search for ways to respond to Eurocentrism, I follow Kimmerle, who engaged in intercultural dialogues between African and Western philosophies. Mutually respectful and transformative dialogues can lead to mutual understanding and a more equal relation between Africa and the West, in the sense that this relation becomes more open to African philosophies and less Eurocentric.
    The role of polycyclic aromatic hydrocarbons in developmental toxicity of petroleum substances
    Kamelia, Lenny - \ 2019
    Wageningen University. Promotor(en): I.M.C.M. Rietjens; P.J. Boogaard. - Wageningen : Wageningen University - ISBN 9789463950619 - 287
    cum laude

    REACH requires prenatal developmental toxicity (PDT) testing for substances registered in the EU at a volume of ≥100 tonnes/year. One of the consequences is that many petroleum substances (PS) will need to be tested for their potential adverse effect on prenatal development according to the current OECD 414 testing guidelines. This will involve a huge number of experimental animals and a considerable amount of resources. Therefore, the application of in vitro alternative testing strategies may reduce the animal experimentation and resources needed to study PDT potencies of PS. Furthermore, since some PS with high concentrations of polycyclic aromatic hydrocarbons (PAH) may induce PDT whilst their gas-to-liquid (GTL) analogues, which are synthetic products completely devoid of aromatics, do not induce PDT, it was hypothesized that PDT observed for some PS is caused by certain types of PAH in these products. This hypothesis was tested in the present thesis using a battery of in vitro alternative assays.

    Chapter 1 provided background information and presented the aim of the thesis. In addition, the selected test substances and in vitro alternative assays used in the present thesis were also introduced. In total, 19 samples derived from 6 PS and 2 GTL product categories were tested. These samples were selected because i) they represent a series with a systematic variation in PAH content, being substances containing a range of 3- to 7-ring PAHs including extremes regarding their PAH content (with and without PAHs) and ii) in vivo PDT data for these product categories were available, enabling in vitro-in vivo comparisons. The selected in vitro alternative assays were presented, including the embryonic stem cell test (EST), the zebrafish embryotoxicity test (ZET), and a panel of CALUX reporter gene assays. Finally, the general outline of the thesis was also provided.

    Chapter 2 assessed the applicability of the EST to evaluate in vitro embryotoxic potencies of the DMSO extracts of 9 PS (varying in their PAH content, from 5 PS categories) and 2 GTL products (containing no PAHs) as compared to their in vivo potencies. All DMSO-extracts of PS induced a concentration-dependent inhibition of ES-D3 cell differentiation into beating cardiomyocytes at non-cytotoxic concentrations, and their potency was proportional to their 3- to 7-ring PAH content. In contrast, both GTL extracts, which are completely devoid of PAHs, tested negative in the EST. When the EST results were compared to in vivo PDT data of the corresponding PS, a good correlation was found between in vitro and in vivo results (R2: 0.97). Overall, the EST showed able to evaluate the in vitro embryotoxicity of PS, within and across categories, a result for the in vitro assay that was in line with the in vivo PDT data. The results also supported the hypothesis that PAHs are the primary inducers of the PDT resulting from PS exposure.

    In Chapter 3, the role of endocrine- and dioxin-like activity in the developmental toxicity of PS extracts was investigated using a panel of Chemical Activated LUciferase gene eXpression (CALUX) assays. The same set of samples as in Chapter 2 was tested in the panel of CALUX assays that included agonist and antagonist assays for the androgen, estrogen-α, progesterone, and thyroid-β receptor, and also for the aryl hydrocarbon receptor (AhR). All DMSO-extracts of the PS showed strong AhR agonist activity and weak antiprogesterone, antiandrogen, and estrogenic activities. Only minor effects were seen for thyroid-related and antiestrogenic activity with some products. PS that are grouped in the same class induced similar luciferase expression profiles, suggesting a class specific signature of effects. None of the GTL products showed a meaningful interaction with the selected receptors, thus testing negative in all CALUX assays applied. The AhR-mediated activity of the PS correlated best (R2: 0.80) with the in vitro PDT potency of the corresponding PS as quantified previously in the EST, suggesting an important role of the AhR in mediating this effect. In conclusion, a high potential for endocrine and dioxin-like activity of some PS extracts was elucidated, which correlated with their in vitro PDT, and was driven by the type and level of PAHs present in the PS extracts. The prominent AhR-mediated activity as induced by the PS extracts tested could be one of the underlying mechanisms of PDT by these substances.

    Chapter 4 investigated the usefulness of both the EST and the AhR CALUX assay to evaluate the in vitro PDT potency of an additional series of DMSO-extracts of HFOs, heavy PS containing mainly 3- to 7-ring PAHs, and one HRBO, a highly refined mineral oil that contains no aromatics and no PAHs. All DMSO-extracts of HFOs, but not of the HRBO, resulted in inhibition of ES-D3 cell differentiation in the EST and induced AhR-mediated activity in the AhR CALUX assay, and these potencies were was shown to be proportional to the amount of 3- to 7-ring PAHs they contain. Co-exposure of ES-D3 cells (EST) or H4IIE.luc cells (AhR CALUX assay) with the selected DMSO-extracts of PS and the AhR antagonist trimethoxyflavone (TMF), successfully counteracted the PS-induced inhibition of ES-D3 cell differentiation into cardiomyocytes as well as the AhR-mediated induction of gene expression by these substances. Moreover, also for this series of PS a good concordance was obtained when comparing the EST results with available in vivo PDT data. Altogether, the resulting data corroborate the hypothesis that PS-induced PDT is induced mainly by their 3- to 7-ring PAH content and that the observed PDT is partially mediated via the AhR.

    In Chapter 5, the applicability of the ZET to evaluate developmental toxicity potency of the same set of samples as tested in Chapter 2 and 3 (DMSO-extracts of 9 PS and 2 GTL products) was investigated. All PS extracts, varying in PAH level and content, were able to inhibit the development of zebrafish embryos in a concentration-dependent manner and this potency could be associated with the amount of 3-5 ring PAHs they contain. On the contrary, DMSO-extracts of both GTL products, with no aromatics, showed no effect at all in the ZET. The potencies obtained in the ZET moderately correlated with those previously reported for the EST (R2: 0.61) and the AhR CALUX assay (R2: 0.66), while the correlation with potencies reported in in vivo studies were higher for the EST (R2: 0.85) than the ZET (R2: 0.69). Combining the results obtained from the EST (Chapter 2), AhR CALUX assay (Chapter 3), and ZET (Chapter 5) ranked and clustered the test substances in line with their in vivo potencies and chemical characteristics. It was concluded that the ZET did not outperform the EST as a stand-alone assay for testing PDT of PS but confirms the hypothesis that PAHs are the major inducers of PDT by some PS, and that the ZET is a useful addition to a battery of in vitro tests able to predict the in vivo PDT of PS.

    In Chapter 6 we combined an exogenous biotransformation system, using hamster liver microsomes, with the EST to compare the in vitro PDT potency with and without bioactivation of two model 5-ring PAHs, benzo[a]pyrene (BaP) and dibenz[a,h]anthracene (DBA), and of PAH containing PS and GTL base oil (GTLb) extracts. In the absence of bioactivation, DBA, but not BaP, inhibited the differentiation of ES-D3 cells into beating cardiomyocytes. Upon bioactivation, BaP induced in vitro PDT, while its major metabolite 3-hydroxybenzo[a]pyrene was shown to be active in the EST as well. This indicates that BaP needs metabolic activation to exert its in vitro embryotoxic effect. The PS-induced PDT in the EST was not substantially changed following bioactivation, implying that metabolism may not play a crucial role for PS to exert their in vitro PDT effects. GTL extracts tested negative in the EST, with and without bioactivation. Altogether, although some PAH constituents require metabolic activation to be able to induce PDT, some do not and this latter also appeared to hold for the (majority of) the PS constituents responsible for the in vitro PDT of these complex substances.

    Chapter 7, first presented an overview of the results and main findings, which was combined with a general discussion of the data obtained and with future perspectives for follow-up studies to be performed in the near future. It was concluded that PAHs present in PS are the major inducers of PDT caused by these substances and that this was successfully and adequately assessed using several in vitro alternative assays, including the EST, ZET, and AhR CALUX assay. The results obtained in Chapter 2, 4, and 5 of the thesis were used in a QSAR (quantitative structure activity relationship) approach to predict the in vivo PDT of a series of PS based on their PAH content. More PS extracts, ideally from different PS categories than those tested in the present thesis, should be tested to broaden the applicability domain of the proposed assay battery and the related QSAR approach for PDT testing of PS UVCBs in the future.

    In vitro prenatal developmental toxicity induced by some petroleum substances is mediated by their 3- to 7-ring PAH constituent with a potential role for the aryl hydrocarbon receptor (AhR)
    Kamelia, Lenny ; Haan, Laura de; Ketelslegers, Hans B. ; Rietjens, Ivonne M.C.M. ; Boogaard, Peter J. - \ 2019
    Toxicology Letters 315 (2019). - ISSN 0378-4274 - p. 64 - 76.
    Aryl hydrocarbon receptor - Embryonic stem cell test - Petroleum substances - Polycyclic aromatic hydrocarbons - Prenatal developmental toxicity - UVCBs

    To test the hypothesis that 3–7 ring polycyclic aromatic hydrocarbons (PAHs) are responsible for the prenatal developmental toxicity (PDT) as observed with some petroleum substances (PS), the present study evaluates the PDT potency of DMSO-extracts of 7 heavy fuel oils (HFO), varying in their PAH content, and 1 highly refined base oil (HRBO), containing no aromatics, in the embryonic stem cell test (EST). All DMSO-extracts of HFO inhibit ES-D3 cell differentiation in a concentration-dependent manner and their potency is proportional to the amount of 3–7 ring PAHs they contain. All DMSO-extracts of HFOs also show aryl hydrocarbon receptor (AhR)-mediated activities, as tested in the AhR-CALUX assay. Contrarily, the HRBO-extract tested negative in both assays. Co-exposure of ES-D3 cells with selected DMSO-extracts of PS and the AhR-antagonist trimethoxyflavone, successfully counteracted the PS-induced inhibition of ES-D3 cell differentiation, confirming the role of the AhR in mediating the observed PDT of PS extracts in the EST. A good correlation exists when comparing the in-vitro with the in-vivo PDT potencies of the PS under study. Altogether, our findings corroborate the hypothesis that PS-induced PDT is caused by 3–7 ring PAHs present in these substances and that the observed PDT is partially AhR-mediated.

    The baculovirus Ac108 protein is a per os infectivity factor and a component of the ODV entry complex
    Boogaard, Bob ; Evers, Felix ; Lent, Jan W.M. van; Oers, Monique M. van - \ 2019
    Journal of General Virology 100 (2019)4. - ISSN 0022-1317 - p. 669 - 678.
    m91 - ODV entry complex - per osinfectivity factor - PIF - PIF9 - sf58

    Wild-type ODVs (Wt) have an intact ODV entry complex in their envelope and are orally infectious towards insect larvae (left panel). In the absence of Ac108 (mut ac108), the stable core is still present but nevertheless fails to form an entry complex, affecting the ODV oral infectivity (right panel). The components of the core complex are depicted in yellow and the loosely associated components are depicted in red. PIF7 is depicted in green as its affinity with the complex is currently not known.Baculoviruses orally infect insect larvae when they consume viral occlusion bodies (OBs). OBs consist of a crystalline protein matrix in which the infectious virus particles, the occlusion-derived viruses (ODVs), are embedded. The protein matrix dissolves in the alkaline environment of the insect's midgut lumen. The liberated ODVs can then infect midgut endothelial cells through the action of at least nine different ODV-envelope proteins, called per os infectivity factors (PIFs). These PIF proteins mediate ODV oral infectivity, but are not involved in the systemic spread of the infection by budded viruses (BVs). Eight of the known PIFs form a multimeric complex, named the ODV entry complex. In this study, we show for Autographa californica multiple nucleopolyhedrovirus that mutation of the ac108ORF abolishes the ODV oral infectivity, while production and infectivity of the BVs remains unaffected. Furthermore, repair of the ac108 mutant completely recovered oral infectivity. With an HA-tagged repair mutant, we were able to demonstrate by Western analysis that the Ac108 protein is a constituent of the ODV entry complex, where the formation was abolished in the absence of this protein. Based on these results, we conclude that ac108 encodes a per os infectivity factor (PIF9) that is also an essential constituent of the ODV entry complex.

    Maize crop nutrient input requirements for food security in sub-Saharan Africa
    Berge, H.F.M. ten; Hijbeek, R. ; Loon, M.P. van; Rurinda, J. ; Tesfaye, K. ; Zingore, S. ; Craufurd, P. ; Heerwaarden, J. van; Brentrup, F. ; Schröder, J.J. ; Boogaard, H.L. ; Groot, H.L.E. de; Ittersum, M.K. van - \ 2019
    Global Food Security 23 (2019). - ISSN 2211-9124 - p. 9 - 21.
    Cereals - Crop nutrient requirements - Food self-sufficiency - Intensification - Maize - Soil fertility - Sub-saharan Africa - Yield gaps - Zea mays

    Nutrient limitation is a major constraint in crop production in sub-Saharan Africa (SSA). Here, we propose a generic and simple equilibrium model to estimate minimum input requirements of nitrogen, phosphorus and potassium for target yields in cereal crops under highly efficient management. The model was combined with Global Yield Gap Atlas data to explore minimum input requirements for self-sufficiency in 2050 for maize in nine countries in SSA. We estimate that yields have to increase from the current ca. 20% of water-limited yield potential to approximately 50–75% of the potential depending on the scenario investigated. Minimum nutrient input requirements must rise disproportionately more, with N input increasing 9-fold or 15-fold, because current production largely relies on soil nutrient mining, which cannot be sustained into the future.

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