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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    Evaluation of the health risks related to the presence of cyanogenic glycosides in foods other than raw apricot kernels
    Schrenk, Dieter ; Bignami, Margherita ; Bodin, Laurent ; Chipman, James Kevin ; Mazo, Jesús del; Grasl-Kraupp, Bettina ; Hogstrand, Christer ; Hoogenboom, Laurentius ; Leblanc, Jean Charles ; Nebbia, Carlo Stefano ; Nielsen, Elsa ; Ntzani, Evangelia ; Petersen, Annette ; Sand, Salomon ; Vleminckx, Christiane ; Wallace, Heather ; Benford, Diane ; Brimer, Leon ; Mancini, Francesca Romana ; Metzler, Manfred ; Viviani, Barbara ; Altieri, Andrea ; Arcella, Davide ; Steinkellner, Hans ; Schwerdtle, Tanja - \ 2019
    EFSA Journal 17 (2019)4. - ISSN 1831-4732
    cyanide - cyanogenic glycosides - health-based guidance values - risk assessment

    In 2016, the EFSA Panel on Contaminants in the Food Chain (CONTAM) published a scientific opinion on the acute health risks related to the presence of cyanogenic glycosides (CNGs) in raw apricot kernels in which an acute reference dose (ARfD) of 20 μg/kg body weight (bw) was established for cyanide (CN). In the present opinion, the CONTAM Panel concluded that this ARfD is applicable for acute effects of CN regardless the dietary source. To account for differences in cyanide bioavailability after ingestion of certain food items, specific factors were used. Estimated mean acute dietary exposures to cyanide from foods containing CNGs did not exceed the ARfD in any age group. At the 95th percentile, the ARfD was exceeded up to about 2.5-fold in some surveys for children and adolescent age groups. The main contributors to exposures were biscuits, juice or nectar and pastries and cakes that could potentially contain CNGs. Taking into account the conservatism in the exposure assessment and in derivation of the ARfD, it is unlikely that this estimated exceedance would result in adverse effects. The limited data from animal and human studies do not allow the derivation of a chronic health-based guidance value (HBGV) for cyanide, and thus, chronic risks could not be assessed.

    Assessment of a decontamination process for dioxins and PCBs from fish meal by replacement of fish oil
    Knutsen, Helle Katrine ; Alexander, Jan ; Barregård, Lars ; Bignami, Margherita ; Brüschweiler, Beat ; Ceccatelli, Sandra ; Cottrill, Bruce ; Dinovi, Michael ; Edler, Lutz ; Grasl‐Kraupp, Bettina ; Hoogenboom, Laurentius ; Nebbia, Carlo Stefano ; Oswald, Isabelle P. ; Petersen, Annette ; Rose, Martin ; Roudot, Alain-Claude ; Schwerdtle, Tanja ; Vleminckx, Christiane ; Vollmer, Günter ; Wallace, Heather ; Lundebye, Anne-Katrine ; Metzler, Manfred ; Colombo, Paolo ; Hogstrand, Christer - \ 2018
    EFSA Journal 16 (2018)2. - ISSN 1831-4732
    Following a request from the European Commission, the EFSA Panel on Contaminants in the Food Chain (CONTAM) provided a scientific opinion on the assessment of a decontamination process of fish meal. It consisted of extraction of the fish oil, filtration and adsorption with activated carbon, and replacement with decontaminated fish oil in order to reduce the amount of dioxins (polychlorinated dibenzo‐p‐dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs)), and dioxin‐like (DL‐) and non‐dioxin‐like (NDL‐) polychlorinated biphenyls (PCBs). All feed decontamination processes must comply with the acceptability criteria specified in the Commission Regulation (EU) 2015/786. Data provided by the feed business operator were assessed for efficacy of the process and to demonstrate that the process did not adversely affect the characteristics and the nature of the product. The process was effective in removing PCDD/Fs (97%) and DL‐ and NDL‐PCBs (93%). The fish meal produced complied with EU regulations for these contaminants. The Panel considered that the reference to information available in published literature was a pragmatic approach to demonstrate that the replacement of fish oil and the use of activated carbon to adsorb these contaminants does not lead to any detrimental changes in the nature of the fish meal. However, it was noted that the process could deplete some beneficial constituents (e.g. oil‐soluble vitamins). Information was provided to demonstrate the safe disposal of the waste material. The CONTAM Panel concluded that on the basis of the information submitted by the feed business operator the proposed decontamination process to remove dioxins (PCDD/Fs) and PCBs from the fish meal by oil extraction followed by replacement with decontaminated fish oil, was compliant with the acceptability criteria provided for in Commission Regulation (EU) 2015/786 of 19 May 2015.
    Assessment of a decontamination process for dioxins and PCBs from fish meal by hexane extraction and replacement of fish oil
    Knutsen, Helle Katrine ; Alexander, Jan ; Barregård, Lars ; Bignami, Margherita ; Brüschweiler, Beat ; Ceccatelli, Sandra ; Cottrill, Bruce ; Dinovi, Michael ; Edler, Lutz ; Grasl‐Kraupp, Bettina ; Hoogenboom, Laurentius ; Nebbia, Carlo Stefano ; Oswald, Isabelle P. ; Petersen, Annette ; Rose, Martin ; Roudot, Alain-Claude ; Schwerdtle, Tanja ; Vleminckx, Christiane ; Vollmer, Günter ; Wallace, Heather ; Lundebye, Anne-Katrine ; Metzler, Manfred ; Colombo, Paolo ; Hogstrand, Christer - \ 2018
    EFSA Journal 16 (2018)2. - ISSN 1831-4732
    Following a request from the European Commission, the EFSA Panel on Contaminants in the Food Chain (CONTAM) provided a scientific opinion on the assessment of a decontamination process for fish meal. This process entails solvent (hexane) extraction of fish oil from fish meal to remove dioxins (polychlorinated dibenzo‐p‐dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs)) as well as dioxin‐like (DL‐) and non‐dioxin‐like (NDL‐) polychlorinated biphenyls (PCBs) followed by replacement with decontaminated fish oil. All feed decontamination processes must comply with the acceptability criteria specified in the Commission Regulation (EU) 2015/786. The data provided by the feed business operator were assessed with respect to the efficacy of the process, absence of solvent residues, and on information demonstrating that the process does not adversely affect the nature and characteristics of the product. According to data provided, the process was effective in removing PCDD/Fs and DL‐PCBs by approximately 70% and NDL‐PCBs by about 60%. The data showed that it is possible to meet the current EU requirements with respect to these contaminants, provided that the level of contamination of untreated fish meal is within the range of the tested batches. It is unlikely that hazardous substances (i.e. hexane) remain in the final product. The Panel considered that there is no evidence that fish oil extraction followed by replacement with decontaminated fish oil leads to detrimental changes in the nutritional composition of the fish meal, although some beneficial constituents (e.g. lipophilic vitamins) might be depleted. The feed business operator submitted information to demonstrate safe disposal of the waste material. The CONTAM Panel concluded that the proposed decontamination process to remove dioxins (PCDD/Fs) and PCBs from fish meal by means of solvent extraction and fish oil replacement was assessed to be compliant with the acceptability criteria provided for in Commission Regulation (EU) 2015/786 of 19 May 2015.
    Appropriateness to set a group health‐based guidance value for fumonisins and their modified forms
    Knutsen, Helle-Katrine ; Barregård, Lars ; Bignami, Margherita ; Brüschweiler, Beat ; Ceccatelli, Sandra ; Cottrill, Bruce ; Dinovi, Michael ; Edler, Lutz ; Grasl‐Kraupp, Bettina ; Hogstrand, Christer ; Hoogenboom, Laurentius ; Nebbia, Carlo Stefano ; Petersen, Annette ; Rose, Martin ; Roudot, Alain-Claude ; Schwerdtle, Tanja ; Vleminckx, Christiane ; Vollmer, Günter ; Wallace, Heather ; Dall'Asta, Chiara ; Gutleb, Arno C. ; Humpf, Hans-Ulrich ; Galli, Corrado ; Metzler, Manfred ; Oswald, Isabelle P. ; Parent‐Massin, Dominique ; Binaglia, Marco ; Steinkellner, Hans ; Alexander, Jan - \ 2018
    EFSA Journal 16 (2018)2. - ISSN 1831-4732
    The EFSA Panel on Contaminants in the Food Chain (CONTAM) established a tolerable daily intake (TDI) for fumonisin B1 (FB1) of 1.0 μg/kg body weight (bw) per day based on increased incidence of megalocytic hepatocytes found in a chronic study with mice. The CONTAM Panel considered the limited data available on toxicity and mode of action and structural similarities of FB2–6 and found it appropriate to include FB2, FB3 and FB4 in a group TDI with FB1. Modified forms of FBs are phase I and phase II metabolites formed in fungi, infested plants or farm animals. Modified forms also arise from food or feed processing, and include covalent adducts with matrix constituents. Non‐covalently bound forms are not considered as modified forms. Modified forms of FBs identified are hydrolysed FB1–4 (HFB1–4), partially hydrolysed FB1–2 (pHFB1–2), N‐(carboxymethyl)‐FB1–3 (NCM‐FB1–3), N‐(1‐deoxy‐d‐fructos‐1‐yl)‐FB1 (NDF‐FB1), O‐fatty acyl FB1, N‐fatty acyl FB1 and N‐palmitoyl‐HFB1. HFB1, pHFB1, NCM‐FB1 and NDF‐FB1 show a similar toxicological profile but are less potent than FB1. Although in vitro data shows that N‐fatty acyl FBs are more toxic in vitro than FB1, no in vivo data were available for N‐fatty acyl FBs and O‐fatty acyl FBs. The CONTAM Panel concluded that it was not appropriate to include modified FBs in the group TDI for FB1–4. The uncertainty associated with the present assessment is high, but could be reduced provided more data are made available on occurrence, toxicokinetics and toxicity of FB2–6 and modified forms of FB1–4.
    Identification of Chaoborus kairomone chemicals that induce defences in Daphnia
    Weiss, Linda C. ; Albada, Bauke ; Becker, Sina M. ; Meckelmann, Sven W. ; Klein, Julia ; Meyer, Martin ; Schmitz, Oliver J. ; Sommer, Ulf ; Leo, Markus ; Zagermann, Johannes ; Metzler-Nolte, Nils ; Tollrian, Ralph - \ 2018
    Nature Chemical Biology 14 (2018). - ISSN 1552-4450 - p. 1133 - 1139.

    Infochemicals play important roles in aquatic ecosystems. They even modify food web interactions, such as by inducing defenses in prey. In one classic but still not fully understood example, the planktonic freshwater crustacean Daphnia pulex forms specific morphological defenses (neckteeth) induced by chemical cues (kairomones) released from its predator, the phantom midge larva Chaoborus. On the basis of liquid chromatography, mass spectrometry, and chemical synthesis, we report here the chemical identity of the Chaoborus kairomone. The biologically active cues consist of fatty acids conjugated to the amino group of glutamine via the N terminus. These cues are involved in Chaoborus digestive processes, which explains why they are consistently released despite the disadvantage for its emitter. The identification of the kairomone may allow in-depth studies on multiple aspects of this inducible defense system.

    Scientific opinion: Assessment of a decontamination process for dioxins and dioxin‐like PCBs in fish oil by physical filtration with activated carbon
    Knutsen, Helle Katrine ; Alexander, Jan ; Barregård, Lars ; Bignami, Margherita ; Brüschweiler, Beat ; Ceccatelli, Sandra ; Cottrill, Bruce ; Dinovi, Michael ; Edler, Lutz ; Grasl-Kraupp, Bettina ; Hoogenboom, L.A.P. ; Nebbia, Carlo Stefano ; Oswald, Isabelle P. ; Petersen, Annette ; Rose, Martin ; Roudot, Alain-Claude ; Schwerdtle, Tanja ; Vleminckx, Christiane ; Vollmer, Günter ; Wallace, Heather ; Lundebye, A.K. ; Metzler, Manfred ; Colombo, Paolo ; Hogstrand, Christer - \ 2017
    EFSA Journal 15 (2017)7. - ISSN 1831-4732
    Following a request from the European Commission, the EFSA Panel on Contaminants in the Food Chain (CONTAM) provided a scientific opinion on the assessment of a decontamination process consisting in the adsorption with activated carbon and physical filtration of fish oil in order to reduce the amount of dioxins (polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs)) and dioxin-like polychlorinated biphenyls (DL-PCBs). All feed decontamination processes must comply with the acceptability criteria specified in the Commission Regulation (EU) 2015/786. The data provided by the feed business operator were assessed with respect to the efficacy of the process and on information demonstrating that the process does not adversely affect the characteristics and the nature of the product. As described in scientific literature, the process was effective in removing PCDD/Fs (84%) and DL-PCBs (55%), and therefore, it is possible to meet the current EU requirements with respect to these contaminants, assuming that the level of contamination of untreated fish oil was within the range of the tested batches. The Panel considered that the reference to information available in published literature was a pragmatic approach to demonstrate that the use of activated carbon adsorption does not lead to any detrimental changes in the nature of the fish oil; however, it was noted that the process could deplete some beneficial constituents (e.g. vitamins). Information was provided to demonstrate the safe disposal of the waste material. The CONTAM Panel concluded that on the basis of the information submitted by the feed business operator the proposed decontamination process to remove dioxins (PCDD/Fs) and DL-PCBs from the fish oil by means of physical filtration with activated carbon, was compliant with the acceptability criteria provided for in Commission Regulation (EU) 2015/786 of 19 May 2015.
    Scientific opinion: Assessment of decontamination processes for dioxins and dioxin‐like PCBs in fish oil by physical filtration with activated carbon
    Knutsen, Helle Katrine ; Alexander, Jan ; Barregård, Lars ; Bignami, Margherita ; Brüschweiler, Beat ; Ceccatelli, Sandra ; Cottrill, Bruce ; Dinovi, Michael ; Edler, Lutz ; Grasl‐Kraupp, Bettina ; Hoogenboom, L.A.P. ; Nebbia, Carlo Stefano ; Oswald, Isabelle P. ; Petersen, Annette ; Rose, Martin ; Roudot, Alain-Claude ; Schwerdtle, Tanja ; Vleminckx, Christiane ; Vollmer, Günter ; Wallace, Heather ; Lundebye, A.K. ; Metzler, Manfred ; Colombo, Paolo ; Hogstrand, Christer - \ 2017
    EFSA Journal 15 (2017)12. - ISSN 1831-4732
    Following a request from the European Commission, the EFSA Panel on Contaminants in the Food Chain(CONTAM) provided a scientific opinion on the assessment of decontamination processes involving theadsorption with activated carbon and physicalfiltration offish oil in order to reduce the amount ofdioxins (polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs)) anddioxin-like polychlorinated biphenyls (DL-PCBs). All feed decontamination processes must comply withthe acceptability criteria specified in the Commission Regulation (EU) 2015/786. Two feed businessoperators provided data on their respective decontamination processes, which were assessed in terms ofthe efficacy of the process and the absence of adverse effects in the nature and characteristics of theproduct after decontamination. The processes proved to be able to remove PCDD/Fs (82–95%) andDL-PCBs (26–45%) from thefish oil, depending on the process used by the business operator. Given thatthe level of contamination is within the range of the tested untreatedfish oil, it is possible to meet EUrequirements for these contaminants after decontamination. The CONTAM Panel considered both theevidence provided by one of the business operators and information in the available literature toconclude that the proposed processes do not lead to any detrimental changes in the nature of thefishoil. However, the process can deplete some beneficial constituents (e.g. vitamins). Information wasprovided to demonstrate the safe disposal of the waste material. The CONTAM Panel concluded that, onthe basis of the information submitted by the feed business operators, the proposed decontaminationprocesses to remove dioxins (PCDD/Fs) and DL-PCBs from thefish oil by means of activated carbon andphysicalfiltration were compliant with the acceptability criteria provided for in Commission Regulation(EU) 2015/786 of 19 May 2015.
    Scientific opinion: Appropriateness to set a group health based guidance value for T2 and HT2 toxin and its modified forms
    Knutsen, Helle-Katrine ; Barregård, Lars ; Bignami, Margherita ; Brüschweiler, Beat ; Ceccatelli, Sandra ; Cottrill, Bruce ; Dinovi, Michael ; Edler, Lutz ; Grasl-Kraupp, Bettina ; Hogstrand, Christer ; Hoogenboom, L.A.P. ; Nebbia, Carlo Stefano ; Oswald, Isabelle ; Petersen, Annette ; Rose, Martin ; Roudot, Alain-Claude ; Schwerdtle, Tanja ; Vleminckx, Christiane ; Vollmer, Günter ; Wallace, Heather ; Dall'asta, Chiara ; Gutleb, Arno ; Metzler, Manfred ; Oswald, Isabelle ; Parent-Massin, Dominique ; Binaglia, Marco ; Steinkellner, Hans ; Alexander, Jan - \ 2017
    EFSA Journal 15 (2017)1. - ISSN 1831-4732
    The EFSA Panel on Contaminants in the Food Chain (CONTAM) established a tolerable daily intake (TDI) for T2 and HT2 of 0.02 μg/kg body weight (bw) per day based on a new in vivo subchronic toxicity study in rats that confirmed that immune- and haematotoxicity are the critical effects of T2 and using a reduction in total leucocyte count as the critical endpoint. An acute reference dose (ARfD) of 0.3 μg for T2 and HT2/kg bw was established based on acute emetic events in mink. Modified forms of T2 and HT2 identified are phase I metabolites mainly formed through hydrolytic cleavage of one or more of the three ester groups of T2. Less prominent hydroxylation reactions occur predominantly at the side chain. Phase II metabolism involves conjugation with glucose, modified glucose, sulfate, feruloyl and acetyl groups. The few data on occurrence of modified forms indicate that grain products are their main source. The CONTAM Panel found it appropriate to establish a group TDI and a group ARfD for T2 and HT2 and its modified forms. Potency factors relative to T2 for the modified forms were used to account for differences in acute and chronic toxic potencies. It was assumed that conjugates (phase II metabolites of T2, HT2 and their phase I metabolites), which are not toxic per se, would be cleaved releasing their aglycones. These metabolites were assigned the relative potency factors (RPFs) of their respective aglycones. The RPFs assigned to the modified forms were all either 1 or less than 1. The uncertainties associated with the present assessment are considered as high. Using the established group, ARfD and TDI would overestimate any risk of modified T2 and HT2.
    Scientific opinion: Appropriateness to set a group health based guidance value for nivalenol and its modified forms
    Knutsen, Helle Katrine ; Barregård, Lars ; Bignami, Margherita ; Brüschweiler, Beat ; Ceccatelli, Sandra ; Cottrill, Bruce ; Dinovi, Michael ; Edler, Lutz ; Grasl-Kraupp, Bettina ; Hogstrand, Christer ; Hoogenboom, L.A.P. ; Nebbia, Carlo Stefano ; Oswald, Isabelle P. ; Petersen, Annette ; Rose, Martin ; Roudot, Alain-Claude ; Schwerdtle, Tanja ; Vleminckx, Christiane ; Vollmer, Günter ; Wallace, Heather ; Dall'asta, Chiara ; Gutleb, Arno C. ; Metzler, Manfred ; Parent-Massin, Dominique ; Binaglia, Marco ; Steinkellner, Hans ; Alexander, Jan - \ 2017
    EFSA Journal 15 (2017)4. - ISSN 1831-4732
    The EFSA Panel on Contaminants in the Food Chain (CONTAM) reviewed new studies on nivalenol since the previous opinion on nivalenol published in 2013, but as no new relevant data were identified the tolerable daily intake (TDI) for nivalenol (NIV) of 1.2 μg/kg body weight (bw) established on bases of immuno- and haematotoxicity in rats was retained. An acute reference dose (ARfD) of 14 μg/kg bw was established based on acute emetic events in mink. The only phase I metabolite of NIV identified is de-epoxy-nivalenol (DE-NIV) and the only phase II metabolite is nivalenol-3-glucoside (NIV3Glc). DE-NIV is devoid of toxic activity and was thus not further considered. NIV3Glc can occur in cereals amounting up to about 50% of NIV. There are no toxicity data on NIV3Glc, but as it can be assumed that it is hydrolysed to NIV in the intestinal tract it should be included in a group TDI and in a group ARfD with NIV. The uncertainty associated with the present assessment is considered as high and it would rather overestimate than underestimate any risk.
    Scientific opinion: Assessment of a decontamination process for hydrocyanic acid in linseed intended for use in animal feed
    Knutsen, Helle Katrine ; Alexander, Jan ; Barregård, Lars ; Bignami, Margherita ; Brüschweiler, Beat ; Ceccatelli, Sandra ; Cottrill, Bruce ; Dinovi, Michael ; Edler, Lutz ; Grasl-Kraupp, Bettina ; Hoogenboom, L.A.P. ; Nebbia, Carlo Stefano ; Oswald, Isabelle P. ; Petersen, Annette ; Rose, Martin ; Roudot, Alain-Claude ; Schwerdtle, Tanja ; Vleminckx, Christiane ; Vollmer, Günter ; Wallace, Heather ; Lundebye, Anne-Katrine ; Metzler, Manfred ; Colombo, Paolo ; Hogstrand, Christer - \ 2017
    EFSA Journal 15 (2017)10. - ISSN 1831-4732
    Following a request from the European Commission, the EFSA Panel on Contaminants in the Food Chain (CONTAM) provided a scientific opinion on the assessment of a decontamination process for the enzymatic treatment and subsequent heating of linseed, in order to reduce the amount of hydrocyanic acid (HCN) present as cyanogenic glycosides. Specifically, it is required that the feed decontamination process is compliant with the acceptability criteria specified in the Commission Regulation (EU) 2015/786 of 19 May 2015. With this aim, the CONTAM Panel assessed the data provided by the feed business operator with respect to the efficacy of the process to remove the contaminant from the linseed batches and on information demonstrating that the process does not adversely affect the characteristics and the nature of the product. The data enabled the Panel to conclude that in agreement with the literature the process was able to remove HCN by about 90%, and that it is possible to meet the current EU requirements for quality of linseed with respect to HCN, provided the level of contamination of untreated linseed would be within the range of the tested batches. The Panel noted that the amounts of other products formed during the enzymatic process and remaining in the treated material are not of toxicological concern. The experimental data provided by the feed business operator showed that the characteristics of linseed were not adversely affected by the decontamination process. The CONTAM Panel concluded that, on the basis of the information submitted by the feed business operator, the proposed decontamination process to remove HCN from linseed by means of enzymatic release and subsequent evaporation was compliant with the acceptability criteria provided for in Commission Regulation (EU) 2015/786 of 19 May 2015.
    Highly Potent Antibacterial Organometallic Peptide Conjugates
    Albada, Bauke ; Metzler-Nolte, Nils - \ 2017
    Accounts of Chemical Research 50 (2017)10. - ISSN 0001-4842 - p. 2510 - 2518.
    ConspectusResistance of pathogenic bacteria against currently marketed antibiotics is again increasing. To meet the societal need for effective cures, scientists are faced with the challenge of developing more potent but equally bacteria-specific drugs. Currently, most efforts are directed toward the modification of existing antibiotics, but ideally, compounds with a new mode of action are required. In this Account, we detail our findings in the area of novel metal-based antibiotics. Our strategy is based on the modification of simple antimicrobial peptides (AMPs) with organometallic agents, resulting in organometallic AMPs (OM-AMPs). Since bacteria have most likely never encountered these synthetically prepared unnatural organometallic agents, we anticipated that such agents could well become potentiating players in the antibiotics arena. Moreover, exploiting some of the particular properties of metal complexes should also help to elucidate the mode of action of small cationic AMPs, the molecular details of which have remained elusive despite intensive efforts.Using standard Fmoc/tBu-based solid-phase peptide synthesis approaches, we have prepared various organometallic-peptide conjugates with covalently linked group 8 and 9 metallocenes (ferrocene, ruthenocene, osmocene, and cobaltocenium). As a starting point we took the (RW)3 antibacterial hexapeptide lead structure. After modifying the peptide sequence (generations 1 and 2), changing the nature and position of the organometallic group (generation 3), and optimizing the amino acid chirality (generation 5), we identified several organometallic antibacterial peptides that are currently among the most active synthetic AMPs (synAMPs) that have ever been prepared. Through these rational and systematic optimizations, we were able to increase the antibacterial activity of a short non-organometallic synAMP 18-fold to submicromolar activity, rivaling the activity of vancomycin (often the drug of last resort) against methicillin-resistant Staphylococcus aureus (MRSA). Moreover, by making use of the unique physicochemical properties of ruthenocene, we were able to determine the mode of action of these short AMPs in unprecedented detail. We propose that the OM-AMP integrates into the bacterial membrane and changes its biophysical properties, which ultimately results in detachment of vital enzymes for respiration and cell-wall biosynthesis such as specifically cytochrome c and MurG from their locations in the membrane. Further explorations of these small OM-AMP derivatives that are summarized in this Account include lipid substitution, multivalent display of metalated di- or tripeptides on a trivalent scaffold with different linkers, and increasing the metal-to-peptide ratio such that every tryptophan in the (RW)3 scaffold is eventually replaced by a metalated lysine. While initial experiments with our OM-AMPs for systemic applications were largely disappointing, these OM-AMPs turned out to be potent antibiotics for topical applications. In this sense, two applications are described as examples in this Account, namely, bacterial decontamination of wastewater by reverse osmosis membranes (coated with our OM-AMPs by Cu-catalyzed azide-alkyne cycloaddition reaction) and synergistic activities of one of our synAMPs with colistin and tobramycin for the treatment of Pseudomonas aeruginosa infections that are associated with cystic fibrosis.
    Towards profiles of resistance development and toxicity for the small cationic hexapeptide RWRWRW-NH 2
    Wenzel, Michaela ; Prochnow, Pascal ; Mowbray, Catherine ; Vuong, Cuong ; Höxtermann, Stefan ; Stepanek, Jennifer J. ; Albada, H.B. ; Hall, Judith ; Metzler-Nolte, Nils ; Bandow, Julia E. - \ 2016
    Frontiers in Cell and Developmental Biology 4 (2016)AUG. - ISSN 2296-634X
    Acute - Antimicrobial cationic peptides - Antimicrobial peptide - Antimicrobial peptide resistance - Toxicity mechanisms - Toxicity tests

    RWRWRW-NH 2 (MP196) is an amphipathic hexapeptide that targets the bacterial cytoplasmic membrane and inhibits cellular respiration and cell wall synthesis. In previous studies it showed promising activity against Gram-positive bacteria and no significant cytotoxicity or hemolysis. MP196 is therefore used as lead structure for developing more potent antibiotic derivatives. Here we present a more comprehensive study on the parent peptide MP196 with regard to clinically relevant parameters. We found that MP196 acts rapidly bactericidal killing 97% of initial CFU within 10 min at two times MIC. We were unable to detect resistance in standard 24 and 48 h resistance frequency assays. However, MP196 was effective against some but not all MRSA and VISA strains. Serum binding of MP196 was intermediate and we confirmed its low toxicity against mammalian cell lines. MP196 did neither induce NFκB activation nor cause an increase in IL8 levels at 250 μg/mL, and no IgE-dependent activation of basophil granulocytes was detected at 500 μg/mL. Yet, MP196 demonstrated acute toxicity in mice upon injection into the blood stream. Phase contrast microscopy of mouse blood treated with MP196 revealed a shrinking of erythrocytes at 250 μg/mL and severe morphological changes and lysis of erythrocytes at 500 μg/mL. These data suggest that MP196 derivatization directed at further lowering hemolysis could be instrumental in overcoming acute toxicity. The assessment of hemolysis is a critical step in the evaluation of the clinical potential of promising antimicrobial peptides and should be accompanied by microscopy-based morphological analysis of blood cells.

    Efficient reagent-saving method for the N-terminal labeling of bioactive peptides with organometallic carboxylic acids by solid-phase synthesis
    Slootweg, Jack C. ; Albada, Bauke ; Siegmund, Daniel ; Metzler-Nolte, Nils - \ 2016
    Organometallics 35 (2016)18. - ISSN 0276-7333 - p. 3192 - 3196.
    Labeling of biomolecules with organometallic moieties holds great promise as a tool for chemical biology and for the investigation of biochemical signaling pathways. Herein, we report a robust and reproducible synthetic strategy for the synthesis of ruthenocenecarboxylic acid, giving the acid in 53% overall yield. This organometallic label was conjugated via solid-phase peptide synthesis in near-quantitative yield to a number of different biologically active peptides, using only 1 equiv of the acid and coupling reagents, thereby avoiding wasting the precious organometallic acid. This optimized method of stoichiometric N-terminal acylation was then also successfully applied to conjugating ferrocenecarboxylic acid and a novel organometallic ReI(CO)3 complex, showing the generality of the synthetic procedure.
    Attachment of antimicrobial peptides to reverse osmosis membranes by Cu(i)-catalyzed 1,3-dipolar alkyne-azide cycloaddition
    Bodner, Elias J. ; Kandiyote, Nitzan Shtreimer ; Lutskiy, Marina Yamit ; Albada, Bauke ; Metzler-Nolte, Nils ; Uhl, Wolfgang ; Kasher, Roni ; Arnusch, Christopher J. - \ 2016
    RSC Advances : An international journal to further the chemical sciences 6 (2016)94. - ISSN 2046-2069 - p. 91815 - 91823.

    Biofilms are detrimental to many industrial systems that include reverse osmosis (RO) membranes. Accordingly, the development of surfaces with inherently bactericidal properties has attracted much research attention. Antimicrobial peptides (AMPs) have been shown to be potent antimicrobial and anti-biofilm agents. In the current study, we developed an efficient synthetic procedure for AMP immobilization on RO membranes which is based on the copper(i) mediated Huisgen 1,3-dipolar cycloaddition reaction ("click chemistry"). Optimization of the reaction temperature, time, peptide and catalyst concentration resulted in efficient coupling of peptides to the membrane surface. The reaction conditions did not affect membrane salt rejection, and resulted in only a slight reduction (14%) in pure water flux at the highest temperature tested (80 °C). Short AMPs that consisted of Arg-Trp repeats were attached onto a virgin RO membrane surface, and an RO membrane surface coated with a copolymer of methacrylic acid and poly(ethylene glycol)methacrylate. In a bacterial contact killing assay, the resulting peptide-modified membrane surfaces showed increased antimicrobial activity especially on the virgin membrane as compared to unmodified membranes. This study provides a basis for further research into the attachment of a wide variety of antimicrobials or other entities to surfaces.

    Organometallic-peptide bioconjugates: Synthetic strategies and medicinal applications
    Albada, Bauke ; Metzler-Nolte, N. - \ 2016
    Chemical Reviews 116 (2016)19. - ISSN 0009-2665 - p. 11797 - 11839.
    Peptides are important biological molecular entities in biomedical
    research. They can be prepared in a large variety of shapes, with a host of chemical
    functions, and tailored for specific applications. Organometallic medicinal chemistry is a
    relatively young field that explores biomedical and bioanalytical applications of
    organometallic complexes, that is, metal compounds with at least one direct, covalent
    metal−carbon bond. The conjugation of peptides to such medicinally active
    organometallic moieties started only about 20 years ago, and it has been very beneficial
    for the development of bioorganometallic chemistry in general. Similarly, the biomedical
    properties of peptides have been altered by their conjugation to organometallic (OM)
    moieties. In this review, synthetic methods by which OM moieties can be conjugated to peptides via a carbon−metal bond are
    described, and selected medicinal applications of such conjugates are discussed. Inorganic coordination complexes between metal
    ions and peptides are excluded from this review. Also, the labeling of peptides with radiometals and applications of radiolabeled
    peptides will not be treated herein. First, modifications of the peptide backbone (either N- or C-terminally, or both) with
    organometallic moieties will be described, including the insertion of OM moieties as part of the peptide backbone. Then sidechain
    modifications will be reported, among them the most recent strategies for chemoselective arene metalation on peptides.
    Finally, approaches by which multiple metalation can be achieved are explored. In each section, selected examples of biological
    applications are highlighted
    Advantages of continuous genotype values over genotype classes for GWAS in higher polyploids : A comparative study in hexaploid chrysanthemum
    Grandke, Fabian ; Singh, Priyanka ; Heuven, Henri C.M. ; Haan, Jorn R. de; Metzler, Dirk - \ 2016
    BMC Genomics 17 (2016). - ISSN 1471-2164 - 9 p.
    Association study - Bayz - Continuous genotypes - Linear regression - Partial least squares - Polyploids

    Background: Association studies are an essential part of modern plant breeding, but are limited for polyploid crops. The increased number of possible genotype classes complicates the differentiation between them. Available methods are limited with respect to the ploidy level or data producing technologies. While genotype classification is an established noise reduction step in diploids, it gains complexity with increasing ploidy levels. Eventually, the errors produced by misclassifications exceed the benefits of genotype classes. Alternatively, continuous genotype values can be used for association analysis in higher polyploids. We associated continuous genotypes to three different traits and compared the results to the output of the genotype caller SuperMASSA. Linear, Bayesian and partial least squares regression were applied, to determine if the use of continuous genotypes is limited to a specific method. A disease, a flowering and a growth trait with h 2 of 0.51, 0.78 and 0.91 were associated with a hexaploid chrysanthemum genotypes. The data set consisted of 55,825 probes and 228 samples. Results: We were able to detect associating probes using continuous genotypes for multiple traits, using different regression methods. The identified probe sets were overlapping, but not identical between the methods. Baysian regression was the most restrictive method, resulting in ten probes for one trait and none for the others. Linear and partial least squares regression led to numerous associating probes. Association based on genotype classes resulted in similar values, but missed several significant probes. A simulation study was used to successfully validate the number of associating markers. Conclusions: Association of various phenotypic traits with continuous genotypes is successful with both uni- and multivariate regression methods. Genotype calling does not improve the association and shows no advantages in this study. Instead, use of continuous genotypes simplifies the analysis, saves computational time and results more potential markers.

    Intestinal gene expression in pigs: effects of reduced feed intake during weaning and potential impact of dietary components
    Bauer, E. ; Metzler-Zebeli, B.U. ; Verstegen, M.W.A. ; Mosenthin, R. - \ 2011
    Nutrition Research Reviews 24 (2011)2. - ISSN 0954-4224 - p. 155 - 175.
    total parenteral-nutrition - glucagon-like peptide-2 - chain fatty-acids - growth-factor-i - nf-kappa-b - oligopeptide transporter pept-1 - ischemia-reperfusion injury - inflammatory-bowel-disease - messenger-rna expression - activated receptor-gamma
    The weaning transition is characterised by morphological, histological and microbial changes, often leading to weaning-associated disorders. These intestinal changes can partly be ascribed to the lack of luminal nutrition arising from the reduced feed intake common in pigs after weaning. It is increasingly becoming clear that changes in the supply with enteral nutrients may have major impacts on intestinal gene expression. Furthermore, the major dietary constituents, i.e. carbohydrates, fatty acids and amino acids, participate in the regulation of intestinal gene expression. However, nutrients may also escape digestion by mammalian enzymes in the upper gastrointestinal tract. These nutrients can be used by the microflora, resulting in the production of bacterial metabolites, for example, SCFA, which may affect intestinal gene expression indirectly. The present review provides an insight on possible effects of reduced feed intake on intestinal gene expression, as it may occur post-weaning. Detailed knowledge on effects of reduced feed intake on intestinal gene expression may help to understand weaning-associated intestinal dysfunctions and diseases. Examples are given of intestinal genes which may be altered in their expression due to supply with specific nutrients. In that way, gene expression could be modulated by dietary means, thereby acting as a potential therapeutic tool. This could be achieved, for example, by influencing genes coding for digestive or absorptive proteins, thus optimising digestive function and metabolism, but also with regard to immune response, or by influencing proliferative processes, thereby enhancing mucosal repair. This would be of special interest when designing a diet to overcome weaning-associated problems
    Epidemiology of Clavibacter michiganensis subsp. sepedonicus in relation to control of bacterial ring rot
    Wolf, J.M. van der; Elphinstone, J.G. ; Stead, D.E. ; Metzler, M. ; Müller, P. ; Hukkanen, A. ; Karjalainen, R. - \ 2005
    onbekend : PRI Bioscience (Report / Plant Research International 95) - 38
    clavibacter michiganensis subsp. sepedonicus - clavibacter michiganensis - epidemiologie - plantenziekten - clavibacter michiganensis subsp. sepedonicus - clavibacter michiganensis - epidemiology - plant diseases
    Simultaneous intramammary and intranasal inoculation of lactating cows with bovine herpesvirus 4 induce subclinical mastitis
    Fraefel, C. ; Metzler, A. ; Schwyzer, M. ; Suter, M. ; Tobler, K. - \ 2002
    In: 1th ESVV Veterinary Herpesvirus Symposium p.115-129; 141 ref
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