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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    Physicochemical-guided design of cathelicidin-derived peptides generates membrane active variants with therapeutic potential
    Oliveira, Nelson G.J. ; Cardoso, Marlon H. ; Velikova, Nadya ; Giesbers, Marcel ; Wells, Jerry M. ; Rezende, Taia M.B. ; Vries, Renko de; Franco, Octávio L. - \ 2020
    Scientific Reports 10 (2020)1. - ISSN 2045-2322

    The spread of multi-drug resistance and the slow pace at which antibiotics come onto the market are undermining our ability to treat human infections, leading to high mortality rates. Aiming to overcome this global crisis, antimicrobial peptides are considered promising alternatives to counter bacterial infections with multi-drug resistant bacteria. The cathelicidins comprise a well-studied class of AMPs whose members have been used as model molecules for sequence modifications, aiming at enhanced biological activities and stability, along with reduced toxic effects on mammalian cells. Here, we describe the antimicrobial activities, modes of action and structural characterization of two novel cathelicidin-like peptides, named BotrAMP14 and CrotAMP14, which were re-designed from snake batroxicidin and crotalicidin, respectively. BotrAMP14 and CrotAMP14 showed broad-spectrum antibacterial activity against susceptible microorganisms and clinical isolates with minimal inhibitory concentrations ranging from 2–35.1 μM. Moreover, both peptides had low cytotoxicity against Caco-2 cells in vitro. In addition, in vivo toxicity against Galleria mellonella moth larvae revealed that both peptides led to>76% larval survival after 144 h. Microscopy studies suggest that BotrAMP14 and CrotAMP14 destabilize E. coli membranes. Furthermore, circular dichroism and molecular dynamics simulations indicate that, in a membrane-like environment, both peptides adopt α-helical structures that interact with bilayer phospholipids through hydrogen bonds and electrostatic interaction. Thus, we concluded that BotrAMP14 and CrotAMP14 are helical membrane active peptides, with similar antibacterial properties but lower cytotoxicity than the larger parent peptides batroxicidin and crotalicidin, having advantages for drug development strategies.

    Mixed ancestry from wild and domestic lineages contributes to the rapid expansion of invasive feral swine
    Smyser, Timothy J. ; Tabak, Michael A. ; Slootmaker, Chris ; Robeson, Michael S. ; Miller, Ryan S. ; Bosse, Mirte ; Megens, Hendrik Jan ; Groenen, Martien A.M. ; Paiva, Samuel Rezende ; Faria, Danielle Assis de; Blackburn, Harvey D. ; Schmit, Brandon S. ; Piaggio, Antoinette J. - \ 2020
    Molecular Ecology 29 (2020)6. - ISSN 0962-1083
    admixture - feral swine - invasive species - secondary introductions - Sus scrofa

    Invasive alien species are a significant threat to both economic and ecological systems. Identifying the processes that give rise to invasive populations is essential for implementing effective control strategies. We conducted an ancestry analysis of invasive feral swine (Sus scrofa, Linnaeus, 1758), a highly destructive ungulate that is widely distributed throughout the contiguous United States, to describe introduction pathways, sources of newly emergent populations and processes contributing to an ongoing invasion. Comparisons of high-density single nucleotide polymorphism genotypes for 6,566 invasive feral swine to a comprehensive reference set of S. scrofa revealed that the vast majority of feral swine were of mixed ancestry, with dominant genetic associations to Western heritage breeds of domestic pig and European populations of wild boar. Further, the rapid expansion of invasive feral swine over the past 30 years was attributable to secondary introductions from established populations of admixed ancestry as opposed to direct introductions of domestic breeds or wild boar. Spatially widespread genetic associations of invasive feral swine to European wild boar deviated strongly from historical S. scrofa introduction pressure, which was largely restricted to domestic pigs with infrequent, localized wild boar releases. The deviation between historical introduction pressure and contemporary genetic ancestry suggests wild boar-hybridization may contribute to differential fitness in the environment and heightened invasive potential for individuals of admixed domestic pig–wild boar ancestry.

    Genetics and genomics of uniformity and resilience in livestock and aquaculture species: A review
    Souza Lung, Laiza Helena de; Carvalheiro, Roberto ; Rezende Neves, Haroldo Henrique de; Mulder, Herman Arend - \ 2020
    Journal of Animal Breeding and Genetics 137 (2020)3. - ISSN 0931-2668 - p. 263 - 280.
    genetic control of residual variance - genetic heterogeneity of residual variance - micro-environmental sensitivity - resilience - uniformity

    Genetic control of residual variance offers opportunities to increase uniformity and resilience of livestock and aquaculture species. Improving uniformity and resilience of animals will improve health and welfare of animals and lead to more homogenous products. Our aims in this review were to summarize the current models and methods to study genetic control of residual variance, genetic parameters and genomic results for residual variance and discuss future research directions. Typically, the genetic coefficient of variation is high (median = 0.27; range 0–0.86) and the heritability of residual variance is low (median = 0.01; range 0–0.10). Higher heritabilities can be achieved when increasing the number of records per animal. Divergent selection experiments have supported the feasibility of selecting for high or low residual variance. Genomic studies have revealed associations in regions related to stress, including those from the heat shock protein family. Although the number of studies is growing, genetic control of residual variance is still poorly understood, but big data and genomics offer great opportunities.

    Genomic regions underlying uniformity of yearling weight in Nellore cattle evaluated under different response variables
    Souza Iung, Laiza Helena de; Mulder, Herman ; Rezende Neves, Haroldo Henrique de; Carvalheiro, Roberto - \ 2018
    São Paulo State University
    beef cattle - DHGLM - genetic heterogeneity of residual variance - growth traits - GWAS - micro-environmental sensitivity
    Background In livestock, residual variance has been studied because of the interest to improve uniformity of production. Several studies have provided evidence that residual variance is partially under genetic control; however, few investigations have elucidated genes that control it. The aim of this study was to identify genomic regions associated with within-family residual variance of yearling weight (YW; N = 423) in Nellore bulls with high density SNP data, using different response variables. For this, solutions from double hierarchical generalized linear models (DHGLM) were used to provide the response variables, as follows: a DGHLM assuming non-null genetic correlation between mean and residual variance (rmv ≠ 0) to obtain deregressed EBV for mean (dEBVm) and residual variance (dEBVv); and a DHGLM assuming rmv = 0 to obtain two alternative response variables for residual variance, dEBVv_r0 and log-transformed variance of estimated residuals (ln_ σ e ̂ 2 $$ {\upsigma}_{\widehat{\mathrm{e}}}^2 $$ ). Results The dEBVm and dEBVv were highly correlated, resulting in common regions associated with mean and residual variance of YW. However, higher effects on variance than the mean showed that these regions had effects on the variance beyond scale effects. More independent association results between mean and residual variance were obtained when null rmv was assumed. While 13 and 4 single nucleotide polymorphisms (SNPs) showed a strong association (Bayes Factor > 20) with dEBVv and ln_ σ e ̂ 2 $$ {\upsigma}_{\widehat{\mathrm{e}}}^2 $$ , respectively, only suggestive signals were found for dEBVv_r0. All overlapping 1-Mb windows among top 20 between dEBVm and dEBVv were previously associated with growth traits. The potential candidate genes for uniformity are involved in metabolism, stress, inflammatory and immune responses, mineralization, neuronal activity and bone formation. Conclusions It is necessary to use a strategy like assuming null rmv to obtain genomic regions associated with uniformity that are not associated with the mean. Genes involved not only in metabolism, but also stress, inflammatory and immune responses, mineralization, neuronal activity and bone formation were the most promising biological candidates for uniformity of YW. Although no clear evidence of using a specific response variable was found, we recommend consider different response variables to study uniformity to increase evidence on candidate regions and biological mechanisms behind it.
    Genomic regions underlying uniformity of yearling weight in Nellore cattle evaluated under different response variables
    Souza Iung, Laiza Helena de; Mulder, Herman Arend ; Rezende Neves, Haroldo Henrique de; Carvalheiro, Roberto - \ 2018
    BMC Genomics 19 (2018). - ISSN 1471-2164
    Beef cattle - DHGLM - Genetic heterogeneity of residual variance - Growth traits - GWAS - Micro-environmental sensitivity

    Background: In livestock, residual variance has been studied because of the interest to improve uniformity of production. Several studies have provided evidence that residual variance is partially under genetic control; however, few investigations have elucidated genes that control it. The aim of this study was to identify genomic regions associated with within-family residual variance of yearling weight (YW; N=423) in Nellore bulls with high density SNP data, using different response variables. For this, solutions from double hierarchical generalized linear models (DHGLM) were used to provide the response variables, as follows: a DGHLM assuming non-null genetic correlation between mean and residual variance (rmv0) to obtain deregressed EBV for mean (dEBVm) and residual variance (dEBVv); and a DHGLM assuming rmv=0 to obtain two alternative response variables for residual variance, dEBVv_r0 and log-transformed variance of estimated residuals (ln_ σ ě 2 $$ (\upsigma)_(\widehat(\mathrm(e)))^2 $$ ). Results: The dEBVm and dEBVv were highly correlated, resulting in common regions associated with mean and residual variance of YW. However, higher effects on variance than the mean showed that these regions had effects on the variance beyond scale effects. More independent association results between mean and residual variance were obtained when null rmv was assumed. While 13 and 4 single nucleotide polymorphisms (SNPs) showed a strong association (Bayes Factor>20) with dEBVv and ln_ σ ě 2 $$ (\upsigma)_(\widehat(\mathrm(e)))^2 $$ , respectively, only suggestive signals were found for dEBVv_r0. All overlapping 1-Mb windows among top 20 between dEBVm and dEBVv were previously associated with growth traits. The potential candidate genes for uniformity are involved in metabolism, stress, inflammatory and immune responses, mineralization, neuronal activity and bone formation. Conclusions: It is necessary to use a strategy like assuming null rmv to obtain genomic regions associated with uniformity that are not associated with the mean. Genes involved not only in metabolism, but also stress, inflammatory and immune responses, mineralization, neuronal activity and bone formation were the most promising biological candidates for uniformity of YW. Although no clear evidence of using a specific response variable was found, we recommend consider different response variables to study uniformity to increase evidence on candidate regions and biological mechanisms behind it.

    An acidic model pro-peptide affects the secondary structure, membrane interactions and antimicrobial activity of a crotalicidin fragment
    Júnior, Nelson G.O. ; Cardoso, Marlon H. ; Cândido, Elizabete S. ; Broek, Danielle van den; Lange, Niek de; Velikova, Nadya ; Kleijn, J.M. ; Wells, Jerry M. ; Rezende, Taia M.B. ; Franco, Octávio Luiz ; Vries, Renko de - \ 2018
    Scientific Reports 8 (2018)1. - ISSN 2045-2322

    In order to study how acidic pro-peptides inhibit the antimicrobial activity of antimicrobial peptides, we introduce a simple model system, consisting of a 19 amino-acid long antimicrobial peptide, and an N-terminally attached, 10 amino-acid long acidic model pro-peptide. The antimicrobial peptide is a fragment of the crotalicidin peptide, a member of the cathelidin family, from rattlesnake venom. The model pro-peptide is a deca (glutamic acid). Attachment of the model pro-peptide only leads to a moderately large reduction in the binding to- and induced leakage of model liposomes, while the antimicrobial activity of the crotalicidin fragment is completely inhibited by attaching the model pro-peptide. Attaching the pro-peptide induces a conformational change to a more helical conformation, while there are no signs of intra- or intermolecular peptide complexation. We conclude that inhibition of antimicrobial activity by the model pro-peptide might be related to a conformational change induced by the pro-peptide domain, and that additional effects beyond induced changes in membrane activity must also be involved.

    Varicellovirus UL49.5 proteins differentially affect the function of the transporter associated with antigen processing, TAP
    Koppers-Lalic, D. ; Verweij, M.C. ; Lipinska, A.D. ; Wang, Y. ; Quinten, E. ; Reits, E.A. ; Koch, J. ; Loch, S. ; Rezende, M.M. ; Daus, F.J. ; Bienkowska-Szewczyk, K. ; Osterrieder, N. ; Mettenleiter, T.C. ; Heemskerk, M.H.M. ; Tampe, R. ; Neefjes, J.J. ; Chowdhury, S.I. ; Ressing, M.E. ; Rijsewijk, F.A.M. ; Wiertz, E.J.H.J. - \ 2008
    PLoS Pathogens 4 (2008)5. - ISSN 1553-7366 - 14 p.
    mhc class-i - major histocompatibility complex - peptide-loading complex - cytomegalovirus us6 glycoprotein - viral immune evasion - equine herpesvirus-1 - molecular-mechanism - down-regulation - finger protein - ligase mk3
    Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I-restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV- 1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms.
    Varicelloviruses avoid T cell recognition by UL49.5-mediated inactivation of the transporter associated with antigen processing
    Koppers-Lalic, D. ; Reits, E.A. ; Ressing, M.E. ; Lipinska, A.D. ; Abele, R. ; Koch, J. ; Marcondes Rezende, M. ; Admiraal, P. ; Leeuwen, D. ; Bienkowska-Szewczyk, K. ; Mettenleiter, T.C. ; Rijsewijk, F.A.M. ; Tampe, R. ; Neefjes, J. ; Wiertz, E.J. - \ 2005
    Proceedings of the National Academy of Sciences of the United States of America 102 (2005)14. - ISSN 0027-8424 - p. 5144 - 5149.
    class-i expression - disulfide-linked complex - peptide-loading complex - virus protein icp47 - endoplasmic-reticulum - equine herpesvirus-1 - glycoprotein-m - transmembrane domains - molecular-mechanism - down-regulation
    Detection and elimination of virus-infected cells by cytotoxic T lymphocytes depends on recognition of virus-derived peptides presented by MHC class I molecules. A critical step in this process is the translocation of peptides from the cytoplasm into the endoplasmic reticulum by the transporter associated with antigen processing (TAP). Here, we identified the bovine herpesvirus 1-encoded UL49.5 protein as a potent inhibitor of TAP. The expression of UL49.5 results in down-regulation of MHC class I molecules at the cell surface and inhibits detection and lysis of the cells by cytotoxic T lymphocytes. UL49.5 homologs encoded by two other varicelloviruses, pseudorabies-virus and equine herpesvirus 1, also block TAP. Homologs of UL49.5 are widely present in herpesviruses, acting as interaction partners for glycoprotein M, but in several varicelloviruses UL49.5 has uniquely evolved additional functions that mediate its participation in TAP inhibition. Inactivation of TAP by UL49.5 involves two events: inhibition of peptide transport through a conformational arrest of the transporter and degradation of TAP by proteasomes. UL49.5 is degraded along with TAP via a reaction that requires the cytoplasmic tail of UL49.5. Thus, UL49.5 represents a unique immune evasion protein that inactivates TAP through a unique two-tiered process
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