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.

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Analyzing metabolomics-based challenge tests
Vis, D.J. ; Westerhuis, J.A. ; Jacobs, D.M. ; Duynhoven, J.P.M. van; Wopereis, S. ; Ommen, B. van; Hendriks, M.M.W.B. ; Smilde, A.K. - \ 2015
Metabolomics 11 (2015)1. - ISSN 1573-3882 - p. 50 - 63.
glucose-tolerance test - insulin sensitivity - mathematical-models - component analysis - plasma metabolome - health - asca - reconstruction - phenotype - discovery
Challenge tests are used to assess the resilience of human beings to perturbations by analyzing responses to detect functional abnormalities. Well known examples are allergy tests and glucose tolerance tests. Increasingly, metabolomics analysis of blood or serum samples is used to analyze the biological response of the individual to these challenges. The information content of such metabolomics challenge test data involves both the disturbance and restoration of homeostasis on a metabolic level and is thus inherently different from the analysis of steady state data. It opens doors to study the variation of resilience between individuals beyond the classical biomarkers; preferably in terms of underlying biological processes. We review challenge tests in which metabolomics was used to analyze the biological response. Specifically, we describe strategies to perform statistical analyses on the responses and we will show some examples of these strategies applied to a postprandial challenge that was used to study a diet with anti-inflammatory properties. Finally we discuss open issues and give recommendation for further research.
Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis
Hes, F.J. ; Ruano, D. ; Nieuwenhuis, M. ; Tops, C.M.J. ; Schrumpf, M. ; Nielsen, M. ; Huijts, P.E. ; Wijnen, J. ; Wagner, A. ; Gomet Garcia, E.B. ; Sijmons, R.H. ; Menko, F.H. ; Letteboer, T.G. ; Hoogerbrugge, N. ; Harryvan, J.L. ; Kampman, E. ; Morreau, H. ; Vasen, H.F. ; Wezel, T.G. van - \ 2014
Journal of Medical Genetics 51 (2014)1. - ISSN 0022-2593 - p. 55 - 60.
genome-wide association - susceptibility loci - genetic-variants - apc - mutations - hereditary - families - metaanalysis - mechanisms - phenotype
Background Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20–30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas. Methods We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs). Results We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC. Conclusions These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.
Combating inflammaging through a Mediterranean whole diet approach: The NU-AGE project's conceptual framework and design
Santoro, A. ; Pini, E. ; Scurti, M. ; Palmas, G. ; Berendsen, A.M. ; Brzozowska, A.M. ; Groot, C.P.G.M. de; Feskens, E.J.M. ; Vos, W.M. de - \ 2014
Mechanisms of Ageing and Development 136-137 (2014). - ISSN 0047-6374 - p. 3 - 13.
cd8(+) t-cells - style diet - cellular senescence - older-adults - longevity - immunosenescence - phenotype - frailty - system - muscle
The development of a chronic, low grade, inflammatory status named “inflammaging” is a major characteristic of ageing, which plays a critical role in the pathogenesis of age-related diseases. Inflammaging is both local and systemic, and a variety of organs and systems contribute inflammatory stimuli that accumulate lifelong. The NU-AGE rationale is that a one year Mediterranean whole diet (considered by UNESCO a heritage of humanity), newly designed to meet the nutritional needs of the elderly, will reduce inflammaging in fully characterized subjects aged 65–79 years of age, and will have systemic beneficial effects on health status (physical and cognitive). Before and after the dietary intervention a comprehensive set of analyses, including omics (transcriptomics, epigenetics, metabolomics and metagenomics) will be performed to identify the underpinning molecular mechanisms. NU-AGE will set up a comprehensive database as a tool for a systems biology approach to inflammaging and nutrition. NU-AGE is highly interdisciplinary, includes leading research centres in Europe on nutrition and ageing, and is complemented by EU multinational food industries and SMEs, interested in the production of functional and enriched/advanced traditional food tailored for the elderly market, and European Federations targeting policy makers and major stakeholders, from consumers to EU Food & Drink Industries.
Variably protease-sensitive prionopathy in the UK: a retrospective review 1991-2008
Head, M.W. ; Yull, H.M. ; Ritchie, D.L. ; Langeveld, J.P.M. ; Fletcher, N.A. ; Knight, R.S. ; Ironside, J.W. - \ 2013
Brain 136 (2013)4. - ISSN 0006-8950 - p. 1102 - 1115.
creutzfeldt-jakob-disease - abnormal prion protein - straussler-scheinker-disease - atypical scrapie - phenotype - patient - prp
Variably protease-sensitive prionopathy is a newly described human prion disease of unknown aetiology lying out with the hitherto recognized phenotypic spectrum of Creutzfeldt-Jakob disease. Two cases that conform to the variably protease-sensitive prionopathy phenotype have been identified prospectively in the U.K. since the first description of the condition in 2008 in the U.S.A. To determine the incidence and phenotype of variably protease-sensitive prionopathy within a single well-defined cohort, we have conducted a retrospective review of patients referred to the National Creutzfeldt-Jakob Disease Research & Surveillance Unit during the period 1991-2008. The approach taken was to screen frozen brain tissue by western blotting for the form of protease-resistant prion protein that characterizes variably protease-sensitive prionopathy, followed by neuropathological and clinical review of candidate cases. Cases diagnosed as sporadic Creutzfeldt-Jakob disease with atypical neuropathology were also reviewed. Four hundred and sixty-five cases were screened biochemically, yielding four candidate cases of variably protease-sensitive prionopathy. One was discounted on pathological and clinical grounds, and one was a known case of variably protease-sensitive prionopathy previously reported, leaving two new cases, which were confirmed biochemically and neuropathologically as variably protease-sensitive prionopathy. A third new case that lacked frozen tissue was recognized retrospectively on neuropathological grounds alone. This means that five cases of variably protease-sensitive prionopathy have been identified (prospectively and retrospectively) during the surveillance period 1991-2011 in the U.K. Assuming ascertainment levels equivalent to that of other human prion diseases, these data indicate that variably protease-sensitive prionopathy is a rare phenotype within human prion diseases, which are themselves rare. Biochemical investigation indicates that the abnormal protease-resistant prion protein fragment that characterizes variably protease-sensitive prionopathy is detectable at low levels in some cases of sporadic Creutzfeldt-Jakob disease and conversely, that the form of abnormal prion protein that characterizes sporadic Creutzfeldt-Jakob disease can be found in certain brain regions of cases of variably protease-sensitive prionopathy, indicating molecular overlaps between these two disorders.
EURRECA—Framework for Aligning Micronutrient Recommendations
Veer, P. van 't; Grammatikaki, E. ; Matthys, C. ; Raats, M.M. ; Contor, L. - \ 2013
Critical Reviews in Food Science and Nutrition 53 (2013)10. - ISSN 1040-8398 - p. 988 - 998.
nutrition - requirements - challenges - phenotype - alignment - evaluate - biology - network - europe - health
There is currently no standard approach for deriving micronutrient recommendations, and large variations exist across Europe, causing confusion among consumers, food producers, and policy makers. More aligned information could influence dietary behaviors and potentially lead to a healthier population. Funded by the European Commission, EURRECA (EURopean micronutrient RECommendations Aligned) has developed methods and applications to guide Nutrient Recommendation Setting Bodies through the process of setting micronutrient reference values. The EURRECA approach is crystallized into its framework that outlines a standard process for deriving and using dietary reference values for micronutrients in a transparent, systematic, and scientific way. The 9 activities of the framework can be clustered into four stages (i) defining the problem, (ii) monitoring and evaluating, (iii) deriving dietary reference values, and (iv) using dietary reference values in policy making. The EURRECA framework should not be interpreted as a prescriptive description of a linear process, but as a structured guide for checking that all issues essential for deriving requirements have at least been considered.
A Mutation in VEGFC, a Ligand for VEGFR3, is Associated with Autosomal Dominant Milroy-like Primary Lymphedema
Gordon, K. ; Schulte, D. ; Brice, G. ; Simpson, M.A. ; Roukens, M.G. ; Impel, A. Van; Connell, F. ; Kalidas, K. ; Jeffery, S. ; Mortimer, P.S. ; Mansour, S. ; Schulte-Merker, S. ; Ostergaard, P. - \ 2013
Circulation Research 112 (2013)6. - ISSN 0009-7330 - p. 956 - 960.
disease - vegfc - phenotype - variants - system
Rationale: Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity. Objective: To investigate the underlying cause in patients with clinical signs resembling Milroy disease in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation. Methods and Results: Exome sequencing of 5 such patients was performed, and a novel frameshift variant, c.571_572insTT in VEGFC, a ligand for VEGFR3, was identified in 1 proband. The variant cosegregated with the affected status in the family. An assay to assess the biological function of VEGFC activity in vivo, by expressing human VEGFC in the zebrafish floorplate was established. Forced expression of wild-type human VEGFC in the floorplate of zebrafish embryos leads to excessive sprouting in neighboring vessels. However, when overexpressing the human c.571_572insTT variant in the floorplate, no sprouting of vessels was observed, indicating that the base changes have a marked effect on the activity of VEGFC. Conclusions: We propose that the mutation in VEGFC is causative for the Milroy disease-like phenotype seen in this family. This is the first time a mutation in one of the ligands of VEGFR3 has been reported to cause primary lymphedema
Characterization of polarized THP-1 macrophages and polarizing ability of LPS and food compounds
Chanput, W. ; Mes, J.J. ; Savelkoul, H.F.J. ; Wichers, H.J. - \ 2013
Food & Function 4 (2013)2. - ISSN 2042-6496 - p. 266 - 276.
adipose-tissue macrophages - alternative activation - beta-glucans - mononuclear-cells - gene-expression - kappa-b - monocyte - differentiation - induction - phenotype
Little is known about the polarizing potential of currently used human macrophage cell lines, while a better understanding phenomena can support the prediction of effects in vivo based on in vitro analysis. To test the polarization capability of PMA differentiated-THP-1 macrophages (M0), cells were stimulated with 20 ng/ml IFN¿+1µg/ml LPS and 20 ng/ml IL-4, which are known to influence macrophage polarization in vivo and ex vivo into the M1 and M2 state, respectively. Apart from several well-known M1 and M2 markers, also new possible markers for M1 and M2 polarization were analysed in this study. The expression of M1 marker genes was up-regulated in IFN¿+LPS stimulated-M0 THP-1 macrophages. The IL-4 stimulated-M0 THP-1 macrophages expressed M2 cell membrane receptor genes. However, M2 chemokine and their receptor genes were only slightly up-regulated which might be due to complexity of the secondary cell-cell interaction of the chemokine system. Lipopolysaccharide from E.coli (LPS) and food compounds (lentinan, vitamin D3 (vD3) and the combination of lentinan+vitaminD3 (Len+vD3)) were investigated for their polarizing ability on M0 THP-1 macrophages towards either the M1 or M2 state. LPS (700 ng/ml) was able to skew M0 THP-1 macrophages towards the M1 direction since all analysed M1 marker genes were strongly expressed. Lentinan, vD3 and Len+vD3 did not induce expression of either M1 or M2 markers indicating no polarizing ability of these compounds. Based on the expression of M1 and M2 marker genes we concluded that THP-1 macrophages could be successfully polarized into either the M1or M2 state. Therefore, they can be used as a new macrophage polarizing model to estimate the polarizing/switching ability of test food compounds.
A naturally occurring InDel variation in BraA.FLC.b(BrFLC2) associated with flowering time variation in Brassica rapa
Wu, J. ; Wei, K.Y. ; Cheng, F. ; Li, S.K. ; Wang, Q. ; Jianjun Zhao, Jianjun ; Bonnema, A.B. ; Wang, X.W. - \ 2012
BMC Plant Biology 12 (2012). - ISSN 1471-2229 - 9 p.
locus-c flc - arabidopsis-thaliana - gene - vernalization - frigida - phenotype - mutants - protein
Background: Flowering time is an important trait in Brassica rapa crops. FLOWERING LOCUS C (FLC) is a MADS-box transcription factor that acts as a potent repressor of flowering. Expression of FLC is silenced when plants are exposed to low temperature, which activates flowering. There are four copies of FLC in B. rapa. Analyses of different segregating populations have suggested that BraA.FLC.a (BrFLC1) and BraA.FLC.b (BrFLC2) play major roles in controlling flowering time in B. rapa. Results: We analyzed the BrFLC2 sequence in nine B. rapa accessions, and identified a 57-bp insertion/deletion (InDel) across exon 4 and intron 4 resulting in a non-functional allele. In total, three types of transcripts were identified for this mutated BrFLC2 allele. The InDel was used to develop a PCR-based marker, which was used to screen a collection of 159 B. rapa accessions. The deletion genotype was present only in oil-type B. rapa, including ssp. oleifera and ssp. tricolaris, and not in other subspecies. The deletion genotype was significantly correlated with variation in flowering time. In contrast, the reported splicing site variation in BrFLC1, which also leads to a non-functional locus, was detected but not correlated with variation in flowering time in oil-type B. rapa, although it was correlated with variation in flowering time in vegetable-type B. rapa. Conclusions: Our results suggest that the naturally occurring deletion mutation across exon 4 and intron 4 in BrFLC2 gene contributes greatly to variation in flowering time in oil-type B. rapa. The observed different relationship between BrFLC1 or BrFLC2 and flowering time variation indicates that the control of flowering time has evolved separately between oil-type and vegetable-type B. rapa groups.
Overshooting dynamics in a model adaptive radiation
Meyer, J.R. ; Schoustra, S.E. ; LaChapelle, J. ; Kassen, R.K. - \ 2011
Proceedings of the Royal Society. B: Biological Sciences 278 (2011). - ISSN 0962-8452 - p. 392 - 398.
pseudomonas-fluorescens - experimental evolution - experimental populations - diversification - divergence - diversity - phenotype - history
The history of life is punctuated by repeated periods of unusually rapid evolutionary diversification called adaptive radiation. The dynamics of diversity during a radiation reflect an overshooting pattern with an initial phase of exponential-like increase followed by a slower decline. Much attention has been paid to the factors that drive the increase phase, but far less is known about the causes of the decline phase. Decreases in diversity are rarely associated with climatic changes or catastrophic events, suggesting that they may be an intrinsic consequence of diversification. We experimentally identify the factors responsible for losses in diversity during the later stages of the model adaptive radiation of the bacterium Pseudomonas fluorescens. Proximately, diversity declines because of the loss of biofilm-forming niche specialist morphotypes. We show that this loss occurs despite the presence of strong divergent selection late in the radiation and is associated with continued adaptation of resident niche specialists to both the biotic and abiotic environments. These results suggest that losses of diversity in the latter stages of an adaptive radiation may be a general consequence of diversification through competition and lends support to the idea that the conditions favouring the emergence of diversity are different from those that ensure its long-term maintenance
Genetic variants in lipid metabolism are independently associated with multiple features of the metabolic syndrome
Povel, C.M. ; Boer, J.M. ; Imholz, S. ; Dolle, M.E. ; Feskens, E.J.M. - \ 2011
Lipids in Health and Disease 10 (2011). - ISSN 1476-511X - 7 p.
apolipoprotein-e polymorphism - ester transfer protein - insulin-resistance - cholesterol levels - hdl cholesterol - obesity - risk - mice - modulation - phenotype
Background Our objective was to find single nucleotide polymorphisms (SNPs), within transcriptional pathways of glucose and lipid metabolism, which are related to multiple features of the metabolic syndrome (MetS). Methods 373 SNPs were measured in 3575 subjects of the Doetinchem cohort. Prevalence of MetS features, i.e. hyperglycemia, abdominal obesity, decreased HDL-cholesterol levels and hypertension, were measured twice in 6 years. Associations between the SNPs and the individual MetS features were analyzed by log-linear models. For SNPs related to multiple MetS features (P <0.01), we investigated whether these associations were independent of each other. Results Two SNPs, CETP Ile405Val and APOE Cys112Arg, were associated with both the prevalence of low HDL-cholesterol level (Ile405Val P = <.0001; Cys112Arg P = 0.001) and with the prevalence of abdominal obesity (Ile405Val P = 0.007; Cys112Arg P = 0.007). For both SNPs, the association with HDL-cholesterol was partly independent of the association with abdominal obesity and vice versa. Conclusion Two SNPs, mainly known for their role in lipid metabolism, were associated with two MetS features i.e., low HDL-cholesterol concentration, as well as, independent of this association, abdominal obesity. These SNPs may help to explain why low HDL-cholesterol levels and abdominal obesity frequently co-occur
The cytosolic B-glucosidase GBA3 does not influence type 1 Gaucher disease manifestation
Dekker, N. ; Voorn-Brouwer, T. ; Verhoek, M. ; Wennekes, T. ; Narayan, R.S. ; Speijer, D. ; Hollak, C.E.M. ; Overkleeft, H.S. ; Boot, R.G. ; Aerts, J.M.F.G. - \ 2011
Blood Cells Molecules and Diseases 46 (2011)1. - ISSN 1079-9796 - p. 19 - 26.
klotho-related protein - human-liver - nonlysosomal glucosylceramidase - marked elevation - specificity - glucocerebrosidase - phenotype - beta-glucosidase-2 - deglycosylation - identification
GBA3, also known as cytosolic ß-glucosidase, is thought to hydrolyze xenobiotic glycosides in man. Deficiency of glucocerebrosidase (GBA), a ß-glucosidase degrading glucosylceramide, underlies Gaucher disease. We examined GBA3, which recently was proposed to degrade glucosylceramide and influence the clinical manifestation of Gaucher disease. Recombinant GBA3 was found to hydrolyze artificial substrates such as 4-methylumbelliferyl-ß-D-glucoside and C6-NBD-glucosylceramide, but hydrolysis of naturally occurring lipids like glucosylceramide and glucosylsphingosine was hardly detected. Consistent with this, inhibition of GBA3 in cultured cells using a novel inhibitor (alpha-1-C-nonyl-DIX) did not result in an additional increase in glucosylceramide as compared to GBA inhibition alone. Examination of the GBA3 gene led to the identification of a common substitution in its open reading frame (1368T¿A), resulting in a truncated GBA3 protein missing the last a-helix of its (ß/a)8 barrel. Both recombinant 1368A GBA3 and 1368A enzyme from spleen of a homozygous individual were found to be inactive. Amongst non-neuronopathic (type 1) Gaucher disease patients, we subsequently identified individuals being wild-type, heterozygous, or homozygous for the GBA3 1368T¿A mutation. No correlation was observed between GBA3 1368A/T haplotypes and severity of type 1 Gaucher disease manifestation. In conclusion, GBA3 does not seem to modify type 1 Gaucher disease manifestation
Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein
Zou, W.Q. ; Puoti, G. ; Xiao, X. ; Yuan, J. ; Qing, L. ; Cali, I. ; Shimoji, M. ; Langeveld, J.P.M. ; Castellani, R. ; Notari, S. ; Crain, B. ; Schmidt, R. ; Geschwind, M. ; DeArmond, S.J. ; Cairns, N. ; Dickson, D. ; Honig, I. ; Torres, J.M. ; Mastrianni, J. ; Capellari, S. ; Giaccone, G. ; Belay, E.D. ; Schonberger, L.B. ; Cohen, M. ; Perry, G. ; Kong, Q. ; Parchi, P. ; Tagliavini, F. ; Gambetti, P. - \ 2010
Annals of Neurology 68 (2010)2. - ISSN 0364-5134 - p. 162 - 172.
creutzfeldt-jakob-disease - gerstmann-straussler-scheinker - codon 129 - prp - cjd - classification - transmission - phenotype - subtypes - brain
Objective: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Methods: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Results: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with "variably protease-sensitive prionopathy" (VPSPr). None of the subjects had mutations in the PrP gene coding region. Interpretation: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Straussler-Scheinker disease. ANN NEUROL 2010;68:162-172
Effect of tomato pleiotropic ripening mutations on flavour volatile biosynthesis
Kovacs, K. ; Fray, R.G. ; Tikunov, Y.M. ; Graham, N. ; Bradley, G. ; Seymour, G.B. ; Bovy, A.G. ; Grierson, D. - \ 2009
Phytochemistry 70 (2009)8. - ISSN 0031-9422 - p. 1003 - 1008.
high-pigment-1 mutant - hydroperoxide lyase - oxylipin metabolism - signal-transduction - lipoxygenase genes - fruit - ethylene - manipulation - phenotype - expression
Ripening is a tightly controlled and developmentally regulated process involving networks of genes, and metabolites that result in dramatic changes in fruit colour, texture and flavour. Molecular and genetic analysis in tomato has revealed a series of regulatory genes involved in fruit development and ripening, including MADS box and SPB box transcription factors and genes involved in ethylene synthesis, signalling and response. Volatile metabolites represent a significant part of the plant metabolome, playing an important role in plant signalling, defence strategies and probably in regulatory mechanisms. They also play an important role in fruit quality. In order to acquire a better insight into the biochemical and genetic control of flavour compound generation and links between these metabolites and the central regulators of ripening, five pleiotropic mutant tomato lines were subjected to volatile metabolite profiling in comparison with wild-type Ailsa Craig. One hundred and seventeen volatile compounds were identified and quantified using SPME (Solid Phase Microextraction) headspace extraction followed by Gas Chromatography–Mass Spectrometry (GC–MS) and the data were subjected to multivariate comparative analysis. We find that the different mutants each produce distinct volatile profiles during ripening. Through principal component analysis the volatiles most dramatically affected are those derived from fatty-acids. The results are consistent with the suggestion that specific isoforms of lipoxygenase located in the plastids and the enzymes that provide precursors and downstream metabolites play a key role in determining volatile composition.
S layer protein A of Lactobacillus acidophilus NCFM regulates immature dendritic cell and T cell functions
Konstantinov, S.R. ; Smidt, H. ; Vos, W.M. de; Bruijns, S.C. ; Singh, S.K. ; Valence, F. ; Molle, D. ; Lortal, S. ; Altermann, E. ; Klaenhammer, T.R. ; Kooyk, Y. van - \ 2008
Proceedings of the National Academy of Sciences of the United States of America 105 (2008)49. - ISSN 0027-8424 - p. 19474 - 19479.
dc-sign - probiotic bacteria - receptors - lipopolysaccharide - modulation - phenotype - antigen
Dendritic cells (DCs) are antigen-presenting cells that play an essential role in mucosal tolerance. They regularly encounter beneficial intestinal bacteria, but the nature of these cellular contacts and the immune responses elicited by the bacteria are not entirely elucidated. Here, we examined the interactions of Lactobacillus acidophilus NCFM and its cell surface compounds with DCs. L. acidophilus NCFM attached to DCs and induced a concentration-dependent production of IL-10, and low IL-12p70. We further demonstrated that the bacterium binds to DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), a DC- specific receptor. To identify the DC-SIGN ligand present on the bacterium, we took advantage of a generated array of L. acidophilus NCFM mutants. A knockout mutant of L. acidophilus NCFM lacking the surface (S) layer A protein (SlpA) was significantly reduced in binding to DC-SIGN. This mutant incurred a chromosomal inversion leading to dominant expression of a second S layer protein, SlpB. In the SlpB-dominant strain, the nature of the interaction of this bacterium with DCs changed dramatically. Higher concentrations of proinflammatory cytokines such as IL-12p70, TNFalpha, and IL-1beta were produced by DCs interacting with the SlpB-dominant strain compared with the parent NCFM strain. Unlike the SlpA-knockout mutant, T cells primed with L. acidophilus NCFM stimulated DCs produced more IL-4. The SlpA-DC-SIGN interaction was further confirmed as purified SlpA protein ligated directly to the DC-SIGN. In conclusion, the major S layer protein, SlpA, of L. acidophilus NCFM is the first probiotic bacterial DC-SIGN ligand identified that is functionally involved in the modulation of DCs and T cells functions
Genome-wide assessment of worldwide chicken SNP genetic diversity indicates significant absence of rare alleles in commercial breeds
Muir, W.M. ; Wong, G.K. ; Zhang, Y. ; Groenen, M.A.M. ; Crooijmans, R.P.M.A. ; Megens, H.J.W.C. - \ 2008
Proceedings of the National Academy of Sciences of the United States of America 105 (2008)45. - ISSN 0027-8424 - p. 17312 - 17317.
dierveredeling - pluimvee - rassen (dieren) - dierlijke productie - biodiversiteit - genetische diversiteit - allelen - inteelt - genotyping - single nucleotide polymorphism - animal breeding - poultry - breeds - animal production - biodiversity - genetic diversity - alleles - inbreeding - linkage disequilibrium - population-structure - myostatin gene - polymorphism - phenotype - selection - mutation - growth - cattle
Breed utilization, genetic improvement, and industry consolidation are predicted to have major impacts on the genetic composition of commercial chickens. Consequently, the question arises as to whether sufficient genetic diversity remains within industry stocks to address future needs. With the chicken genome sequence and more than 2.8 million single-nucleotide polymorphisms (SNPs), it is now possible to address biodiversity using a previously unattainable metric: missing alleles. To achieve this assessment, 2551 informative SNPs were genotyped on 2580 individuals, including 1440 commercial birds. The proportion of alleles lacking in commercial populations was assessed by (1) estimating the global SNP allele frequency distribution from a hypothetical ancestral population as a reference, then determining the portion of the distribution lost, and then (2) determining the relationship between allele loss and the inbreeding coefficient. The results indicate that 50% or more of the genetic diversity in ancestral breeds is absent in commercial pure lines. The missing genetic diversity resulted from the limited number of incorporated breeds. As such, hypothetically combining stocks within a company could recover only preexisting within-breed variability, but not more rare ancestral alleles. We establish that SNP weights act as sentinels of biodiversity and provide an objective assessment of the strains that are most valuable for preserving genetic diversity. This is the first experimental analysis investigating the extant genetic diversity of virtually an entire agricultural commodity. The methods presented are the first to characterize biodiversity in terms of allelic diversity and to objectively link rate of allele loss with the inbreeding coefficient
Metabolic capacity of Bacillus cereus strains ATCC 14579 and ATCC 10987 interlinked with comparative genomics
Mols, J.M. ; Been, M.W.H.J. de; Zwietering, M.H. ; Moezelaar, R. ; Abee, T. - \ 2007
Environmental Microbiology 9 (2007)12. - ISSN 1462-2912 - p. 2933 - 2944.
listeria-monocytogenes - sequence-analysis - anthracis pxo1 - hemolysin-bl - growth - subtilis - genes - identification - epidemiology - phenotype
Bacillus cereus is an important food-borne pathogen and spoilage organism. In this study, numerous phenotypes and the genomes of B. cereus strains ATCC 14579 and ATCC 10987 were analysed to compare their metabolic capacity and stress resistance potential. The growth performance of the two strains was assessed for nearly 2000 phenotypes, including use of nutrient sources, performance in acid and basic environments, osmo-tolerance and antibiotic resistance. Several food-relevant phenotypic differences were found between ATCC 14579 and ATCC 10987, such as differences in utilization of carbohydrates, peptides, amino acids and ammonia. Subsequently, the genomes of both strains were analysed with INPARANOID to search for strain-specific open reading frames (ORFs). B. cereus ATCC 14579 and ATCC 10987 were found to harbour 983 and 1360 strain-specific ORFs respectively. The strain-specific phenotypic features were interlinked with corresponding genetic features and for several phenotypic differences a related strain-specific genetic feature could be identified. In conclusion, the combination of phenotypic data with strain-specific genomic differences has led to detailed insight into the performance of the two B. cereus strains, and may supply indicators for the performance of these bacteria in different environments and ecological niches.
Detection of type 1 prion protein in variant Creutzfeldt-Jakob disease
Yull, H.M. ; Ritchie, D.L. ; Langeveld, J.P.M. ; Zijderveld, F.G. van; Bruce, M.E. ; Ironside, J.W. ; Head, M.W. - \ 2006
American Journal of Pathology 168 (2006)1. - ISSN 0002-9440 - p. 151 - 157.
bovine spongiform encephalopathy - molecular classification - sheep scrapie - bse - cjd - prpsc - mice - transmissions - heterogeneity - phenotype
Molecular typing of the abnormal form of the prion protein (PrPSc) has come to be regarded as a powerful tool in the investigation of the prion diseases. All evidence thus far presented indicates a single PrPSc molecular type in variant Creutzfeldt-Jakob disease (termed type 2B), presumably resulting from infection with a single strain of the agent (bovine spongiform encephalopathy). Here we show for the first time that the PrPSc that accumulates in the brain in variant Creutzfeldt-Jakob disease also contains a minority type 1 component. This minority type 1 PrPSc was found in all 21 cases of variant Creutzfeldt-Jakob disease tested, irrespective of brain region examined, and was also present in the variant Creutzfeldt-Jakob disease tonsil. The quantitative balance between PrPSc types was maintained when variant Creutzfeldt-Jakob disease was transmitted to wild-type mice and was also found in bovine spongiform encephalopathy cattle brain, indicating that the agent rather than the host specifies their relative representation. These results indicate that PrPSc molecular typing is based on quantitative rather than qualitative phenomena and point to a complex relationship between prion protein biochemistry, disease phenotype and agent strain
The enhanced virulence of very virulent infectious bursal disease virus is partly determined by its B-segment
Boot, H.J. ; Hoekman, A.J.W. ; Gielkens, A.L.J. - \ 2005
Archives of Virology 150 (2005)1. - ISSN 0304-8608 - p. 137 - 144.
type-1 poliovirus - amino-acids - attenuation - vp2 - phenotype - adaptation - sequence - strains - vaccine - rescue
There is a remarkable difference in virulence of infectious bursal disease virus (IBDV) strains ranging from sub-clinical infections for serotype 2 and cell culture adapted serotype 1 strains, to 100% mortality for very virulent serotype 1 strains in young SPF chickens. It is known that cell culture adaptation related attenuation is determined by distinct mutations in the hypervariable region of the VP2 outer capsid protein, encoded on the A-segment. Amino acid mutations in the hypervariable VP2 region however, offer no explanation for the difference in virulence of classical and very virulent serotype 1 strains. Here we show by in vitro and in vivo analysis of rescued segment reassorted IBDVs that virulence factors are not only located on the A-segment, but on the RNA Dependent RNA Polymerase (VP1) encoding B-segment as well. Insight into the virulence factors of very virulent IBDV will contribute to the improvement of live IBDV vaccines.
The light-hyperresponsive high pigment-2dg mutation of tomato: alterations in the fruit metabolome
Bino, R.J. ; Vos, C.H. de; Lieberman, M. ; Hall, R.D. ; Bovy, A.G. ; Jonker, H.H. ; Tikunov, Y.M. ; Lommen, A. ; Moco, S.I.A. ; Levin, I. - \ 2005
New Phytologist 166 (2005)2. - ISSN 0028-646X - p. 427 - 438.
physiological characterization - high-pigment-1 mutant - signal-transduction - photosystem-ii - plant - quality - photomorphogenesis - phenotype - genotypes - homolog
Overall metabolic modifications between fruit of light-hyperresponsive high-pigment (hp) tomato (Lycopersicon esculentum) mutant plants and isogenic nonmutant (wt) control plants were compared. Targeted metabolite analyses, as well as large-scale nontargeted mass spectrometry (MS)-based metabolite profiling, were used to phenotype the differences in fruit metabolite composition. Targeted high-performance liquid chromatography with photodiode array detection (HPLC-PDA) metabolite analyses showed higher levels of isoprenoids and phenolic compounds in hp-2(dg) fruit. Nontargeted GC-MS profiling of red fruits produced 25 volatile compounds that showed a 1.5-fold difference between the genotypes. Analyses of red fruits using HPLC coupled to high-resolution quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) in both ESI-positive and ESI-negative mode generated, respectively, 6168 and 5401 mass signals, of which 142 and 303 showed a twofold difference between the genotypes. hp-2(dg) fruits are characterized by overproduction of many metabolites, several of which are known for their antioxidant or photoprotective activities. These metabolites may now be more closely implicated as resources recruited by plants to respond to and manage light stress. The similarity in metabolic alterations in fruits of hp-1 and hp-2 mutant plants helps us to understand how hp mutations affect cellular processes.
The role of cryptochrome 2 in flowering in Arabidopsis
El-Assal, S.E.D. ; Alonso-Blanco, C. ; Peeters, A.J.M. ; Wagemaker, C. ; Weller, J.L. ; Koornneef, M. - \ 2003
Plant Physiology 133 (2003)4. - ISSN 0032-0889 - p. 1504 - 1516.
landsberg erecta - phytochrome-a - circadian clock - locus-c - genetic-control - time - thaliana - mutants - encodes - phenotype
We have investigated the genetic interactions between cry2 and the various flowering pathways in relation to the regulation of flowering by photoperiod and vernalization. For this, we combined three alleles of CRY2, the wild-type CRY2-Landsberg erecta (Ler), a cry2 loss-of-function null allele, and the gain-of-function CRY2-Cape Verde Islands (Cvi), with mutants representing the various photoreceptors and flowering pathways. The analysis of CRY2 alleles combined with photoreceptor mutants showed that CRY2-Cvi could compensate the loss of phyA and cry1, also indicating that cry2 does not require functional phyA or cry1. The analysis of mutants of the photoperiod pathway showed epistasis of co and gi to the CRY2 alleles, indicating that cry2 needs the product of CO and GI genes to promote flowering. All double mutants of this pathway showed a photoperiod response very much reduced compared with Ler. In contrast, mutations in the autonomous pathway genes were additive to the CRY2 alleles, partially overcoming the effects of CRY2-Cvi and restoring day length responsiveness. The three CRY2 alleles were day length sensitive when combined with FRI-Sf2 and/or FLC-Sf2 genes, which could be reverted when the delay of flowering caused by FRI-Sf2 and FLC-Sf2 alleles was removed by vernalization. In addition, we looked at the expression of FLC and CRY2 genes and showed that CRY2 is negatively regulated by FLC. These results indicate an interaction between the photoperiod and the FLC-dependent pathways upstream to the common downstream targets of both pathways, SOC1 and FT.
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