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Search Results: 1 - 10 of 35035 matches for " van Steeg Harry "
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Preoperative fasting protects aged-corpulent mice against renal ischemia-reperfusion injury
Jongbloed Franny,Uzermans Jan NM,van den Engel Sandra,van Steeg Harry
BMC Proceedings , 2012, DOI: 10.1186/1753-6561-6-s3-p63
MPHASYS: a mouse phenotype analysis system
R Calder, Rudolf B Beems, Harry van Steeg, I Mian, Paul HM Lohman, Jan Vijg
BMC Bioinformatics , 2007, DOI: 10.1186/1471-2105-8-183
Abstract: Here we introduce a Mouse Phenotype Analysis System (MPHASYS), a platform for integrating data generated by studies of mouse models of human biology and disease such as aging and cancer. This computational platform is designed to provide a standardized methodology for working with animal data; a framework for data entry, analysis and sharing; and ontologies and methodologies for ensuring accurate data capture. We describe the tools that currently comprise MPHASYS, primarily ones related to mouse pathology, and outline its use in a study of individual animal-specific patterns of multiple pathology in mice harboring a specific germline mutation in the DNA repair and transcription-specific gene Xpd.MPHASYS is a system for analyzing multiple data types from individual animals. It provides a framework for developing data analysis applications, and tools for collecting and distributing high-quality data. The software is platform independent and freely available under an open-source license [1].As the volume, complexity and breadth of biological data collected on model organisms increases, more flexible and extensible systems for data collection, integration and analysis are required. Existing systems often focus on data obtained in a specific context. For example, the Knockout Mouse Project [2] aims to generate mouse embryonic stem cells containing a null mutation in every gene in the mouse genome; the Mouse Phenome Project [3] and the Mouse Genome Database [4] aim to gather and disseminate baseline phenotypic data for a defined set of inbred mouse strains; the Mouse Tumor Biology Database [5] maintains information on the mouse as a model system of hereditary cancer; and Pathbase [6] is a database of histopathology images derived from mutant or genetically manipulated mice annotated using a systematized ontology (MPATH). Although these systems expand our understanding of particular phenotypes, they focus on experimental observations associated with classes of animals rath
Comparison of clastogen-induced gene expression profiles in wild-type and DNA repair-deficient Rad54/Rad54B cells
Anuska G Mahabir, Mirjam M Schaap, Jeroen LA Pennings, Jan van Benthem, Coenraad FM Hendriksen, Harry van Steeg
BMC Genomics , 2010, DOI: 10.1186/1471-2164-11-24
Abstract: Most exposures resulted in an induction of DNA damage signaling and apoptosis genes and a reduced expression of cell division genes in cells of both genotypes. As expected, responses to N-ac-AAF were very similar in both genotypes. ENU exposure did not lead to significant gene expression changes in cells of both genotypes, presumably due to its short half-life. Gene expression responses to clastogens, however, showed a genotype-dependent effect for BLM and MMC. MMC treated Rad54/Rad54B MEFs showed no induction of p53-signaling, DNA damage response and apoptosis as seen for all the other treatments.These data support our finding that different types of clastogens exist and that responses to these types depend on the DNA repair status of the cells.DNA double-strand breaks (DSBs) have detrimental effects on the integrity of chromosomes and cell viability. Unrepaired or incorrectly repaired DSBs can lead to loss of chromosomes or cell cycle arrest which may lead to uncontrolled cell growth, cell death or carcinogenesis [1,2]. DSBs mainly arise through exogenous DNA-damaging agents (clastogens) and endogenous sources. Clastogens can be divided into compounds that induce single/double-strand breaks, like bleomycin (BLM) and γ-radiation, and compounds that induce interstrand crosslinks (ICLs), like mitomycin C (MMC). The latter are extremely cytotoxic [3].The clastogenic potential of chemicals can be tested with different types of genotoxicity assays. In previous studies we measured the lacZ mutant frequencies (lacZ MF) in both wild-type (WT) and DNA repair-deficient Rad54/Rad54B MEFs derived from mice carrying the lacZ gene in a plasmid vector. Cells were treated with both mutagenic (causing gene mutations) and clastogenic (causing chromosome aberrations) compounds [4]. The Rad54/Rad54B MEFs have a defect in the Rad54 and the Rad54B genes (both involved in Homologous Recombination (HR) repair), which we assume may cause a shift in the repair of single- or double-strand br
High Preservation of CpG Cytosine Methylation Patterns at Imprinted Gene Loci in Liver and Brain of Aged Mice
Silvia Gravina, Martijn E. T. Dollé, Tao Wang, Harry van Steeg, Paul Hasty, Jan Hoeijmakers, Jan Vijg
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073496
Abstract: A gradual loss of the correct patterning of 5-methyl cytosine marks in gene promoter regions has been implicated in aging and age-related diseases, most notably cancer. While a number of studies have examined DNA methylation in aging, there is no consensus on the magnitude of the effects, particularly at imprinted loci. Imprinted genes are likely candidate to undergo age-related changes because of their demonstrated plasticity in utero, for example, in response to environmental cues. Here we quantitatively analyzed a total of 100 individual CpG sites in promoter regions of 11 imprinted and non-imprinted genes in liver and cerebral cortex of young and old mice using mass spectrometry. The results indicate a remarkably high preservation of methylation marks during the aging process in both organs. To test if increased genotoxic stress associated with premature aging would destabilize DNA methylation we analyzed two DNA repair defective mouse models showing a host of premature aging symptoms in liver and brain. However, also in these animals, at the end of their life span, we found a similarly high preservation of DNA methylation marks. We conclude that patterns of DNA methylation in gene promoters of imprinted genes are surprisingly stable over time in normal, postmitotic tissues and that the multiple documented changes with age are likely to involve exceptions to this pattern, possibly associated with specific cellular responses to age-related changes other than genotoxic stress.
Benzo(a)pyrene induces similar gene expression changes in testis of DNA repair proficient and deficient mice
Nicole Verhofstad, Jeroen LA Pennings, Conny van Oostrom, Jan van Benthem, Frederik J van Schooten, Harry van Steeg, Roger WL Godschalk
BMC Genomics , 2010, DOI: 10.1186/1471-2164-11-333
Abstract: Two-Way ANOVA revealed only 4 genes differentially expressed between wild type and Xpc-/- mice, and 984 genes between testes of B[a]P treated and untreated mice irrespective of the mouse genotype. However, the level in which these B[a]P regulated genes are expressed differs between Wt and Xpc-/- mice (p = 0.000000141), and were predominantly involved in the regulation of cell cycle, translation, chromatin structure and spermatogenesis, indicating a general stress response. In addition, analysis of cell cycle phase dependent gene expression revealed that expression of genes involved in G1-S and G2-M phase arrest was increased after B[a]P exposure in both genotypes. A slightly higher induction of average gene expression was observed at the G2-M checkpoint in Xpc-/- mice, but this did not reach statistical significance (P = 0.086). Other processes that were expected to have changed by exposure, like apoptosis and DNA repair, were not found to be modulated at the level of gene expression.Gene expression in testis of untreated Xpc-/- and wild type mice were very similar, with only 4 genes differentially expressed. Exposure to benzo(a)pyrene affected the expression of genes that are involved in cell cycle regulation in both genotypes, indicating that the presence of unrepaired DNA damage in testis blocks cell proliferation to protect DNA integrity in both DNA repair proficient and deficient animals.Exposure to chemicals like benzo(a)pyrene (B[a]P) can lead to structural changes in DNA and as a consequence to the development of diseases with a genetic basis [1]. Changes in the DNA sequence can be induced by exposure to chemicals during life, but may also be inherited via mutations in the spermatogonial stem cells; in that way increasing the risk of developing abnormalities or diseases in the offspring [2,3]. The mutagenic potential of B[a]P in male germ cells, however, has still not been fully established. B[a]P related DNA damage was observed at all stages of spermatogene
Public Accountability in the European Union: Is the European Parliament able to hold the European Council accountable?
Marianne van de Steeg
European Integration Online Papers , 2009,
Abstract: The European Council occupies a central role in European politics. Yet it is not officially accountable to any public or parliamentary body for the decisions it makes on behalf of European citizens. National parliaments are only entitled to exert control over their own Heads of Government or State. The European Parliament, as a supranational institution, is the only parliamentary body that regularly discusses European politics with the European Council as a collective, namely via the European Council Presidency. As such, it alone has the possibility to hold the Council accountable for the agreements made at European Summits. However, the European Parliament has limited rights to impose pressure on the European Council Presidency. Nonetheless, despite the lack of a formal accountability arrangement, the European Council Presidency is more forthcoming than could have been expected.
Age-Related Neuronal Degeneration: Complementary Roles of Nucleotide Excision Repair and Transcription-Coupled Repair in Preventing Neuropathology
Dick Jaarsma equal contributor ,Ingrid van der Pluijm equal contributor,Monique C. de Waard,Elize D. Haasdijk,Renata Brandt,Marcel Vermeij,Yvonne Rijksen,Alex Maas,Harry van Steeg,Jan H. J. Hoeijmakers,Gijsbertus T. J. van der Horst
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002405
Abstract: Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR–deficient Csa?/? and Csb?/? CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER–deficient Xpa?/? and Xpc?/? XP mice, but also occurred in XpdXPCS mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR–deficient mice are compatible with focal dysmyelination in CS patients. Both TCR–deficient and NER–deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa?/?, Csb?/?) or highly sporadic (Xpa?/?, Xpc?/?) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR–deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa?/? and Csb?/? TCR–deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR–deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival.
Homeostatic Imbalance between Apoptosis and Cell Renewal in the Liver of Premature Aging XpdTTD Mice
Jung Yoon Park, Mi-Ook Cho, Shanique Leonard, Brent Calder, I. Saira Mian, Woo Ho Kim, Susan Wijnhoven, Harry van Steeg, James Mitchell, Gijsbertus T. J. van der Horst, Jan Hoeijmakers, Pinchas Cohen, Jan Vijg, Yousin Suh
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002346
Abstract: Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. XpdTTD mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W), display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing XpdTTD mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the XpdTTD mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the XpdTTD mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis.
Deletion of Individual Ku Subunits in Mice Causes an NHEJ-Independent Phenotype Potentially by Altering Apurinic/Apyrimidinic Site Repair
Yong Jun Choi, Han Li, Mi Young Son, Xiao-hong Wang, Jamie L. Fornsaglio, Robert W. Sobol, Moonsook Lee, Jan Vijg, Sandra Imholz, Martijn E. T. Dollé, Harry van Steeg, Erwin Reiling, Paul Hasty
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086358
Abstract: Ku70 and Ku80 form a heterodimer called Ku that forms a holoenzyme with DNA dependent-protein kinase catalytic subunit (DNA-PKCS) to repair DNA double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. As expected mutating these genes in mice caused a similar DSB repair-defective phenotype. However, ku70-/- cells and ku80-/- cells also appeared to have a defect in base excision repair (BER). BER corrects base lesions, apurinic/apyrimidinic (AP) sites and single stand breaks (SSBs) utilizing a variety of proteins including glycosylases, AP endonuclease 1 (APE1) and DNA Polymerase β (Pol β). In addition, deleting Ku70 was not equivalent to deleting Ku80 in cells and mice. Therefore, we hypothesized that free Ku70 (not bound to Ku80) and/or free Ku80 (not bound to Ku70) possessed activity that influenced BER. To further test this hypothesis we performed two general sets of experiments. The first set showed that deleting either Ku70 or Ku80 caused an NHEJ-independent defect. We found ku80-/- mice had a shorter life span than dna-pkcs-/- mice demonstrating a phenotype that was greater than deleting the holoenzyme. We also found Ku70-deletion induced a p53 response that reduced the level of small mutations in the brain suggesting defective BER. We further confirmed that Ku80-deletion impaired BER via a mechanism that was not epistatic to Pol β. The second set of experiments showed that free Ku70 and free Ku80 could influence BER. We observed that deletion of either Ku70 or Ku80, but not both, increased sensitivity of cells to CRT0044876 (CRT), an agent that interferes with APE1. In addition, free Ku70 and free Ku80 bound to AP sites and in the case of Ku70 inhibited APE1 activity. These observations support a novel role for free Ku70 and free Ku80 in altering BER.
The Progeroid Phenotype of Ku80 Deficiency Is Dominant over DNA-PKCS Deficiency
Erwin Reiling, Martijn E. T. Dollé, Sameh A. Youssef, Moonsook Lee, Bhawani Nagarajah, Marianne Roodbergen, Piet de With, Alain de Bruin, Jan H. Hoeijmakers, Jan Vijg, Harry van Steeg, Paul Hasty
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093568
Abstract: Ku80 and DNA-PKCS are both involved in the repair of double strand DNA breaks via the nonhomologous end joining (NHEJ) pathway. While ku80?/? mice exhibit a severely reduced lifespan and size, this phenotype is less pronounced in dna-pkcs?/? mice. However, these observations are based on independent studies with varying genetic backgrounds. Here, we generated ku80?/?, dna-pkcs?/? and double knock out mice in a C57Bl6/J*FVB F1 hybrid background and compared their lifespan, end of life pathology and mutation frequency in liver and spleen using a lacZ reporter. Our data confirm that inactivation of Ku80 and DNA-PKCS causes reduced lifespan and bodyweights, which is most severe in ku80?/? mice. All mutant mice exhibited a strong increase in lymphoma incidence as well as other aging-related pathology (skin epidermal and adnexal atrophy, trabacular bone reduction, kidney tubular anisokaryosis, and cortical and medullar atrophy) and severe lymphoid depletion. LacZ mutation frequency analysis did not show strong differences in mutation frequencies between knock out and wild type mice. The ku80?/? mice had the most severe phenotype and the Ku80-mutation was dominant over the DNA-PKCS-mutation. Presumably, the more severe degenerative effect of Ku80 inactivation on lifespan compared to DNA-PKCS inactivation is caused by additional functions of Ku80 or activity of free Ku70 since both Ku80 and DNA-PKCS are essential for NHEJ.
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