Nucleotide Excision Repair in Cancer, Ageing and Stress Resistance

The genetic information that takes care of the proper functioning of all cell types that makes up an organism is organized in DNA. This so-called blue print of life is continuously attacked by a variety of genotoxic agents and environmental stresses that can damage the DNA (Figure 1). For instance, ultraviolet radiation (UV) causes helix-distorting lesions, cis-syn-cyclobutane pyrimidine dimers (CPDs) and pyrimidine-(6,4)-pyrimidone products (6-4PPs) (Sancar, 1996). On the other hand, ionizing radiation (IR) can cause formation of single strand breaks (SSBs) and double strand breaks (DSBs) (van Gent et al., 2001). The organism’s own metabolism generates reactive oxygen species (ROS) (including superoxide anions, hydrogen peroxide and hydroxyl radicals and their numerous subsequent reaction products) lipid peroxidation products, oestrogen metabolites, reactive carbonyl species, endogenous alkylating agents, spontaneous hydrolysis and deamination products (De Bont and van Larebeke, 2004). These result in DNA damages like oxidative DNA lesions, including 8-oxo-2’-deoxyguanosine (oxodG), thymine glycols, cyclopurines and SSBs and DSBs (Hoeijmakers, 2001). Finally, spontaneous modifications of nucleotides such as hydrolysis leading to abasic sites are common in cells. In total this adds up to 104-105 lesions per cell per day (Lindahl, 1993). The consequences of DNA damage can be severe and may lead to cellular malfunctioning caused by hampered transcriptio

Crossing borders; when science meets industry

Economic growth is ultimately driven by advances in productivity. In turn, productivity growth is driven by R&D and by utilisation of the public knowledge pool. This public knowledge pool is generated by universities and public research institutions. Underutilisation by firms of results from public research can deter economic growth, and the question then emerges how to bring science to the market. In this report we explore whether in Europe public knowledge is underutilised by firms, and investigate the quantitative importance of various knowledge transmission channels (such as publications, informal contacts, consulting). Next we study characteristics of universities and firms that may prevent an effective knowledge transfer. Finally we look at a number of policy initiatives designed to foster science-to-industry knowledge spillovers in the Netherlands and a selection of other countries.

Rescue of Progeria in Trichothiodystrophy by Homozygous Lethal Xpd Alleles

Although compound heterozygosity, or the presence of two different mutant alleles of the same gene, is common in human recessive disease, its potential to impact disease outcome has not been well documented. This is most likely because of the inherent difficulty in distinguishing specific biallelic effects from differences in environment or genetic background. We addressed the potential of different recessive alleles to contribute to the enigmatic pleiotropy associated with XPD recessive disorders in compound heterozygous mouse models. Alterations in this essential helicase, with functions in both DNA repair and basal transcription, result in diverse pathologies ranging from elevated UV sensitivity and cancer predisposition to accelerated segmental progeria. We report a variety of biallelic effects on organismal phenotype attributable to combinations of recessive Xpd alleles, including the following: (i) the ability of homozygous lethal Xpd alleles to ameliorate a variety of disease symptoms when their essential basal transcription function is supplied by a different disease-causing allele, (ii) differential developmental and tissue-specific functions of distinct Xpd allele products, and (iii) interallelic complementation, a phenomenon rarely reported at clinically relevant loci in mammals. Our data suggest a re-evaluation of the contribution of “null” alleles to XPD disorders and highlight the potential of combinations of recessive alleles to affect both normal and pathological phenotypic plasticity in mammals

Naar een betere startpositie op de arbeidsmarkt

MBO students with a non-Western migration background experience a less successful entry into the labor market than MBO students without a migration background. There are various explanations for the backlog, which partly lie within the sphere of influence of students, study programs and employers. MBO programs are strongly focused on the internship period in strengthening the starting position of MBO students with a non-Western migration background

Risking innovation:Understanding risk and public service innovation - evidence from a four nation study

This paper presents new evidence about the governance of risk in public service innovation. It finds that risk is currently poorly understood with public service organizations. Either it is presented as a professional issue or it is dealt with purely as an actuarial or health and safety issue. There is little understanding of risk as a core component of innovation. In response, this paper argues for a more nuanced risk governance approach that calls for transparent decision-making on risk in public service innovation in relation to its intended outcomes. Politicians and public service managers need to understand that risk is an inherent element of innovation, because it engages with uncertain outcomes. A framework needs to be evolved to balance these risks against potential benefits and which can drive forward transparent risk governance involving politicians, public service mangers, citizens and local communities and other key stakeholders. This approach also needs to accept that failure can often by an outcome of innovation. The key here is not to maintain the blame culture that has dominate the debate to date but rather to embrace failure as an opportunity to learn and to improve public services and their outcomes

Job Resources and Matching Active Coping Styles as Moderators of the Longitudinal Relation Between Job Demands and Job Strain

Background: Only in a few longitudinal studies it has been examined whether job resources should be matched to job demands to show stress-buffering effects of job resources (matching hypothesis), while there are no empirical studies in which the moderating effect of matching personal characteristics on the stress-buffering effect of job resources has been examined. Purpose: In this study, both the matching hypothesis and the moderating effect of matching active coping styles were examined with respect to the longitudinal relation between job demands, job resources, and job strain.Method: The study group consisted of 317 beginning teachers from Belgium. The two-wave survey data with a 1-year time lag were analyzed by means of structural equation modeling and multiple group analyses. Results: Data did not support the matching hypothesis. In addition, no support was found for the moderating effect of specific active coping styles, irrespective of the level of match. Conclusion: To show stress-buffering effects of job resources, it seems to make no difference whether or not specific types of job demands and job resources are matched, and whether or not individual differences in specific active coping styles are taken into account