Cells deficient in the base excision repair protein, DNA polymerase beta, are hypersensitive to oxaliplatin chemotherapy

A significant proportion of human cancers overexpress DNA polymerase beta (Pol beta), the major DNA polymerase involved in base excision repair. The underlying mechanism and biological consequences of overexpression of this protein are unknown. We examined whether Pol beta, expressed at levels found in tumor cells, is involved in the repair of DNA damage induced by oxaliplatin treatment and whether the expression status of this protein alters the sensitivity of cells to oxaliplatin. DNA damage induced by oxaliplatin treatment of HCT116 and HT29 colon cancer cells was observed to be associated with the stabilization of Pol beta protein on chromatin. In comparison with HCT116 colon cancer cells, isogenic oxaliplatin-resistant (HCT-OR) cells were found to have higher constitutive levels of Pol beta protein, faster in vitro repair of a DNA substrate containing a single nucleotide gap and faster repair of 1,2-GG oxaliplatin adduct levels in cells. In HCT-OR cells, small interfering RNA knockdown of Pol beta delayed the repair of oxaliplatin-induced DNA damage. In a different model system, Pol beta-deficient fibroblasts were less able to repair 1,2-GG oxaliplatin adducts and were hypersensitive to oxaliplatin treatment compared with isogenic Pol beta-expressing cells. Consistent with previous studies, Pol beta-deficient mouse fibroblasts were not hypersensitive to cisplatin treatment. These data provide the first link between oxaliplatin sensitivity and DNA repair involving Pol beta. They demonstrate that Pol beta modulates the sensitivity of cells to oxaliplatin treatment. Oncogene (2010) 29, 463-468; doi:10.1038/onc.2009.327; published online 19 October 2009

The Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer's Disease

Rare mutations in AßPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AßPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.

Is everyone Irish on St Patrick's Day? Divergent expectations and experiences of collective self-objectification at a multicultural parade

We examine experiences of collective self-objectification (CSO) (or its failure) among participants in a ‘multicultural’ St Patrick's Day parade. A two-stage interview study was carried out in which 10 parade participants (five each from ethnic majority and minority groups) were interviewed before and after the event. In pre-event interviews, all participants understood the parade as an opportunity to enact social identities, but differed in the category definitions and relations they saw as relevant. Members of the white Irish majority saw the event as being primarily about representing Ireland in a positive, progressive, light, whereas members of minority groups saw it as an opportunity to have their groups' identities and belonging in Ireland recognized by others. Post-event interviews revealed that, for the former group, the event succeeded in giving expression to their relevant category definitions. The latter group, on the other hand, cited features of the event such as inauthentic costume design and a segregated structure as reasons for why the event did not provide the group recognition they sought. The accounts revealed a variety of empowering and disempowering experiences corresponding to the extent of enactment. We consider the implications in terms of CSO, the performative nature of dual identities, as well as the notion of multicultural recognition.

Patrick Moore, Arthur C. Clarke and ‘British Outer Space’ in the mid 20th century

This article seeks to explore a notion of 'British outer space' in the mid 20th century with reference to the British Interplanetary Society and the works of Patrick Moore and Arthur C. Clarke. Geographies of outer space have been examined following early work by Denis Cosgrove on the Apollo space photographs. Cosgrove's work has encouraged a growing body of work that seeks to examine both the 'Earth from space' perspective as well as its reciprocal, 'space from Earth'. This article aligns itself with the latter viewpoint, in attempting to define a national culture of 'British outer space'. This is found to have an important connection with the British Interplanetary Society, founded in 1933 near Liverpool, which went on to influence the works of Patrick Moore, who edited the magazine Spaceflight and presented the television programme The Sky at Night, and Arthur C. Clarke, who became known as a science fiction writer through his early novels in the 1950s. The themes of audience participation and human destiny in outer space are examined in a close reading of these two case studies, and further engagement with cultures of outer space in geography is encouraged. © The Author(s) 2012.

Book review of Atlas of Anatomy by Patrick W. Tank and Thomas R. Gest:Book review of Atlas of Anatomy

Book review of Atlas of Anatomy by Patrick W. Tank and Thomas R. Gest

Sex hormone binding globulin and insulin resistance

Sex hormone binding globulin (SHBG) is a glycoprotein composed of two 373-amino-acid subunits. The SHBG gene and a promotor region have been identified. The SHBG receptor has yet to be cloned but is known to act through a G-protein-linked second-messenger system following plasma membrane binding. The principal function of SHBG has traditionally been considered to be that of a transport protein for sex steroids, regulating circulating concentrations of free (unbound) hormones and their transport to target tissues. Recent research suggests that SHBG has functions in addition to the binding and transport of sex steroids. Observational studies have associated a low SHBG concentration with an increased incidence of type 2 diabetes mellitus (DM) independent of sex hormone levels in men and women. Genetic studies using Mendelian randomization analysis linking three single nucleotide polymorphisms of the SHBG gene to risk of developing type 2 DM suggest SHBG may have a role in the pathogenesis of type 2 DM. The correlation between SHBG and insulin resistance that is evident in a number of cross-sectional studies is in keeping with the suggestion that the association between SHBG and incidence of type 2 DM is explained by insulin resistance. Several potential mechanisms may account for this association, including the identification of dietary factors that influence SHBG gene transcription. Further research to characterize the SHBG-receptor and the SHBG second messenger system is required. An interventional study examining the effects on insulin resistance of altering SHBG concentrations may help in determining whether this association is causal.

Predictive Maintenance for Improved Sustainability - An Ion Beam Etch Endpoint Detection System Use Case

In modern semiconductor manufacturing facilities maintenance strategies are increasingly shifting from traditional preventive maintenance (PM) based approaches to more efficient and sustainable predictive maintenance (PdM) approaches. This paper describes the development of such an online PdM module for the endpoint detection system of an ion beam etch tool in semiconductor manufacturing. The developed system uses optical emission spectroscopy (OES) data from the endpoint detection system to estimate the RUL of lenses, a key detector component that degrades over time. Simulation studies for historical data for the use case demonstrate the effectiveness of the proposed PdM solution and the potential for improved sustainability that it affords.