Activation of DNA-PK by Ionizing Radiation Is Mediated by Protein Phosphatase 6

DNA-dependent protein kinase (DNA-PK) plays a critical role in DNA damage repair, especially in non-homologous end-joining repair of double-strand breaks such as those formed by ionizing radiation (IR) in the course of radiation therapy. Regulation of DNA-PK involves multisite phosphorylation but this is incompletely understood and little is known about protein phosphatases relative to DNA-PK. Mass spectrometry analysis revealed that DNA-PK interacts with the protein phosphatase-6 (PP6) SAPS subunit PP6R1. PP6 is a heterotrimeric enzyme that consists of a catalytic subunit, plus one of three PP6 SAPS regulatory subunits and one of three ankyrin repeat subunits. Endogenous PP6R1 co-immunoprecipitated DNA-PK, and IR enhanced the amount of complex and promoted its import into the nucleus. In addition, siRNA knockdown of either PP6R1 or PP6 significantly decreased IR activation of DNA-PK, suggesting that PP6 activates DNA-PK by association and dephosphorylation. Knockdown of other phosphatases PP5 or PP1γ1 and subunits PP6R3 or ARS-A did not reduce IR activation of DNA-PK, demonstrating specificity for PP6R1. Finally, siRNA knockdown of PP6R1 or PP6 but not other phosphatases increased the sensitivity of glioblastoma cells to radiation-induced cell death to a level similar to DNA-PK deficient cells. Our data demonstrate that PP6 associates with and activates DNA-PK in response to ionizing radiation. Therefore, the PP6/PP6R1 phosphatase is a potential molecular target for radiation sensitization by chemical inhibition

Urban futures and the code for sustainable homes

Copyright © 2012 ICE Publishing Ltd. Permission is granted by ICE Publishing to print one copy for personal use. Any other use of these PDF files is subject to reprint fees.A 6?6 ha (66 000 m2) regeneration site, commonly referred to as Luneside East, is to be turned from a run down, economically under-achieving area of Lancaster, UK, into a new, distinctive, vibrant, sustainable quarter of the city. As a result several aspects of water planning for 350 new homes and 8000 m2 of workspace needed to be considered before any infrastructure investment was undertaken. This included assessment of the future capacity requirements (i.e. inflows and outflows) for water infrastructure (i.e. mains water supply, wastewater disposal, rainwater storage and stormwater disposal) much of which will be located underground. This paper looks at the implications of various water management strategies on the Luneside East site (e.g. water-efficient appliances, greywater recycling and rainwater harvesting) in line with current policy measures that focus on technology changes alone (e.g. the code for sustainable homes). Based on these findings this paper outlines some basic implications for technological resilience discussed in the context of four ‘world views’ – that is, the urban futures scenarios considered in this special issue. Conclusions are drawn as to how far this can take engineers, planners and developers in understanding and planning for resilient water infrastructure within a development like Luneside East

The Role of Sexual and Reproductive Rights in Social Work Practice

The understanding and promotion of sexual and reproductive rights are essential in the social work profession, not only to improve the health status of affected populations but to advocate effectively for social justice and to respond to globalized realities. This article highlights the relevance of sexual and reproductive rights in the philosophical foundation and practice of social work, emphasizes the impact of reproductive health and rights on women's lives, and proposes a social work agenda that will embrace and promote sexual and reproductive rights. It uses policy statements from the International Federation of Social Workers as well as a human rights framework focused on sexual and reproductive rights that stems from the global feminist movement.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Head and neck osteosarcoma in adults: the province of alberta experience over 26 years

OBJECTIVE: The goal of this study was to describe the incidence, treatment, and outcomes of osteosarcomas in the head and neck over 26 years in the province of Alberta, Canada. DESIGN: Retrospective analysis of 14 patients identified and treated in Alberta between 1974 and 1999. Overall and disease-specific survival were the most important outcomes of interest. RESULTS: The average age was 43 years. The maxilla was the most common primary site. The majority of the patients received surgical treatment in combination with adjuvant chemotherapy. Disease-specific survival was 42% at 2 years and 30.1% at 5 years. Four patients developed osteosarcomas in the field of previous radiation. CONCLUSIONS: Osteosarcoma of the head and neck is very aggressive. In our series, mostly high-grade malignancy affected a middle-aged population. Surgical resection is difficult owing to anatomic restraints, and adjuvant chemotherapy should be considered in most patients. The series is notable for the poor outcome, with a 5-year actuarial survival of 30%. This may reflect the lack of a standardized treatment protocol