Mutagenesis by third-strand-directed psoralen adducts in repair-deficient human cells: high frequency and altered spectrum in a xeroderma pigmentosum variant.

Psoralen-conjugated triple-helix-forming oligonucleotides have been used to generate site-specific mutations within mammalian cells. To investigate factors influencing the efficiency of oligonucleotide-mediated gene targeting, the processing of third-strand-directed psoralen adducts was compared in normal and repair-deficient human cells. An unusually high mutation frequency and an altered mutation pattern were seen in xeroderma pigmentosum variant (XPV) cells compared with normal, xeroderma pigmentosum group A (XPA), and Fanconi anemia cells. In XPV, targeted mutations were produced in the supF reporter gene carried in a simian virus 40 vector at a frequency of 30%, 3-fold above that in normal or Fanconi anemia cells and 6-fold above that in XPA. The mutations generated by targeted psoralen crosslinks and monoadducts in the XPV cells formed a pattern distinct from that in the other three cell lines, with mutations occurring not just at the damaged site but also at adjacent base pairs. Hence, the XPV cells may have an abnormality in trans-lesion bypass synthesis during repair and/or replication, implicating a DNA polymerase or an accessory factor as a basis of the defect in XPV. These results may help to elucidate the repair deficiency in XPV, and they raise the possibility that genetic manipulation via triplex-targeted mutagenesis may be enhanced by modulation of the XPV-associated activity in normal cells.

Phosphorylated and unphosphorylated forms of human single-stranded DNA-binding protein are equally active in simian virus 40 DNA replication and in nucleotide excision repair.

The trimeric human single-stranded DNA-binding protein (HSSB; also called RP-A) plays an essential role in DNA replication, nucleotide excision repair, and homologous DNA recombination. The p34 subunit of HSSB is phosphorylated at the G1/S boundary of the cell cycle or upon exposure of cells to DNA damage-inducing agents including ionizing and UV radiation. We have previously shown that the phosphorylation of p34 is catalyzed by both cyclin-dependent kinase-cyclin A complex and DNA-dependent protein kinase. In this study, we investigated the effect of phosphorylation of p34 by these kinases on the replication and repair function of HSSB. We observed no significant difference with the unphosphorylated and phosphorylated forms of HSSB in the simian virus 40 DNA replication or nucleotide excision repair systems reconstituted with purified proteins. The phosphorylation status of the p34 subunit of HSSB was unchanged during the reactions. We suggest that the phosphorylated HSSB has no direct effect on the basic mechanism of DNA replication and nucleotide excision repair reactions in vitro, although we cannot exclude a role of p34 phosphorylation in modulating HSSB function in vivo through a yet poorly understood control pathway in the cellular response to DNA damage and replication.

Optimization of test and maintenance of ageing components consisting of multiple items and addressing effectiveness

There are many models in the literature that have been proposed in the last decades aimed at assessing the reliability, availability and maintainability (RAM) of safety equipment, many of them with a focus on their use to assess the risk level of a technological system or to search for appropriate design and/or surveillance and maintenance policies in order to assure that an optimum level of RAM of safety systems is kept during all the plant operational life. This paper proposes a new approach for RAM modelling that accounts for equipment ageing and maintenance and testing effectiveness of equipment consisting of multiple items in an integrated manner. This model is then used to perform the simultaneous optimization of testing and maintenance for ageing equipment consisting of multiple items. An example of application is provided, which considers a simplified High Pressure Injection System (HPIS) of a typical Power Water Reactor (PWR). Basically, this system consists of motor driven pumps (MDP) and motor operated valves (MOV), where both types of components consists of two items each. These components present different failure and cause modes and behaviours, and they also undertake complex test and maintenance activities depending on the item involved. The results of the example of application demonstrate that the optimization algorithm provide the best solutions when the optimization problem is formulated and solved considering full flexibility in the implementation of testing and maintenance activities taking part of such an integrated RAM model.

Double-strand break repair gene polymorphisms and risk of breast or ovarian cancer

Deficiencies in DNA repair have been hypothesized to increase cancer risk and excess cancer incidence is a feature of inherited diseases caused by defects in DNA damage recognition and repair. We investigated, using a case-control design, whether the double-strand break repair gene polymorphisms RAD51 5' untranslated region -135 G > C, XRCC2 R188H G > A, and XRCC3 T241M C > T were associated with risk of breast or ovarian cancer in Australian women. Sample sets included 1,456 breast cancer cases and 793 age-matched controls ages under 60 years of age, 549 incident ovarian cancer cases, and 335 controls of similar age distribution. For the total sample and the subsample of Caucasian women, there were no significant differences in genotype distribution between breast cancer cases and controls or between ovarian cancer cases and combined control groups. The crude odds ratios (OR) and 95% confidence intervals (95% CI) associated with the RAD51 GC/CC genotype frequency was OR, 1.10; 95% CI, 0.80-1.41 for breast cancer and OR, 1.22; 95% CI, 0.92-1.62 for ovarian cancer. Similarly, there were no increased risks associated with the XRCC2 GA/AA genotype (OR, 0.98; 95% CI, 0.76-1.26 for breast cancer and OR, 0.93; 95% CI, 0.69-1.25 for ovarian cancer) or the XRCC3 CT/TT genotype (OR, 0.92; 95% Cl, 0.77-1.10 for breast cancer and OR, 0.87; 95% CI, 0.71-1.08 for ovarian cancer). Results were little changed after adjustment for age and other measured risk factors. Although there was little statistical power to detect modest increases in risk for the homozygote variant genotypes, particularly for the rare RAD51 and XRCC2 variants, the data suggest that none of these variants play a major role in the etiology of breast or ovarian cancer.

Renal structural and functional repair in a mouse model of reversal of ureteral obstruction

The end point of immune and nonimmune renal injury typically involves glomerular and tubulointerstitial fibrosis. Although numerous studies have focused on the events that lead to renal fibrosis, less is known about the mechanisms that promote cellular repair and tissue remodeling. Described is a model of renal injury and repair after the reversal of unilateral ureteral obstruction (UUO) in male C57b1/6J mice. Male mice (20 to 25 g) underwent 10 d of UUO with or without 1, 2, 4, or 6 wk of reversal of UUO (R-UUO). UUO resulted in cortical tubular cell atrophy and tubular dilation in conjunction with an almost complete ablation of the outer medulla. This was associated with interstitial macrophage infiltration; increased hydroxyproline content; and upregulated type I, III, IV, and V collagen expression. The volume density of kidney occupied by renal tubules that exhibited a brush border was measured as an assessment of the degree of repair after R-UUO. After 6 wk of R-UUO, there was an increase in the area of kidney occupied by repaired tubules (83.7 +/- 5.9%), compared with 10 d UUO kidneys (32.6 +/- 7.3%). This coincided with reduced macrophage numbers, decreased hydroxyproline content, and reduced collagen accumulation and interstitial matrix expansion, compared with obstructed kidneys from UUO mice. GFR in the 6-wk R-UUO kidneys was restored to 43 to 88% of the GFR in the contralateral unobstructed kidneys. This study describes the regenerative potential of the kidney after the established interstitial matrix expansion and medullary ablation associated with UUO in the adult mouse.

Conversation repair and adult cochlear implantation: A qualitative case study

Conversation breakdown and repair has been suggested to be a common site of the disability arising from acquired hearing impairment in adults. This qualitative case study reports on certain consequences of the use of general versus specific conversation repair initiators for the resolution of repair sequences. The 47 repair sequences analysed in this paper arose in a single 20-minute free and unstructured conversation between an adult bilateral cochlear implantee and his wife, audio-recorded in a clinic setting. The repairs analysed in this paper were undertaken in response to either general (n = 18) or specific (n = 29) repair requests. No difference was found in the number of turns taken to resolve repairs in response to general or specific repair requests. Qualitative analysis demonstrated that uttering the repair initiator in the immediate vicinity of the miscommunicated portion of talk provided the primary cue to the conversation partner about the location and the content of what had been misunderstood. These preliminary findings imply a change to rehabilitation counselling offered to familiar communication partners. Copyright © 2006 John Wiley & Sons, Ltd.

Iowa Construction and Maintenance Traffic Control Handbook, 1976

This Handbook has been prepared by the Iowa DOT as a guide and supplement to the MUTCD. It provides in one document a large number of illustrations which can be easily adapted to specific conditions by field personnel. It is intended to supersede all previous non-conforming standards now being used throughout the state and to provide uniform guidelines for all agencies, public and private, who must conduct construction and maintenance activities on the streets and highways of the state. The illustrations contained herein serve as a quick reference for field personnel to follow, however, no amount of detailed instructions can adequately cover every situation. For this reason, sound judgment is required in using these illustrations to cover actual field conditions.

Exercise and Lifestyle Therapy Improves Weight Maintenance in Young People With Psychosis: A Service Evaluation

INTRODUCTION Young people with psychosis typically have higher rates of premature cardiovascular disease and metabolic disorders compared to non-psychotic peers. This has been primarily due to a sedentary lifestyle, poor diet composition, misuse of harmful substances and higher rates of obesity and smoking. When prescribed obesogenic antipsychotic medication, a weight gain of >12 kg within 2 years is typical. PURPOSE: To examine the benefits of a 12 wk exercise and lifestyle intervention entitled ‘Supporting Health and Promoting Exercise’ (SHAPE) for young people recently diagnosed with psychosis. METHODS Participants (n=26; 8 females; mean age 27.7 ± 5.1) engaged in weekly 45’ education sessions on healthy lifestyle behaviors, including: managing anxiety and depression, mindfulness and relaxation training, substance misuse, smoking cessation, healthy eating and nutritional advice, dental and sexual health care. This was followed by a 45’ exercise session including activities such as circuit and resistance training, yoga, and badminton, led by qualified exercise instructors. Anthropometric data were measured at baseline, 12 wk and 12 month post-intervention. Lifestyle behaviors and clinical measurements, including resting heart rate, blood pressure, total cholesterol, triglycerides, HbA1c and prolactin, were assessed at baseline and 12 months post-intervention as part of their routine clinical care plan. Significant differences over time were assessed using Paired Sample t-tests. RESULTS SHAPE participants (n=26) presented with first episode psychosis (n=11), schizophrenia (n=11), bipolar disorder (n=2), at risk mental state (n=1), and persistent delusion disorder (n=1) of which 52% were prescribed highly obesogenic antipsychotic medications (Clozapine and Olanzepine). Mean baseline data suggests participants were at an increased health risk due to elevated values in mean BMI (70% were overweight or obese), waist circumference, resting heart rate, and triglycerides (see Table 1 & 2). Over 50% reported smoking daily and 85% had elevated resting blood pressure (>120/80 mm Hg). At 12 wk post-intervention, no changes were observed in mean BMI or waist circumference (see Table 1); 19 participants either maintained (mean 0.5 kg: range ± 2 kg) or decreased (mean -5.7 kg: range 2-7 kg) weight; 7 participants increased weight (mean 4.9 kg: range 2.0-9.6 kg). At 12 month post-intervention (n=16), no change was evident in mean BMI, waist circumference, or any other clinical variable (see Table 2). Positive impacts on lifestyle behaviors included 7 participants eating ~400g of fruit/vegetables daily, 2 ceased substance use, 2 ceased alcohol use, 4 ceased smoking and 5 were less sedentary. CONCLUSION At the start of the programme, participants were already at an increased risk for cardiometabolic disorders. Findings suggest that SHAPE supported young people with psychosis to: -attenuate their physical health risk following a 12 wk exercise and lifestyle intervention which were sustained at 12 months follow up. -make positive lifestyle behavior changes leading to sustained improvements in weight maintenance and physical health.

Investigating key decision problems to optimize the operation and maintenance strategy of offshore wind farms

This paper investigates three decision problems with potential to optimize operation and maintenance and logistics strategies for offshore wind farms: the timing of pre-determined jack-up vessel campaigns; selection of crew transfer vessel fleet; and timing of annual services. These problems are compared both in terms of potential cost reduction and the stochastic variability and associated uncertainty of the outcome. Pre-determined jack-up vessel campaigns appear to have a high cost reduction potential but also a higher stochastic variability than the other decision problems. The paper also demonstrates the benefits and difficulties of considering problems together rather than solving them in isolation.

Procurement Case Study and Decision-making Strategies

Objectives The procurement research of Sydney Opera House FM Exemplar Project aims to develop innovative methods and guidelines for the procurement of FM services, applicable to iconic and / or performing arts centre facilities, or facilities with similar FM functions. The initial procurement report in June 2005 analysed the strategic objectives and operational requirements that provide ‘demand statements’ as evaluation criteria in the service procurement process. The subsequent interim procurement report in September 2005 discussed the elements contributing to the criteria for decision-making in the service procurement process. This procurement report concentrates on the research on procurement strategies and innovative methods using a case study approach. The objectives of this report are: • to investigate service procurement methods and process in iconic and/or performing arts centre facilities; • to showcase FM innovation in Sydney Opera House through a case study; • to establish a preliminary decision-making framework and guidelines for selection of appropriate FM procurement routes to provide a useful model for FM community. Findings Findings from this procurement research are presented as follows. • FM innovation and experience of Sydney Opera House • Innovative procurement methods and processes, drawn from a case study of Sydney Opera House as exemplar • An integrated performance framework to link maintenance service functions to high level organisational objective and strategies • Procurement methods and contract outcomes, focusing on building maintenance and cleaning services of Sydney Opera House • Multi-dimensional assessment of Service Providers • General decision-making strategies and guidelines for selection of appropriate FM procurement routes Further Research Whilst the Sydney Opera House case study emphasises the experience of Sydney Opera House, a study of procurement strategies and methods from published research and FM good practice will supply facilities managers with alternative procurement routes. Further research on the procurement theme will develop a final decision-making model for the procurement of FM services, drawn from the evaluation of the case study outcomes, as well as FM good practice and findings from current published research.

Whole of life cycle cost analysis in bridge rehabilitation

The report presents a methodology for whole of life cycle cost analysis of alternative treatment options for bridge structures, which require rehabilitation. The methodology has been developed after a review of current methods and establishing that a life cycle analysis based on a probabilistic risk approach has many advantages including the essential ability to consider variability of input parameters. The input parameters for the analysis are identified as initial cost, maintenance, monitoring and repair cost, user cost and failure cost. The methodology utilizes the advanced simulation technique of Monte Carlo simulation to combine a number of probability distributions to establish the distribution of whole of life cycle cost. In performing the simulation, the need for a powerful software package, which would work with spreadsheet program, has been identified. After exploring several products on the market, @RISK software has been selected for the simulation. In conclusion, the report presents a typical decision making scenario considering two alternative treatment options.

Report : stochastic analysis of road asset data for maintenance cost prediction

Reliable budget/cost estimates for road maintenance and rehabilitation are subjected to uncertainties and variability in road asset condition and characteristics of road users. The CRC CI research project 2003-029-C ‘Maintenance Cost Prediction for Road’ developed a method for assessing variation and reliability in budget/cost estimates for road maintenance and rehabilitation. The method is based on probability-based reliable theory and statistical method. The next stage of the current project is to apply the developed method to predict maintenance/rehabilitation budgets/costs of large networks for strategic investment. The first task is to assess the variability of road data. This report presents initial results of the analysis in assessing the variability of road data. A case study of the analysis for dry non reactive soil is presented to demonstrate the concept in analysing the variability of road data for large road networks. In assessing the variability of road data, large road networks were categorised into categories with common characteristics according to soil and climatic conditions, pavement conditions, pavement types, surface types and annual average daily traffic. The probability distributions, statistical means, and standard deviation values of asset conditions and annual average daily traffic for each type were quantified. The probability distributions and the statistical information obtained in this analysis will be used to asset the variation and reliability in budget/cost estimates in later stage. Generally, we usually used mean values of asset data of each category as input values for investment analysis. The variability of asset data in each category is not taken into account. This analysis method demonstrated that it can be used for practical application taking into account the variability of road data in analysing large road networks for maintenance/rehabilitation investment analysis.

Engaging, enraging public relations and the role of the other

The intention of this paper is to further the discussion around the development of theories of public relations by introducing to the mix the concept of the Other from the field of cultural studies. The development of discipline-specific theories as part of a “scholarly body of knowledge” (Wylie, 1994, p.2) – or at least a “unique” knowledge base (Parkinson, 2001) – has been suggested as one of the defining characteristics of a true profession. In the case of public relations, this is a development that has occurred relatively recently. Since public relations first began to emerge as a distinct practice in the early part of the 20th century, there has been a tendency to appropriate theories from other areas (such as organisational and media studies) to create a relevant theory base to explore, describe and predict public relations activities. However, these theories were often rarely more than a ‘best fit’ solution, and resulting areas of discrepancy led to much confusion surrounding the form and function of public relations. It could be argued therefore that the development of dedicated public relations theory – ideas that encompass the creation, maintenance and enhancement of relationships between organisations and publics as primary motivations – only began in the latter half of the 20th century with the work of people such as Grunig and Hunt, and latterly Ledingham and Bruning among others.

Truck overloading study in developing countries and strategies to minimize its impact

Overloading truck traffic is an untenable problem around the world. The occurrence of overloaded truck traffic can be evidence of rapid development of an economy. Most of the developing countries emphasize the development of economy, thus supporting reform of infrastructure is limited. This research investigates the relationship between truck overloading and the condition of road damage. The objective of this research is to determine the amount of economic loss due to overloaded truck traffic is. Axle load will be used to calculate the total ESAL to pavement. This study intends to provide perspective on the relationship between change in axle load due to overloading and the resultant service life of pavement. It can then be used in the estimation of pavement damage in other developing countries facing the problem of truck overloading. In conclusion, economical loss was found, which include reduction of pavement life and increase in maintenance and rehabilitation (M&R) cost. As a result, net present value (NPV) of pavement investment with overloading truck traffic is higher than normal truck traffic.

Predication, propagation, and mediation SFL, CDA, and the inculcation of evaluative meaning systems

In this chapter I propose a theoretical framework for understanding the role of mediation processes in the inculcation, maintenance, and change of evaluative meaning systems, or axiologies, and how such a perspective can provide a useful and complementary dimension to analysis for SFL and CDA. I argue that an understanding of mediation—the movement of meaning across time and space—is essential for the analysis of meaning. Using two related texts as examples, I show how an understanding of mediation can aid SFL and CDA practitioners in the analysis of social change.