hSSB1 interacts directly with the MRN complex stimulating its recruitment to DNA double-strand breaks and its endo-nuclease activity

hSSB1 is a recently discovered single-stranded DNA binding protein that is essential for efficient repair of DNA double-strand breaks (DSBs) by the homologous recombination pathway. hSSB1 is required for the efficient recruitment of the MRN complex to sites of DSBs and for the efficient initiation of ATM dependent signalling. Here we explore the interplay between hSSB1 and MRN. We demonstrate that hSSB1 binds directly to NBS1, a component of the MRN complex, in a DNA damage independent manner. Consistent with the direct interaction, we observe that hSSB1 greatly stimulates the endo-nuclease activity of the MRN complex, a process that requires the C-terminal tail of hSSB1. Interestingly, analysis of two point mutations in NBS1, associated with Nijmegen breakage syndrome, revealed weaker binding to hSSB1, suggesting a possible disease mechanism.

hSSB1 rapidly binds at the sites of DNA double-strand breaks and is required for the efficient recruitment of the MRN complex

hSSB1 is a newly discovered single-stranded DNA (ssDNA)-binding protein that is essential for efficient DNA double-strand break signalling through ATM. However, the mechanism by which hSSB1 functions to allow efficient signalling is unknown. Here, we show that hSSB1 is recruited rapidly to sites of double-strand DNA breaks (DSBs) in all interphase cells (G1, S and G2) independently of, CtIP, MDC1 and the MRN complex (Rad50, Mre11, NBS1). However expansion of hSSB1 from the DSB site requires the function of MRN. Strikingly, silencing of hSSB1 prevents foci formation as well as recruitment of MRN to sites of DSBs and leads to a subsequent defect in resection of DSBs as evident by defective RPA and ssDNA generation. Our data suggests that hSSB1 functions upstream of MRN to promote its recruitment at DSBs and is required for efficient resection of DSBs. These findings, together with previous work establish essential roles of hSSB1 in controlling ATM activation and activity, and subsequent DSB resection and homologous recombination (HR).

Involvement of Exo1b in DNA damage-induced apoptosis

Apoptosis is essential for the maintenance of inherited genomic integrity. During DNA damage-induced apoptosis, mechanisms of cell survival, such as DNA repair are inactivated to allow cell death to proceed. Here, we describe a role for the mammalian DNA repair enzyme Exonuclease 1 (Exo1) in DNA damage-induced apoptosis. Depletion of Exo1 in human fibroblasts, or mouse embryonic fibroblasts led to a delay in DNA damage-induced apoptosis. Furthermore, we show that Exo1 acts upstream of caspase-3, DNA fragmentation and cytochrome c release. In addition, induction of apoptosis with DNA-damaging agents led to cleavage of both isoforms of Exo1. The cleavage of Exo1 was mapped to Asp514, and shown to be mediated by caspase-3. Expression of a caspase-3 cleavage site mutant form of Exo1, Asp514Ala, prevented formation of the previously observed fragment without any affect on the onset of apoptosis. We conclude that Exo1 has a role in the timely induction of apoptosis and that it is subsequently cleaved and degraded during apoptosis, potentially inhibiting DNA damage repair.

Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks

DNA double-strand break (DSB) repair via the homologous recombination pathway is a multi-stage process, which results in repair of the DSB without loss of genetic information or fidelity. One essential step in this process is the generation of extended single-stranded DNA (ssDNA) regions at the break site. This ssDNA serves to induce cell cycle checkpoints and is required for Rad51 mediated strand invasion of the sister chromatid. Here, we show that human Exonuclease 1 (Exo1) is required for the normal repair of DSBs by HR. Cells depleted of Exo1 show chromosomal instability and hypersensitivity to ionising radiation (IR) exposure. We find that Exo1 accumulates rapidly at DSBs and is required for the recruitment of RPA and Rad51 to sites of DSBs, suggesting a role for Exo1 in ssDNA generation. Interestingly, the phosphorylation of Exo1 by ATM appears to regulate the activity of Exo1 following resection, allowing optimal Rad51 loading and the completion of HR repair. These data establish a role for Exo1 in resection of DSBs in human cells, highlighting the critical requirement of Exo1 for DSB repair via HR and thus the maintenance of genomic stability.

Performance comparison of VSC-based shunt and series compensators used for load voltage control in distribution systems

In this paper, the performance of voltage-source converter-based shunt and series compensators used for load voltage control in electrical power distribution systems has been analyzed and compared, when a nonlinear load is connected across the load bus. The comparison has been made based on the closed-loop frequency resopnse characteristics of the compensated distribution system. A distribution static compensator (DSTATCOM) as a shunt device and a dynamic voltage restorer (DVR) as a series device are considered in the voltage-control mode for the comparison. The power-quality problems which these compensator address include voltage sags/swells, load voltage harmonic distortions, and unbalancing. The effect of various system parameters on the control performance of the compensator can be studied using the proposed analysis. In particular, the performance of the two compensators are compared with the strong ac supply (stiff source) and weak ac-supply (non-still source) distribution system. The experimental verification of the analytical results derived has been obtained using a laboratory model of the single-phase DSTATCOM and DVR. A generalized converter topology using a cascaded multilevel inverter has been proposed for the medium-voltage distribution system. Simulation studies have been performed in the PSCAD/EMTDC software to verify the results in the three-phase system.

Optimal voltage support mechanism in distribution networks

Optimal scheduling of voltage regulators (VRs), fixed and switched capacitors and voltage on customer side of transformer (VCT) along with the optimal allocaton of VRs and capacitors are performed using a hybrid optimisation method based on discrete particle swarm optimisation and genetic algorithm. Direct optimisation of the tap position is not appropriate since in general the high voltage (HV) side voltage is not known. Therefore, the tap setting can be determined give the optimal VCT once the HV side voltage is known. The objective function is composed of the distribution line loss cost, the peak power loss cost and capacitors' and VRs' capital, operation and maintenance costs. The constraints are limits on bus voltage and feeder current along with VR taps. The bus voltage should be maintained within the standard level and the feeder current should not exceed the feeder-rated current. The taps are to adjust the output voltage of VRs between 90 and 110% of their input voltages. For validation of the proposed method, the 18-bus IEEE system is used. The results are compared with prior publications to illustrate the benefit of the employed technique. The results also show that the lowest cost planning for voltage profile will be achieved if a combination of capacitors, VRs and VCTs is considered.

Sharing with Creative Commons : a business model for content creators

Creative Commons (CC) is often seen as a social movement, dismissed by critics as a tool for hobbyists or academics who do not sell their creations to make a living. However, this paper argues that the licensing of creative copyright works under a CC licence does not preclude commercial gain. If used wisely, CC licences can be a useful tool for creators in their quest for commercial success. In particular, this paper argues that the sharing of creative works online under a CC licence allows creators to circumvent traditional distribution channels dominated by content intermediaries, whilst maintaining a level of control over their copyright works (i.e. explicitly reserving some rights but not all rights). This will be illustrated by case studies on how CC is being used by content creators and intermediaries respectively, and how successful their respective methods are in harnessing this tool.

Variability of input parameters related to pollutants build-up in stormwater quality modelling

The variability of input parameters is the most important source of overall model uncertainty. Therefore, an in-depth understanding of the variability is essential for uncertainty analysis of stormwater quality model outputs. This paper presents the outcomes of a research study which investigated the variability of pollutants build-up characteristics on road surfaces in residential, commercial and industrial land uses. It was found that build-up characteristics vary highly even within the same land use. Additionally, industrial land use showed relatively higher variability of maximum build-up, build-up rate and particle size distribution, whilst the commercial land use displayed a relatively higher variability of pollutant-solid ratio. Among the various build-up parameters analysed, D50 (volume-median-diameter) displayed the relatively highest variability for all three land uses.

Effects of different practice task constraints on fluctuations of player heart rate in small-sided football games

This paper analyzes effects of different practice task constraints on heart rate (HR) variability during 4v4 smallsided football games. Participants were sixteen football players divided into two age groups (U13, Mean age: 12.4±0.5 yrs; U15: 14.6±0.5). The task consisted of a 4v4 sub-phase without goalkeepers, on a 25x15 m field, of 15 minutes duration with an active recovery period of 6 minutes between each condition. We recorded players’ heart rates using heart rate monitors (Polar Team System, Polar Electro, Kempele, Finland) as scoring mode was manipulated (line goal: scoring by dribbling past an extended line; double goal: scoring in either of two lateral goals; and central goal: scoring only in one goal). Subsequently, %HR reserve was calculated with the Karvonen formula. We performed a time-series analysis of HR for each individual in each condition. Mean data for intra-participant variability showed that autocorrelation function was associated with more short-range dependence processes in the “line goal” condition, compared to other conditions, demonstrating that the “line goal” constraint induced more randomness in HR response. Relative to inter-individual variability, line goal constraints demonstrated lower %CV and %RMSD (U13: 9% and 19%; U15: 10% and 19%) compared with double goal (U13: 12% and 21%; U15: 12% and 21%) and central goal (U13: 14% and 24%; U15: 13% and 24%) task constraints, respectively. Results suggested that line goal constraints imposed more randomness on cardiovascular stimulation of each individual and lower inter-individual variability than double goal and central goal constraints.

The ecological dynamics of 1v1 sub-phases in association football

This paper analyzes effects of different practice task constraints on heart rate (HR) variability during 4v4 smallsided football games. Participants were sixteen football players divided into two age groups (U13, Mean age: 12.4±0.5 yrs; U15: 14.6±0.5). The task consisted of a 4v4 sub-phase without goalkeepers, on a 25x15 m field, of 15 minutes duration with an active recovery period of 6 minutes between each condition. We recorded players’ heart rates using heart rate monitors (Polar Team System, Polar Electro, Kempele, Finland) as scoring mode was manipulated (line goal: scoring by dribbling past an extended line; double goal: scoring in either of two lateral goals; and central goal: scoring only in one goal). Subsequently, %HR reserve was calculated with the Karvonen formula. We performed a time-series analysis of HR for each individual in each condition. Mean data for intra-participant variability showed that autocorrelation function was associated with more short-range dependence processes in the “line goal” condition, compared to other conditions, demonstrating that the “line goal” constraint induced more randomness in HR response. Relative to inter-individual variability, line goal constraints demonstrated lower %CV and %RMSD (U13: 9% and 19%; U15: 10% and 19%) compared with double goal (U13: 12% and 21%; U15: 12% and 21%) and central goal (U13: 14% and 24%; U15: 13% and 24%) task constraints, respectively. Results suggested that line goal constraints imposed more randomness on cardiovascular stimulation of each individual and lower inter-individual variability than double goal and central goal constraints.

From bricks to clicks : hybrid commercial spaces in the landscape of early literacy and learning

In their quest for resources to support children’s early literacy learning and development, parents encounter and traverse different spaces in which discourses and artifacts are produced and circulated. This paper uses conceptual tools from the field of geosemiotics to examine some commercial spaces designed for parents and children which foreground preschool learning and development. Drawing on data generated in a wider study I discuss some of the ways in which the material and virtual commercial spaces of a transnational shopping mall company and an educational toy company operate as sites of encounter between discourses and artifacts about children’s early learning and parents of preschoolers. I consider how companies connect with and ‘situate’ people as parents and customers, and then offer pathways designed for parents to follow as they attempt to meet their very young children’s learning and development needs. I argue that these pathways are both material and ideological, and that are increasingly tending to lead parents to the online commercial spaces of the world wide web. I show how companies are using the online environment and hybrid offline and online spaces and flows to reinforce an image of themselves as authoritative brokers of childhood resources for parents that is highly valuable in a policy climate which foregrounds lifelong learning and school readiness.

Digital dawn : a revolution in movie distribution?

How will the digital technology revolution impact the movie business? Hollywood developed a highly successful industrial system that has functioned well for almost a century in the sense that it enabled the Major film studios to largely control and dominate the industry. However, the new digital technology may now be propelling Hollywood toward the biggest technological transition since the creation of the studio system almost a century ago. For example, Major Hollywood studios are already beginning to provide video-on-demand (VOD) digital distribution of movies over the Internet. This article examines what is happening, and why. It sets out the background and the incipient changes already occurring. It makes an argument regarding the fundamental strategic dynamics, that acetate film was the key to the control of the Hollywood system, and speculates about how a shift away from acetate film to digital video may transform that system. The focus is on the impact on how the Major studios release and market their movies, and how new market and marketing opportunities for the low-budget independent filmmaking sector may arise.

Body-site distribution of skin cancer, pre-malignant and common benign pigmented lesions excised in general practice

Background Concern about skin cancer is a common reason for people from predominantly fair-skinned populations to present to primary care doctors. Objectives To examine the frequency and body-site distribution of malignant, pre-malignant and benign pigmented skin lesions excised in primary care. Methods This prospective study conducted in Queensland, Australia, included 154 primary care doctors. For all excised or biopsied lesions, doctors recorded the patient's age and sex, body site, level of patient pressure to excise, and the clinical diagnosis. Histological confirmation was obtained through pathology laboratories. Results Of 9650 skin lesions, 57·7% were excised in males and 75·0% excised in patients ≥50years. The most common diagnoses were basal cell carcinoma (BCC) (35·1%) and squamous cell carcinoma (SCC) (19·7%). Compared with the whole body, the highest densities for SCC, BCC and actinic keratoses were observed on chronically sun-exposed areas of the body including the face in males and females, the scalp and ears in males, and the hands in females. The density of BCC was also high on intermittently or rarely exposed body sites. Females, younger patients and patients with melanocytic naevi were significantly more likely to exert moderate/high levels of pressure on the doctor to excise. Conclusions More than half the excised lesions were skin cancer, which mostly occurred on the more chronically sun-exposed areas of the body. Information on the type and body-site distribution of skin lesions can aid in the diagnosis and planned management of skin cancer and other skin lesions commonly presented in primary care.