INT6/EIF3E interacts with ATM and is required for proper execution of the DNA damage response in human cells

Altered expression of the INT6 gene, encoding the e subunit of the translational initiation factor eIF3, occurs in human breast cancers, but how INT6 relates to carcinogenesis remains unestablished. Here, we show that INT6 is involved in the DNA damage response. INT6 was required for cell survival following γ-irradiation and G(2)-M checkpoint control. RNA interference-mediated silencing of INT6 reduced phosphorylation of the checkpoint kinases CHK1 and CHK2 after DNA damage. In addition, INT6 silencing prevented sustained accumulation of ataxia telangiectasia mutated (ATM) at DNA damage sites in cells treated with γ-radiation or the radiomimetic drug neocarzinostatin. Mechanistically, this result could be explained by interaction of INT6 with ATM, which together with INT6 was recruited to the sites of DNA damage. Finally, INT6 silencing also reduced ubiquitylation events that promote retention of repair proteins at DNA lesions. Accordingly, accumulation of the repair factor BRCA1 was defective in the absence of INT6. Our findings reveal unexpected and striking connections of INT6 with ATM and BRCA1 and suggest that the protective action of INT6 in the onset of breast cancers relies on its involvement in the DNA damage response.

A yellow filter improves response times to low-contrast targets and traffic hazards

Purpose Anecdotal evidence suggests that some sunglass users prefer yellow tints for outdoor activities, such as driving, and research has suggested that such tints improve the apparent contrast and brightness of real-world objects. The aim of this study was to establish whether yellow filters resulted in objective improvements in performance for visual tasks relevant to driving. Methods Response times of nine young (age [mean ± SD], 31.4 ± 6.7 years) and nine older (age, [mean ± SD], 74.6 ± 4.8) adults were measured using video presentations of traffic hazards (driving hazard perception task) and a simple low-contrast grating appeared at random peripheral locations on a computer screen. Response times were compared when participants wore a yellow filter (with and without a linear polarizer) versus a neutral density filter (with and without a linear polarizer). All lens combinations were matched to have similar luminance transmittances (˜27%). Results In the driving hazard perception task, the young but not the older participants responded significantly more rapidly to hazards when wearing a yellow filter than with a luminance-matched neutral density filter (mean difference, 450 milliseconds). In the low-contrast grating task, younger participants also responded more quickly for the yellow filter condition but only when combined with a polarizer. Although response times increased with increasing stimulus eccentricity for the low-contrast grating task, for the younger participants, this slowing of response times with increased eccentricity was reduced in the presence of a yellow filter, indicating that perception of more peripheral objects may be improved by this filter combination. Conclusions Yellow filters improve response times for younger adults for visual tasks relevant to driving.

Lineage-specific biomarkers predict response to FGFR inhibition

In this issue of Cancer Discovery, Guagnano and colleagues use a large and diverse annotated collection of cancer cell lines, the Cancer Cell Line Encyclopedia, to correlate whole-genome expression and genomic alteration datasets with cell line sensitivity data to the novel pan-fibroblast growth factor receptor (FGFR) inhibitor NVP-BGJ398. Their findings underscore not only the preclinical use of such cell line panels in identifying predictive biomarkers, but also the emergence of the FGFRs as valid therapeutic targets, across an increasingly broad range of malignancies.

Response to “Topical agent therapy for prevention and treatment of radiodermatitis : a meta-analysis”

To the Editor; It was with interest that I read the recent article by Zhang et al. published in Supportive Care in Cancer [1]. This paper highlighted the importance of radiodermatitis (RD) being an unresolved and distressing clinical issue in patients with cancer undergoing radiation therapy. However, I am concerned with a number of clinical and methodological issues within this paper: (i) the clinical and operational definition of prophylaxis and treatment of RD; (ii) the accuracy of the identification of trials; and (iii) the appropriateness of the conduct of the meta-analyses...

A known-groups evaluation of the Response Bias Scale in a neuropsychological setting

We evaluated the Minnesota Multiphasic Personality Inventory-Second Edition (MMPI-2) Response Bias Scale (RBS). Archival data from 83 individuals who were referred for neuropsychological assessment with no formal diagnosis (n = 10), following a known or suspected traumatic brain injury (n = 36), with a psychiatric diagnosis (n = 20), or with a history of both trauma and a psychiatric condition (n = 17) were retrieved. The criteria for malingered neurocognitive dysfunction (MNCD) were applied, and two groups of participants were formed: poor effort (n = 15) and genuine responders (n = 68). Consistent with previous studies, the difference in scores between groups was greatest for the RBS (d = 2.44), followed by two established MMPI-2 validity scales, F (d = 0.25) and K (d = 0.23), and strong significant correlations were found between RBS and F (rs = .48) and RBS and K (r = −.41). When MNCD group membership was predicted using logistic regression, the RBS failed to add incrementally to F. In a separate regression to predict group membership, K added significantly to the RBS. Receiver-operating curve analysis revealed a nonsignificant area under the curve statistic, and at the ideal cutoff in this sample of >12, specificity was moderate (.79), sensitivity was low (.47), and positive and negative predictive power values at a 13% base rate were .25 and .91, respectively. Although the results of this study require replication because of a number of limitations, this study has made an important first attempt to report RBS classification accuracy statistics for predicting poor effort at a range of base rates.

Peripheral compartment innate immune response to Haemophilus influenzae and Streptococcus pneumoniae in chronic obstructive pulmonary disease patients.

Alterations in innate immunity that predispose to chronic obstructive pulmonary disease (COPD) exacerbations are poorly understood. We examined innate immunity gene expression in peripheral blood polymorphonuclear leukocytes (PMN) and monocytes stimulated by Haemophilus influenzae and Streptococcus pneumoniae. Thirty COPD patients (15 rapid and 15 non-rapid lung function decliners) and 15 smokers without COPD were studied. Protein expression of IL-8, IL-6, TNF-α and IFN-γ (especially monocytes) increased with bacterial challenge. In monocytes stimulated with S. pneumoniae, TNF-α protein expression was higher in COPD (non-rapid decliners) than in smokers. In co-cultures of monocytes and PMN, mRNA expression of TGF-β1 and MYD88 was up-regulated, and CD14, TLR2 and IFN-γ down-regulated with H. influenzae challenge. TNF-α mRNA expression was increased with H. influenzae challenge in COPD. Cytokine responses were similar between rapid and non-rapid decliners. TNF-α expression was up-regulated in non-rapid decliners in response to H. influenzae (monocytes) and S. pneumoniae (co-culture of monocytes and PMN). Exposure to bacterial pathogens causes characteristic innate immune responses in peripheral blood monocytes and PMN in COPD. Bacterial exposure significantly alters the expression of TNF-α in COPD patients, although not consistently. There did not appear to be major differences in innate immune responses between rapid and non-rapid decliners.

Flotation process response of Ok Tedi fluorine bearing minerals

Orebodies at Ok Tedi contain a number of different fluorine bearing minerals. Some of these minerals report to concentrate and are responsible for the presence of the penalty element, fluorine, within the concentrate. Previous analytical work has tended to examine geological samples for content, rather than determine the metallurgical behaviour of the different mineralogical species. This investigation utilised X-Ray Diffraction combined with Scanning Electron Microscope/Electron Microprobe to identify the fluorine bearing minerals in flotation test products. Seven fluorine bearing minerals were identified, viz., talc, phlogopite, amphibole (tremolite and actinolite), sphene, apatite, biotite and clay. Talc was found exclusively in the skarn ore type. Phlogopite and amphiboles (tremolite and actinolite) were found to occur in both skarn and porphyry ores, while sphene, apatite, biotite and clay were found only in the porphyry ores. Of the fluorine bearing minerals observed, only talc exhibited natural hydrophobicity to any significant degree. Phlogopite and the amphibole minerals were found to be hydrophillic, whilst the remaining minerals occurred in insufficient quantities to determine the flotation behaviour. Ok Tedi copper concentrate fluorine content prior to skarn ore treatment in the mill (typically 350ppm) was previously identified as deriving from phlogopite, while talc was believed to be the source of intermittent high concentrate fluorine contents when skarn ores were treated. This paper provides supporting evidence for this belief, and reports the nature of fluorine bearing mineral flotation behaviour.

Managing the health effects of temperature in response to climate change : challenges ahead

BACKGROUND: Although many studies have shown that high temperatures are associated with an increased risk of mortality and morbidity, there has been little research on managing the process of planned adaptation to alleviate the health effects of heat events and climate change. In particular, economic evaluation of public health adaptation strategies has been largely absent from both the scientific literature and public policy discussion. OBJECTIVES: his paper aims to discuss how public health organizations should implement adaptation strategies, and how to improve the evidence base for policies to protect health from heat events and climate change. DISCUSSION: Public health adaptation strategies to cope with heat events and climate change fall into two categories: reducing the heat exposure and managing the health risks. Strategies require a range of actions, including timely public health and medical advice, improvements to housing and urban planning, early warning systems, and the assurance that health care and social systems are ready to act. Some of these actions are costly, and the implementation should be based on the cost-effectiveness analysis given scarce financial resources. Therefore, research is required not only on the temperature-related health costs, but also on the costs and benefits of adaptation options. The scientific community must ensure that the health co-benefits of climate change policies are recognized, understood and quantified. CONCLUSIONS: The integration of climate change adaptation into current public health practice is needed to ensure they increase future resilience. The economic evaluation of temperature-related health costs and public health adaptation strategies are particularly important for policy decisions.

Thai family support (TFS) : working with families of young substance users in primary health care

Living with substance users negatively impacts upon family members in many ways, and distress is common. Despite these deep and wide-ranging impacts, supportive interventions for family members in their own right are rarely available. Thailand has substantial and growing problems with substance use, and there is very little support or family members of drug users, especially in community setting. The Thai Family Support (TFS) program was designed for implementation in primary health care units (PCUs) in Thailand. TFS was based on two approaches with existing empirical support in Western contexts—the 5-step method and CRAFT—with adaptations to a Thai setting that included integration with Buddhist practices. Its aims were to increase well-being of family members, reduce mental distress, improve family relationships between family members, and engage substance users in behaviour change. A small-scale randomised controlled trial on TFS with a Delayed Treatment control was conducted, with assessments at 8 weeks (Post 1) and 20-24 weeks (Post 2). Structured interviews with participants and PCU staff and an examination of five case studies augmented the quantitative results. Mixed Model Analyses were applied to quantitative outcomes, and thematic analysis was used for qualitative data. Thirty-six participants (18 in each of Immediate and Delayed Conditions) were recruited. A significant difference at Baseline between the two conditions was observed on the Thai GHQ-28 and Gender, but it was not possible to statistically control for these effects. There was a significant Time by Condition interaction on the Thai GHQ-28, WHOQOL-BREF-THAI and FAS, reflecting greater improvements in the Immediate condition by Post 1, but with the Delayed condition meeting or exceeding that effect by Post 2. On FES Cohesion and Conflict, there were falls across conditions at Post 2, but only Cohesion also showed a Time by Condition interaction, and that effect was consistent with a delayed impact of treatment. Overall, TFS by PCU staff in the Delayed Condition gave similar results to TFS conducted by the researcher, supporting the viability of its dissemination to standard health services. Qualitative data also confirmed the quantitative results. Most participants reported physiological and psychological improvements even though their substance-using relative did not change their drug use behaviour. After completing TFS, participants reported increased knowledge, group support and sharing feeling, having positive patient-professional relationship, having greater knowledge of substance abuse and social support. In particular, they changed their behaviour towards the substance user, resulting in improvements to family relationships. PCU staff gave similar responses on the efficacy of TFS, and saw it as feasible for routine use, although some implementation challenges were identified. The cultural adaptation and in particular the religious activities, were recognised by participants and PCU staff as an important component of TFS to support psychological health and well-being. Findings from this study showed the impact of substance use on family members and difficulties that they experienced when living with the substance users, resulting distresses and burden that may develop severe mental health disease. Drug use policies should be modified to support family members and response to their needs effectively for early prevention. This study also gave preliminary support for application of the TFS program in rural primary care settings and identified some policies that will be required for it to be disseminated more broadly.

Digital Copyright Exchange Feasibility Study : Response to the Hooper Consultation from the Big Innovation Centre

In this submission, we provide evidence for our view that copyright policy in the UK must encourage new digital business models which meet the changing needs of consumers and foster innovation in the UK both within, and beyond, the creative industries. We illustrate our arguments using evidence from the music industry. However, we believe that our key points on the relationship between the copyright system and innovative digital business models apply across the UK creative industries.

Skill development and social inclusion via peer assisted learning in first-year higher education : an evaluation of student experiences across two law units

Because professions seek graduates who can 'collaborate, share skills and knowledge, and communicate' (Kruck and Reif, 2001, p 37), it is important that university graduates are not equipped solely with the content knowledge of their discipline, but also with prospective employment skills. Furthermore, when students 'interact more in positive ways with their teachers and peers, they gain more in terms of essential skills and competencies, such as critical thinking, problem~solving [and] effective communication' (NSSE, 2000, p 2)./n this way, peer assisted fellowing has the potential to enhance students' professional development, and provide the social inclusion and engagement necessary for effective learning. This session describes two peer assisted learning models embedded within first year QUT Faculty of Law units. Through a partnership between teaching staff, student mentors and mentees, the models aim to facilitate student socialisation whilst supplementing understanding of substantive law with the development of academic and work·related skills. Mentor and mentee perceptions, and program implications, are considered.

Load-unloading response of intact and artificially degraded articular cartilage correlated with near infrared (NIR) absorption spectra

The conventional mechanical properties of articular cartilage, such as compressive stiffness, have been demonstrated to be limited in their capacity to distinguish intact (visually normal) from degraded cartilage samples. In this paper, we explore the correlation between a new mechanical parameter, namely the reswelling of articular cartilage following unloading from a given compressive load, and the near infrared (NIR) spectrum. The capacity to distinguish mechanically intact from proteoglycan-depleted tissue relative to the "reswelling" characteristic was first established, and the result was subsequently correlated with the NIR spectral data of the respective tissue samples. To achieve this, normal intact and enzymatically degraded samples were subjected to both NIR probing and mechanical compression based on a load-unload-reswelling protocol. The parameter δ(r), characteristic of the osmotic "reswelling" of the matrix after unloading to a constant small load in the order of the osmotic pressure of cartilage, was obtained for the different sample types. Multivariate statistics was employed to determine the degree of correlation between δ(r) and the NIR absorption spectrum of relevant specimens using Partial Least Squared (PLS) regression. The results show a strong relationship (R(2)=95.89%, p<0.0001) between the spectral data and δ(r). This correlation of δ(r) with NIR spectral data suggests the potential for determining the reswelling characteristics non-destructively. It was also observed that δ(r) values bear a significant relationship with the cartilage matrix integrity, indicated by its proteoglycan content, and can therefore differentiate between normal and artificially degraded proteoglycan-depleted cartilage samples. It is therefore argued that the reswelling of cartilage, which is both biochemical (osmotic) and mechanical (hydrostatic pressure) in origin, could be a strong candidate for characterizing the tissue, especially in regions surrounding focal cartilage defects in joints.

Low temperature response of nanostructured tungsten oxide thin films toward hydrogen and ethanol

Semiconducting metal oxide based gas sensors usually operate in the temperature range 200–500 °C. In this paper, we present a new WO3 thin film based gas sensor for H2 and C2H5OH, operating at 150 °C. Nanostructured WO3 thin films were synthesized by thermal evaporation method. The properties of the as-deposited films were modified by annealing in air at 300 °C and 400 °C. Various analytical techniques such as AFM, TEM, XPS, XRD and Raman spectroscopy have been employed to characterize their properties. A clear indication from TEM and XRD analysis is that the as-deposited WO3 films are highly amorphous and no improvement is observed in the crystallinity of the films after annealing at 300 °C. Annealing at 400 °C significantly improved the crystalline properties of the films with the formation of about 5 nm grains. The films annealed at 300 °C show no response to C2H5OH (ethanol) and a little response to H2, with maximum response obtained at 280 °C. The films annealed at 400 °C show a very good response to H2 and a moderate response to C2H5OH (ethanol) at 150 °C. XPS analysis revealed that annealing of the WO3 thin films at 400 °C produces a significant change in stoichiometry, increasing the number of oxygen vacancies in the film, which is highly beneficial for gas sensing. Our results demonstrate that gas sensors with significant performance at low operating temperatures can be obtained by annealing the WO3 films at 400 °C and optimizing the crystallinity and nanostructure of the as-deposited films.

Hybrid graphene and graphitic carbon nitride nanocomposite : gap opening, electron–hole puddle, interfacial charge transfer, and enhanced visible light response

Opening up a band gap and finding a suitable substrate material are two big challenges for building graphene-based nanodevices. Using state-of-the-art hybrid density functional theory incorporating long range dispersion corrections, we investigate the interface between optically active graphitic carbon nitride (g-C3N4) and electronically active graphene. We find an inhomogeneous planar substrate (g-C3N4) promotes electronrich and hole-rich regions, i.e., forming a well-defined electron−hole puddle, on the supported graphene layer. The composite displays significant charge transfer from graphene to the g-C3N4 substrate, which alters the electronic properties of both components. In particular, the strong electronic coupling at the graphene/g-C3N4 interface opens a 70 meV gap in g-C3N4-supported graphene, a feature that can potentially allow overcoming the graphene’s band gap hurdle in constructing field effect transistors. Additionally, the 2-D planar structure of g-C3N4 is free of dangling bonds, providing an ideal substrate for graphene to sit on. Furthermore, when compared to a pure g-C3N4 monolayer, the hybrid graphene/g-C3N4 complex displays an enhanced optical absorption in the visible region, a promising feature for novel photovoltaic and photocatalytic applications.