mTOR inhibition and levels of the DNA repair protein MGMT in T98G glioblastoma cells

Background: Glioblastoma multiforme (GBM), the most common and most aggressive type of primary adult brain tumour, responds poorly to conventional treatment. Temozolomide (TMZ) chemotherapy remains the most commonly used treatment, despite a large proportion of tumours displaying TMZ resistance. 60% of GBM tumours have unmethylated MGMT promoter regions, resulting in an overexpression of the DNA repair protein O6 -methylguanine-DNA methyltransferase (MGMT), which is responsible for tumour resistance to TMZ chemotherapy. Tumours also often exhibit hyperactive PI3-kinase/mTOR signalling, which enables them to resynthesise proteins quickly. Since MGMT is a suicide protein that is degraded upon binding to and repairing TMZ-induced O6-methylguanine adducts, it has been hypothesized that inhibition of translation via the mTOR signalling pathway could generate a tumour-specific reduction in MGMT protein and increase TMZ sensitivity. Methods: MGMT was monitored at the post-transcriptional, translational and protein levels, to determine what effect mTOR inhibition was having on MGMT protein expression in vitro. Results: We show that inhibiting mTOR signalling is indeed associated with acute inhibition of protein synthesis. Western blots show that despite this, relative to loading control proteins, steady state levels of MGMT protein increased and MGMT mRNA was retained in heavy polysomes. Whilst TMZ treatment resulted in maintained MGMT protein levels, concomitant treatment of T98G cells with TMZ and KU0063794 resulted in increased MGMT protein levels without changes in total mRNA levels. Conclusions: These in vitro data suggest that, counterintuitively, mTOR inhibition may not be a useful adjunct to TMZ therapy and that more investigation is needed before applying mTOR inhibitors in a clinical setting

Environmental and parental influences on the body size of N.E. Atlantic herring, Clupea harengus, larvae.

Morley, S. A. (1998). Environmental and parental influences on the size of herring larvae. Ph.D. thesis submitted to the University of Liverpool for the degree of Doctor of Philosophy Investigations were carried out into the effects of mean egg dry weight and incubation temperature on the size of larvae from four N.E. Atlantic herring stocks (Buchan, Manx, Clyde and Celtic Sea). Hatching characterisitics (length, weight and yolk volume) of Buchan, Manx and Clyde herring were investigated. The time of hatching was inversely related to incubation temperature, although there was some variation between experiments in the date of peak hatching. The total length of larvae increased through the hatching period. In all experiments mean egg dry weight per female was strongly related to the average length, weight and yolk volume of larvae at hatching. The same regression model could be applied to all stocks. There were, however, stock-specific responses of hatching characteristics to incubation temperature although a reduction in length at hatching at higher temperatures was the most consistent response. Development at low temperature resulted in a modification of the length-weight relationship; larvae of the same weight were longer at lower temperatures. Both the increase in length of larvae during the hatching period and the variation in the timing of peak hatching have implications for the comparison of larvae hatching at different temperatures. The otoliths of Manx herring larvae [from "large" (> 0.33mg mean dry weight) and "small" «0.2Smg mean dry weight) eggs] were marked with either alizarin complexone or calcein so that larvae from pairs of large and small egg batches could be reared under identical conditions (at both 10 and I3.S0C) and relative growth monitored. Within each rearing tank large eggs generally produced larger larvae at hatch (length and weight) with higher growth rates (both weight and length specific). There were significant differences both between eggs from different females and between rearing tanks that confounded the comparisons between rearing temperatures. Fultons Condition factor is not thought to be a good measure of nutritional condition of herring larvae smaller than ISmm total length but may be used as a relative measure of body reserves (ReF) and give an indication of ability to withstand periods of poor feeding. This is indicated by a period of high mortality of larvae hatched from small eggs at 10°C, which corresponded with the time period when these larvae had the lowest body reserves. Video recording of the foraging behaviour of laboratory reared herring larvae was used to investigate differences between the feeding strategies of groups of larvae of the same size but different ages, i.e. fast and slow growers. Slow growing larvae searched larger areas, thus expending more energy, than fast growing larvae, but there was no difference in food acquisition. The difference in behaviour tended to increase through development A simple energetics calculation suggested that approximately 50% of the difference in growth rate could be explained by the extra swimming costs of slower growing larvae. The size of Celtic Sea and Manx herring eggs were experimentally reduced in order to investigate if the volume of yolk in each egg determines the size of hatching larvae. Length at hatch was determined by the volume of yolk in each egg but body weight was not. The development and chemical composition of embryos and larvae needs to be investigated in a further series of experiments. All results are discussed in terms of the influence of larval size on survival

Evaluation of an Inexpensive Growth Medium for Direct Detection of Escherichia coli in Temperate and Sub-Tropical Waters

The cost and complexity of traditional methods for the detection of faecal indicator bacteria, including E. coli, hinder widespread monitoring of drinking water quality, especially in lowincome countries and outside controlled laboratory settings. In these settings the problem is exacerbated by the lack of inexpensive media for the detection of E. coli in drinking water. We developed a new low-cost growth medium, aquatest (AT), and validated its use for the direct detection of E. coli in temperate and sub-tropical drinking waters using IDEXX QuantiTray1. AT was compared with IDEXX Colilert-181 and either EC-MUG or MLSB for detecting low levels of E. coli from water samples from temperate (n = 140; Bristol, UK) and subtropical regions (n = 50, Pretoria/Tshwane, South Africa). Confirmatory testing (n = 418 and 588, respectively) and the comparison of quantitative results were used to assess performance. Sensitivity of AT was higher than Colilert-181 for water samples in the UK [98.0% vs. 86.9%; p<0.0001] and South Africa [99.5% vs. 93.2%; p = 0.0030]. There was no significant difference in specificity, which was high for both media (>95% in both settings). Quantitative results were comparable and within expected limits. AT is reliable and accurate for the detection of E. coli in temperate and subtropical drinking water. The composition of the new medium is reported herein and can be used freely

The Self stepping into the shoes of the Other: Understanding and developing self-perceptions of empathy among prospective physical education teachers through a special school placement

Teachers who demonstrate a high degree of empathy are said to have more positive attitudes towards pupils with disabilities. Therefore, this article sought to explore the influence of a special school placement on prospective teachers’ self-perceptions of empathy. Thirty-two final year undergraduate students participated in focus group interviews and were selected because they aspired to be a physical education teacher and had attended a placement in a special school. Interview transcripts were analysed and the following themes constructed: Stepping into the shoes of the Other; Frustrated ‘for’ not ‘with’ pupils with disabilities; Empathy for planning inclusive lessons and ‘reading’ pupil body language; and Knowing when not to show empathy. All prospective teachers felt that: (a) they could empathise with pupils with disabilities; (b) situated learning experiences within the placement enabled them to reflect on the ways in which their empathy influences their teaching now and could continue to do so in the future; and (c) it was important that teachers demonstrated empathy. Thus, it is recommended that all prospective teachers gain some experience teaching in special schools. Our research also warns against teachers claiming the last, conclusive word about who children with disabilities are, what they think, how they feel and what they want, in myriad contexts and situations

Information rigidities and the news-adjusted output gap

A vector-autoregressive model of actual output and expected output obtained from surveys is used to test for information rigidities and to provide a characterisation of output dynamics that accommodates these information structures. News on actual and expected outputs is decomposed to identify innovations understood to have short-lived effects and these are used with the model to derive a ‘news-adjusted output gap׳ measure. The approach is applied to US data over 1970q1–2014q2 and the new gap measure is shown to provide a good leading indicator of inflation

Latest Quaternary palaeoceanographic change in the eastern North Atlantic based upon a dinoflagellate cyst event ecostratigraphy

AbstractThe analyses of dinoflagellate cyst records, from the latest Quaternary sediments recovered from DSDP Core 610A taken on the Feni Ridge in the southern Rockall Trough, and part of core MD01-2461 on the continental margin of the Porcupine Seabight in the eastern North Atlantic Ocean, has provided evidence for significant oceanographic change encompassing the Last Glacial Maximum (LGM) and part of the Holocene. This together with other published records has led to a regional evaluation of oceanographic change in the eastern North Atlantic over the past 68 ka, based upon a distinctive dinoflagellate event ecostratigraphy. These changes reflect changes in the surface waters of the North Atlantic Current (NAC), and perhaps the deeper thermohaline Atlantic Meridional Overturning Circulation (AMOC), driving fundamental regime changes within the phytoplanktonic communities. Three distinctive dinoflagellate cyst associations based upon both factor and cluster analyses have been recognised. Associations characterised by Bitectatodinium tepikiense (between 61.1 ± 6.2 to 13.4 ± 1.1 ka BP), Nematosphaeropsis labyrinthus (between 10.5 ± 0.3 and 11.45 ± 0.8 ka. BP), and the cyst of Protoceratium reticulatum (between 8.5 ± 0.9 and 5.2 ± 1.3 ka. BP) indicate major change within the eastern North Atlantic oceanography. The transitions between these changes occur over a relatively short time span (c.1.5 ka), given our sampling resolution, and have the potential to be incorporated into an event stratigraphy through the latest Quaternary as recommended by the INTIMATE (INTegrating Ice core, MArine and TErrestrial records) group. The inclusion of a dinoflagellate cyst event stratigraphy would highlight changes within the phytoplankton of the North Atlantic Ocean as a fully glacial world changed to our present interglacial

Associations between sports participation, adiposity and obesity-related health behaviors in Australian adolescents

Background The purpose of this study was to examine the relationship between organized sports participation, weight status, physical activity, screen time, and important food habits in a large nationally representative sample of Australian adolescents. Methods Nationally representative cross-sectional study of 12,188 adolescents from 238 secondary schools aged between 12 and 17 years (14.47 ± 1.25 y, 53% male, 23% overweight/obese). Participation in organized sports, compliance with national physical activity, screen time, and fruit and vegetable consumption guidelines, and consumption of sugar-sweetened beverages and high-fat foods were self-reported. Weight status and adiposity (BMI, waist circumference) were measured. Results Organized sports participation was higher among males and those residing in rural/remote areas. Underweight adolescents reported the lowest levels of participation. Higher levels of participation were associated with an increased likelihood of complying with national physical activity (OR = 2.07 [1.67-2.58]), screen time (OR = 1.48 [1.19-1.84]), and fruit and vegetable consumption guidelines (OR = 1.32 [1.05-1.67]). There was no association between organized sport participation and weight status, adiposity, consumption of sugar-sweetened beverages or high-fat foods. Conclusions Participation in organized sports was associated with a greater likelihood to engage in a cluster of health behaviors, including meeting physical activity guidelines, electronic screen time recommendations, and fruit and vegetable consumption guidelines. However, participation in organized sports was not associated with unhealthy dietary behaviors including the consumption of sugar-sweetened beverages and high-fat foods. There is no association between participation in organized sports and likelihood to be overweight or obese. The role of sports in promoting healthy weight and energy balance is unclear

The Profumo affair in popular culture: The Keeler Affair (1963) and ‘the commercial exploitation of a public scandal’

This article demonstrates that the Profumo affair, which obsessed Britain for large parts of 1963, was not simply a political scandal, but was also an important cultural event. Focussing on the production of The Keeler Affair, a feature film that figured prominently in contemporary coverage of the scandal but which has been largely overlooked since, the article shows that this film emerged from a situation in which cultural entrepreneurs, many of them associated with the satire boom, sought to exploit the scandal for financial gain. Many Profumo-related cultural products found an audience, and thus formed an integral part of, and helped to shape public attitudes towards, the Profumo affair. However, these products did not go uncontested, and resistance to them, and especially to the idea that Keeler might benefit materially from her role in the scandal, speak to concerns about cultural mediations of sex, politics and humour in early-1960s Britain