Active Notch1 confers a transformed phenotype to primary human melanocytes

The importance of mitogen-activated protein kinase signaling in melanoma is underscored by the prevalence of activating mutations in N-Ras and B-Raf, yet clinical development of inhibitors of this pathway has been largely ineffective, suggesting that alternative oncogenes may also promote melanoma. Notch is an interesting candidate that has only been correlated with melanoma development and progression; a thorough assessment of tumor-initiating effects of activated Notch on human melanocytes would clarify the mounting correlative evidence and perhaps identify a novel target for an otherwise untreatable disease. Analysis of a substantial panel of cell lines and patient lesions showed that Notch activity is significantly higher in melanomas than their nontransformed counterparts. The use of a constitutively active, truncated Notch transgene construct (N(IC)) was exploited to determine if Notch activation is a "driving" event in melanocytic transformation or instead a "passenger" event associated with melanoma progression. N(IC)-infected melanocytes displayed increased proliferative capacity and biological features more reminiscent of melanoma, such as dysregulated cell adhesion and migration. Gene expression analyses supported these observations and aided in the identification of MCAM, an adhesion molecule associated with acquisition of the malignant phenotype, as a direct target of Notch transactivation. N(IC)-positive melanocytes grew at clonal density, proliferated in limiting media conditions, and also exhibited anchorage-independent growth, suggesting that Notch alone is a transforming oncogene in human melanocytes, a phenomenon not previously described for any melanoma oncogene. This new information yields valuable insight into the basic epidemiology of melanoma and launches a realm of possibilities for drug intervention in this deadly disease.

Phenomenological modeling of cell-to-cell and beat-to-beat variability in isolated Guinea Pig ventricular myocytes

Experimental action potential (AP) recordings in isolated ventricular myoctes display significant temporal beat-to-beat variability in morphology and duration. Furthermore, significant cell-to-cell differences in AP also exist even for isolated cells originating from the same region of the same heart. However, current mathematical models of ventricular AP fail to replicate the temporal and cell-to-cell variability in AP observed experimentally. In this study, we propose a novel mathematical framework for the development of phenomenological AP models capable of capturing cell-to-cell and temporal variabilty in cardiac APs. A novel stochastic phenomenological model of the AP is developed, based on the deterministic Bueno-Orovio/Fentonmodel. Experimental recordings of AP are fit to the model to produce AP models of individual cells from the apex and the base of the guinea-pig ventricles. Our results show that the phenomenological model is able to capture the considerable differences in AP recorded from isolated cells originating from the location. We demonstrate the closeness of fit to the available experimental data which may be achieved using a phenomenological model, and also demonstrate the ability of the stochastic form of the model to capture the observed beat-to-beat variablity in action potential duration.

Reduced variance in monozygous twins for multiple MR parameters : implications for disease studies and the genetic basis of brain structure

Twin studies offer the opportunity to determine the relative contribution of genes versus environment in traits of interest. Here, we investigate the extent to which variance in brain structure is reduced in monozygous twins with identical genetic make-up. We investigate whether using twins as compared to a control population reduces variability in a number of common magnetic resonance (MR) structural measures, and we investigate the location of areas under major genetic influences. This is fundamental to understanding the benefit of using twins in studies where structure is the phenotype of interest. Twenty-three pairs of healthy MZ twins were compared to matched control pairs. Volume, T2 and diffusion MR imaging were performed as well as spectroscopy (MRS). Images were compared using (i) global measures of standard deviation and effect size, (ii) voxel-based analysis of similarity and (iii) intra-pair correlation. Global measures indicated a consistent increase in structural similarity in twins. The voxel-based and correlation analyses indicated a widespread pattern of increased similarity in twin pairs, particularly in frontal and temporal regions. The areas of increased similarity were most widespread for the diffusion trace and least widespread for T2. MRS showed consistent reduction in metabolite variation that was significant in the temporal lobe N-acetylaspartate (NAA). This study has shown the distribution and magnitude of reduced variability in brain volume, diffusion, T2 and metabolites in twins. The data suggest that evaluation of twins discordant for disease is indeed a valid way to attribute genetic or environmental influences to observed abnormalities in patients since evidence is provided for the underlying assumption of decreased variability in twins.

Are motivational deficits part of the behavioural phenotype of Down syndrome?

Motivational deficits are generally accepted to be part of the behavioural phenotype associated with Down syndrome (DS). A motivational profile comprising low or inconsistent levels of task persistence, avoidance of challenging activities and over-dependence on adult direction has been described. However, comparisons are usually made between children with DS and those who are developing typically, without the inclusion of samples with intellectual disability (ID) from aetiologies other than DS. Such comparisons are needed to determine the extent to which motivational deficits are specific to DS, as opposed to being a feature of ID generally. Methods: The current study collected data about the personality-motivation profiles of children in three groups matched for mental age. They consisted of 80 typically developing (TD)3–7 year old children, 62 children with DS aged 7–15 years, and 54 children with moderate ID aged 7–15 years. Parents completed the 37-item EZ-Personality Questionnaire (EZPQ; Zigler et al., 2002), a measure of personality-motivational functioning. Results: There were significant differences between TD children and those with ID on all EZPQ scales. In most respects children with DS did not differ significantly from others with moderate ID, although they were rated as having greater expectancy of success and fewer negative reactions. Conclusion: The finding that children with DS are less motivated than TD children of the same mental age is consistent with previous studies in which parents have rated motivation. It seems, however, that motivation difficulties are associated with ID more generally, rather than being specific to those with DS. The study raises questions about phenotypic versus experiential effects on motivation for children with ID.

Environmental factors controlling temporal and spatial variability in the soil-atmosphere exchange of CO2, CH4 and N2O from an Australian subtropical rainforest

The temporal variations in CO2, CH4 and N2O fluxes were measured over two consecutive years from February 2007 to March 2009 from a subtropical rainforest in south-eastern Queensland, Australia, using an automated sampling system. A concurrent study using an additional 30 manual chambers examined the spatial variability of emissions distributed across three nearby remnant rainforest sites with similar vegetation and climatic conditions. Interannual variation in fluxes of all gases over the 2 years was minimal, despite large discrepancies in rainfall, whereas a pronounced seasonal variation could only be observed for CO2 fluxes. High infiltration, drainage and subsequent high soil aeration under the rainforest limited N2O loss while promoting substantial CH4 uptake. The average annual N2O loss of 0.5 ± 0.1 kg N2O-N ha−1 over the 2-year measurement period was at the lower end of reported fluxes from rainforest soils. The rainforest soil functioned as a sink for atmospheric CH4 throughout the entire 2-year period, despite periods of substantial rainfall. A clear linear correlation between soil moisture and CH4 uptake was found. Rates of uptake ranged from greater than 15 g CH4-C ha−1 day−1 during extended dry periods to less than 2–5 g CH4-C ha−1 day−1 when soil water content was high. The calculated annual CH4 uptake at the site was 3.65 kg CH4-C ha−1 yr−1. This is amongst the highest reported for rainforest systems, reiterating the ability of aerated subtropical rainforests to act as substantial sinks of CH4. The spatial study showed N2O fluxes almost eight times higher, and CH4 uptake reduced by over one-third, as clay content of the rainforest soil increased from 12% to more than 23%. This demonstrates that for some rainforest ecosystems, soil texture and related water infiltration and drainage capacity constraints may play a more important role in controlling fluxes than either vegetation or seasonal variability

Socio-environmental variability and Barmah Forest virus disease transmission : a review of epidemiological evidence and future prospects

Barmah Forest Virus (BFV) disease is the most rapidly emerging mosquito-borne disease in Australia. BFV transmission depends on factors such as climate, virus, vector and the human population. However, the impact of climatic and social factors on BFV remains to be determined. This paper provided an overview of current research and discusses the future research directions on the BFV transmission. These research findings could be regarded as an impetus towards BFV prevention and control strategies.

Consecutive days of cold water immersion: effects on cycling performance and heart rate variability.

We investigated performance and heart rate (HR) variability (HRV) over consecutive days of cycling with post-exercise cold water immersion (CWI) or passive recovery (PAS). In a crossover design, 11 cyclists completed two separate 3-day training blocks (120 min cycling per day, 66 maximal sprints, 9 min time trialling [TT]), followed by 2 days of recovery-based training. The cyclists recovered from each training session by standing in cold water (10 °C) or at room temperature (27 °C) for 5 min. Mean power for sprints, total TT work and HR were assessed during each session. Resting vagal-HRV (natural logarithm of square-root of mean squared differences of successive R-R intervals; ln rMSSD) was assessed after exercise, after the recovery intervention, during sleep and upon waking. CWI allowed better maintenance of mean sprint power (between-trial difference [90 % confidence limits] +12.4 % [5.9; 18.9]), cadence (+2.0 % [0.6; 3.5]), and mean HR during exercise (+1.6 % [0.0; 3.2]) compared with PAS. ln rMSSD immediately following CWI was higher (+144 % [92; 211]) compared with PAS. There was no difference between the trials in TT performance (-0.2 % [-3.5; 3.0]) or waking ln rMSSD (-1.2 % [-5.9; 3.4]). CWI helps to maintain sprint performance during consecutive days of training, whereas its effects on vagal-HRV vary over time and depend on prior exercise intensity.

The effect of post-exercise hydrotherapy on subsequent exercise performance and heart rate variability

We investigated the effect of hydrotherapy on time-trial performance and cardiac parasympathetic reactivation during recovery from intense training. On three occasions, 18 well-trained cyclists completed 60 min high-intensity cycling, followed 20 min later by one of three 10-min recovery interventions: passive rest (PAS), cold water immersion (CWI), or contrast water immersion (CWT). The cyclists then rested quietly for 160 min with R-R intervals and perceptions of recovery recorded every 30 min. Cardiac parasympathetic activity was evaluated using the natural logarithm of the square root of mean squared differences of successive R-R intervals (ln rMSSD). Finally, the cyclists completed a work-based cycling time trial. Effects were examined using magnitude-based inferences. Differences in time-trial performance between the three trials were trivial. Compared with PAS, general fatigue was very likely lower for CWI (difference [90% confidence limits; -12% (-18; -5)]) and CWT [-11% (-19; -2)]. Leg soreness was almost certainly lower following CWI [-22% (-30; -14)] and CWT [-27% (-37; -15)]. The change in mean ln rMSSD following the recovery interventions (ln rMSSD(Post-interv)) was almost certainly higher following CWI [16.0% (10.4; 23.2)] and very likely higher following CWT [12.5% (5.5; 20.0)] compared with PAS, and possibly higher following CWI [3.7% (-0.9; 8.4)] compared with CWT. The correlations between performance, ln rMSSD(Post-interv) and perceptions of recovery were unclear. A moderate correlation was observed between ln rMSSD(Post-interv) and leg soreness [r = -0.50 (-0.66; -0.29)]. Although the effects of CWI and CWT on performance were trivial, the beneficial effects on perceptions of recovery support the use of these recovery strategies.

Exercise, appetite and weight management: understanding the compensatory responses in eating behaviour and how they contribute to variability in exercise-induced weight loss

Does exercise promote weight loss? One of the key problems with studies assessing the efficacy of exercise as a method of weight management and obesityis that mean data are presented and the individual variability in response is overlooked. Recent data have highlighted the need to demonstrate and characterise the individual variability in response to exercise. Do people who exercise compensate for the increase in energy expenditure via compensatory increases in hunger and food intake? The authors address the physiological, psychological and behavioural factors potentially involved in the relationship between exercise and appetite, and identify the research questions that remain unanswered. A negative consequence of the phenomena of individual variability and compensatory responses has been the focus on those who lose little weight in response to exercise; this has been used unreasonably as evidence to suggest that exercise is a futile method of controlling weight and managing obesity. Most of the evidence suggests that exercise is useful for improving body composition and health. For example, when exercise-induced mean weight loss is <1.0 kg, significant improvements in aerobic capacity (+6.3 ml/kg/min), systolic (−6.00 mm Hg) and diastolic (−3.9 mm Hg) blood pressure, waist circumference (−3.7 cm) and positive mood still occur. However, people will vary in their responses to exercise; understanding and characterising this variability will help tailor weight loss strategies to suit individuals.