Enhanced sensitivity to rapamycin following long-term oestrogen deprivation in MCF-7, T-47-D and ZR-75-1 human breast cancer cells

Human breast cancer cells (MCF-7, T-47-D and ZR-75-1) can adapt to circumvent any reduced growth rate during long-term oestrogen deprivation, and this provides three model systems to investigate mechanisms of endocrine resistance in breast cancer. In this paper we report consistent differences in the effects of three growth inhibitors following long-term oestrogen deprivation in all three cell models. Long-term oestrogen deprivation of MCF-7, T-47-D and ZR-75-1 cells resulted in reduced growth inhibition by PD98059 (2–10 µg/ml), implying a loss of dependence on mitogen-activated protein kinase pathways for growth. The growth inhibitor LY294002 (2–10 µM) inhibited growth of both oestrogen-maintained and oestrogen-deprived cells with similar dose–responses, implying continued similar dependence on phosphoinositide 3-kinase (PI3K) pathways with no alteration after adaptation to oestrogen independent growth. However, by contrast, long-term oestrogen deprivation resulted in an increased sensitivity to growth inhibition by rapamycin, which was not reduced by readdition of oestradiol. The enhanced inhibition of long-term oestrogen-deprived MCF-7-ED, T-47-D-ED and ZR-75-1-ED cell growth by combining rapamycin with LY294002 at concentrations where each alone had little effect, offers preclinical support to the development of therapeutic combinations of rapamycin analogues with other PI3K inhibitors in endocrine-resistant breast cancer.

Sensitivity analysis of a cyanobacterial growth and movement model under two different flow regimes

Bloom-forming and toxin-producing cyanobacteria remain a persistent nuisance across the world. Modelling cyanobacterial behaviour in freshwaters is an important tool for understanding their population dynamics and predicting the location and timing of the bloom events in lakes, reservoirs and rivers. A new deterministic–mathematical model was developed, which simulates the growth and movement of cyanobacterial blooms in river systems. The model focuses on the mathematical description of the bloom formation, vertical migration and lateral transport of colonies within river environments by taking into account the major factors that affect the cyanobacterial bloom formation in rivers including light, nutrients and temperature. A parameter sensitivity analysis using a one-at-a-time approach was carried out. There were two objectives of the sensitivity analysis presented in this paper: to identify the key parameters controlling the growth and movement patterns of cyanobacteria and to provide a means for model validation. The result of the analysis suggested that maximum growth rate and day length period were the most significant parameters in determining the population growth and colony depth, respectively.

Acute effects of meal fatty acid composition on insulin sensitivity in healthy post-menopausal women

Postprandial plasma insulin concentrations after a single high-fat meal may be modified by the presence of specific fatty acids although the effects of sequential meal ingestion are unknown. The aim of the present study was to examine the effects of altering the fatty acid composition in a single mixed fat-carbohydrate meal on glucose metabolism and insulin sensitivity of a second meal eaten 5 h later. Insulin sensitivity was assessed using a minimal model approach. Ten healthy post-menopausal women underwent four two-meal studies in random order. A high-fat breakfast (40 g fat) where the fatty acid composition was predominantly saturated fatty acids (SFA), n-6 polyunsaturated fatty acids (PUFA), long-chain n-3 PUFA or monounsaturated fatty acids (MUFA) was followed 5 h later by a low-fat, high-carbohydrate lunch (5.7 g fat), which was identical in all four studies. The plasma insulin response was significantly higher following the SFA meal than the other meals after both breakfast and lunch (P<0.006) although there was no effect of breakfast fatty acid composition on plasma glucose concentrations. Postprandial insulin sensitivity (SI(Oral)) was assessed for 180 min after each meal. SI(Oral) was significantly lower after lunch than after breakfast for all four test meals (P=0.019) following the same rank order (SFA < n-6 PUFA < n-3 PUFA < MUFA) for each meal. The present study demonstrates that a single meal rich in SFA reduces postprandial insulin sensitivity with 'carry-over' effects for the next meal.

A sensitivity study for water availability in the Northern Caucasus based on climate projections

A strong climatic warming is currently observed in the Caucasus mountains, which has profound impact on runoff generation in the glaciated Glavny (Main) Range and on water availability in the whole region. To assess future changes in the hydrological cycle, the output of a general circulation model was downscaled statistically. For the 21st century, a further warming by 4–7 °C and a slight precipitation increase is predicted. Measured and simulated meteorological variables were used as input into a runoff model to transfer climate signals into a hydrological response under both present and future climate forcings. Runoff scenarios for the mid and the end of the 21st century were generated for different steps of deglaciation. The results show a satisfactory model performance for periods with observed runoff. Future water availability strongly depends on the velocity of glacier retreat. In a first phase, a surplus of water will increase flood risk in hot years and after continuing glacier reduction, annual runoff will again approximate current values. However, the seasonal distribution of streamflow will change towards runoff increase in spring and lower flows in summer.

Variation in the sensitivity of DOC release between different organic soils following H2SO4 and sea-salt additions

Long-term monitoring data from eastern North America and Europe indicate a link between increased dissolved organic carbon (DOC) concentrations in surface waters over the last two decades and decreased atmospheric pollutant and marine sulphur (S) deposition. The hypothesis is that decreased acidity and ionic strength associated with declining S deposition has increased the solubility of DOC. However, the sign and magnitude of DOC trends have varied between sites, and in some cases at sites where S deposition has declined, no significant increase in DOC has been observed, creating uncertainty about the causal mechanisms driving the observed trends. In this paper, we demonstrate chemical regulation of DOC release from organic soils in batch experiments caused by changes in acidity and conductivity (measured as a proxy for ionic strength) associated with controlled SO42− additions. DOC release from the top 10 cm of the O-horizon of organo-mineral soils and peats decreased by 21–60% in response to additions of 0–437 µeq SO42− l−1 sulphuric acid (H2SO4) and neutral sea-salt solutions (containing Na+, Mg2+, Cl−, SO42−) over a 20-hour extraction period. A significant decrease in the proportion of the acid-sensitive coloured aromatic humic acids (measured by specific ultra-violet absorbance (SUVA) at 254 nm) was also found with increasing acidity (P < 0.05) in most, but not all, soils, confirming that DOC quality, as well as quantity, changed with SO42− additions. DOC release appeared to be more sensitive to increased acidity than to increased conductivity. By comparing the change in DOC release with bulk soil properties, we found that DOC release from the O-horizon of organo-mineral soils and semi-confined peats, which contained greater exchangeable aluminium (Al) and had lower base saturation (BS), were more sensitive to SO42− additions than DOC release from blanket peats with low concentrations of exchangeable Al and greater BS. Therefore, variation in soil type and acid/base status between sites may partly explain the difference in the magnitude of DOC changes seen at different sites where declines in S deposition have been similar.

Forecast impact of targeted observations: sensitivity to observation error and proximity to steep orography

For a targeted observations case, the dependence of the size of the forecast impact on the targeted dropsonde observation error in the data assimilation is assessed. The targeted observations were made in the lee of Greenland; the dependence of the impact on the proximity of the observations to the Greenland coast is also investigated. Experiments were conducted using the Met Office Unified Model (MetUM), over a limited-area domain at 24-km grid spacing, with a four-dimensional variational data assimilation (4D-Var) scheme. Reducing the operational dropsonde observation errors by one-half increases the maximum forecast improvement from 5% to 7%–10%, measured in terms of total energy. However, the largest impact is seen by replacing two dropsondes on the Greenland coast with two farther from the steep orography; this increases the maximum forecast improvement from 5% to 18% for an 18-h forecast (using operational observation errors). Forecast degradation caused by two dropsonde observations on the Greenland coast is shown to arise from spreading of data by the background errors up the steep slope of Greenland. Removing boundary layer data from these dropsondes reduces the forecast degradation, but it is only a partial solution to this problem. Although only from one case study, these results suggest that observations positioned within a correlation length scale of steep orography may degrade the forecast through the anomalous upslope spreading of analysis increments along terrain-following model levels.

Dependence of Indian monsoon rainfall on moisture fluxes across the Arabian Sea and the impact of coupled model sea surface temperature biases

The Arabian Sea is an important moisture source for Indian monsoon rainfall. The skill of climate models in simulating the monsoon and its variability varies widely, while Arabian Sea cold sea surface temperature (SST) biases are common in coupled models and may therefore influence the monsoon and its sensitivity to climate change. We examine the relationship between monsoon rainfall, moisture fluxes and Arabian Sea SST in observations and climate model simulations. Observational analysis shows strong monsoons depend on moisture fluxes across the Arabian Sea, however detecting consistent signals with contemporaneous summer SST anomalies is complicated in the observed system by air/sea coupling and large-scale induced variability such as the El Niño-Southern Oscillation feeding back onto the monsoon through development of the Somali Jet. Comparison of HadGEM3 coupled and atmosphere-only configurations suggests coupled model cold SST biases significantly reduce monsoon rainfall. Idealised atmosphere-only experiments show that the weakened monsoon can be mainly attributed to systematic Arabian Sea cold SST biases during summer and their impact on the monsoon-moisture relationship. The impact of large cold SST biases on atmospheric moisture content over the Arabian Sea, and also the subsequent reduced latent heat release over India, dominates over any enhancement in the land-sea temperature gradient and results in changes to the mean state. We hypothesize that a cold base state will result in underestimation of the impact of larger projected Arabian Sea SST changes in future climate, suggesting that Arabian Sea biases should be a clear target for model development.

Flight to quality? An investigation of the attributes of sold properties in hot and cold markets

This paper uses sales transaction data in order to examine whether flight from risk phenomena took place in the US office property investment market during the financial crisis of 2007-2009. The effect of the crisis on the pricing of property quality attributes, mainly summarized by the class category of each building, is investigated. In addition, the paper examines how turnover levels were affected by the market downturn and whether there were significant variations between different real estate quality types. The results of the hedonic regression models suggest that the price spread between Class, A, B and C grew significantly during the downturn. We also find that property attributes such as size, height and age are priced significantly different in ‘hot’ and ‘cold’ markets.

The solar influence on the probability of relatively cold UK winters in the future

Recent research has suggested that relatively cold UK winters are more common when solar activity is low (Lockwood et al 2010 Environ. Res. Lett. 5 024001). Solar activity during the current sunspot minimum has fallen to levels unknown since the start of the 20th century (Lockwood 2010 Proc. R. Soc. A 466 303–29) and records of past solar variations inferred from cosmogenic isotopes (Abreu et al 2008 Geophys. Res. Lett. 35 L20109) and geomagnetic activity data (Lockwood et al 2009 Astrophys. J. 700 937–44) suggest that the current grand solar maximum is coming to an end and hence that solar activity can be expected to continue to decline. Combining cosmogenic isotope data with the long record of temperatures measured in central England, we estimate how solar change could influence the probability in the future of further UK winters that are cold, relative to the hemispheric mean temperature, if all other factors remain constant. Global warming is taken into account only through the detrending using mean hemispheric temperatures. We show that some predictive skill may be obtained by including the solar effect.

Building a left coast: the legacy of the California Popular Front and the challenge to Cold War liberalism in the post-world war two era

The Cold War in the late 1940s blunted attempts by the Truman administration to extend the scope of government in areas such as health care and civil rights. In California, the combined weakness of the Democratic Party in electoral politics and the importance of fellow travelers and communists in state liberal politics made the problem of how to advance the left at a time of heightened Cold War tensions particularly acute. Yet by the early 1960s a new generation of liberal politicians had gained political power in the Golden State and was constructing a greatly expanded welfare system as a way of cementing their hold on power. In this article I argue that the New Politics of the 1970s, shaped nationally by Vietnam and by the social upheavals of the 1960s over questions of race, gender, sexuality, and economic rights, possessed particular power in California because many activists drew on the longer-term experiences of a liberal politics receptive to earlier anti-Cold War struggles. A desire to use political involvement as a form of social networking had given California a strong Popular Front, and in some respects the power of new liberalism was an offspring of those earlier battles.