Selective killing of cancer cells by a small molecule targeting the stress response to ROS

Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage). Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells. Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress.     

A comparison of adaptive structural forecasting methods for electricity sales

This paper presents the results of a study to determine whether new forecasting technologies might be of use to electric utilities for sales forecasting up to 3 years into the future. The methods considered included ordinary least squares on dynamic structural models, autocorrelated error models, adaptive variance and adaptive parameter models. Overall, the more adaptive models performed best, but most of the methods proved vastly superior to simple least squares models which do not take dynamics into account.     

Discovery of an aurora on Mars

In the high-latitude regions of Earth, aurorae are the often-spectacular visual manifestation of the interaction between electrically charged particles (electrons, protons or ions) with the neutral upper atmosphere, as they precipitate along magnetic field lines. More generally, auroral emissions in planetary atmospheres "are those that result from the impact of particles other than photoelectrons" (ref. 1). Auroral activity has been found on all four giant planets possessing a magnetic field (Jupiter, Saturn, Uranus and Neptune), as well as on Venus, which has no magnetic field. On the nightside of Venus, atomic O emissions at 130.4 nm and 135.6 nm appear in bright patches of varying sizes and intensities, which are believed to be produced by electrons with energy <300 eV (ref. 7). Here we report the discovery of an aurora in the martian atmosphere, using the ultraviolet spectrometer SPICAM on board Mars Express. It corresponds to a distinct type of aurora not seen before in the Solar System: it is unlike aurorae at Earth and the giant planets, which lie at the foot of the intrinsic magnetic field lines near the magnetic poles, and unlike venusian auroras, which are diffuse, sometimes spreading over the entire disk. Instead, the martian aurora is a highly concentrated and localized emission controlled by magnetic field anomalies in the martian crust.     

Differentiation of the asteroid Ceres as revealed by its shape

The accretion of bodies in the asteroid belt was halted nearly 4.6 billion years ago by the gravitational influence of the newly formed giant planet Jupiter. The asteroid belt therefore preserves a record of both this earliest epoch of Solar System formation and variation of conditions within the solar nebula. Spectral features in reflected sunlight indicate that some asteroids have experienced sufficient thermal evolution to differentiate into layered structures. The second most massive asteroid--4 Vesta--has differentiated to a crust, mantle and core. 1 Ceres, the largest and most massive asteroid, has in contrast been presumed to be homogeneous, in part because of its low density, low albedo and relatively featureless visible reflectance spectrum, similar to carbonaceous meteorites that have suffered minimal thermal processing. Here we show that Ceres has a shape and smoothness indicative of a gravitationally relaxed object. Its shape is significantly less flattened than that expected for a homogeneous object, but is consistent with a central mass concentration indicative of differentiation. Possible interior configurations include water-ice-rich mantles over a rocky core.     

Single mimivirus particles intercepted and imaged with an X-ray laser

X-ray lasers offer new capabilities in understanding the structure of biological systems, complex materials and matter under extreme conditions. Very short and extremely bright, coherent X-ray pulses can be used to outrun key damage processes and obtain a single diffraction pattern from a large macromolecule, a virus or a cell before the sample explodes and turns into plasma. The continuous diffraction pattern of non-crystalline objects permits oversampling and direct phase retrieval. Here we show that high-quality diffraction data can be obtained with a single X-ray pulse from a non-crystalline biological sample, a single mimivirus particle, which was injected into the pulsed beam of a hard-X-ray free-electron laser, the Linac Coherent Light Source. Calculations indicate that the energy deposited into the virus by the pulse heated the particle to over 100,000?K after the pulse had left the sample. The reconstructed exit wavefront (image) yielded 32-nm full-period resolution in a single exposure and showed no measurable damage. The reconstruction indicates inhomogeneous arrangement of dense material inside the virion. We expect that significantly higher resolutions will be achieved in such experiments with shorter and brighter photon pulses focused to a smaller area. The resolution in such experiments can be further extended for samples available in multiple identical copies.     

Inhibition of transplanted mouse tumors by heterologous transfer RNA

Summary Injections of yeast tRNA to C57BL mice decreased takes and inhibited growth of syngeneic transplanted tumors. Mice remaining free of tumors as result of this treatment failed to develop tumors after challenge with 5×10⁴ cells of the same tumor.This work was supported in part by a grant from the Stanley Johnson Foundation, Berne, Switzerland.     

Climate change and the resurgence of malaria in the East African highlands

The public health and economic consequences of Plasmodium falciparum malaria are once again regarded as priorities for global development. There has been much speculation on whether anthropogenic climate change is exacerbating the malaria problem, especially in areas of high altitude where P. falciparum transmission is limited by low temperature. The International Panel on Climate Change has concluded that there is likely to be a net extension in the distribution of malaria and an increase in incidence within this range. We investigated long-term meteorological trends in four high-altitude sites in East Africa, where increases in malaria have been reported in the past two decades. Here we show that temperature, rainfall, vapour pressure and the number of months suitable for P. falciparum transmission have not changed significantly during the past century or during the period of reported malaria resurgence. A high degree of temporal and spatial variation in the climate of East Africa suggests further that claimed associations between local malaria resurgences and regional changes in climate are overly simplistic.