Planetary science: are there active glaciers on Mars?

Head et al. interpret spectacular images from the Mars Express high-resolution stereo camera as evidence of geologically recent rock glaciers in Tharsis and of a piedmont ('hourglass') glacier at the base of a 3-km-high massif east of Hellas. They attribute growth of the low-latitude glaciers to snowfall during periods of increased spin-axis obliquity. The age of the hourglass glacier, considered to be inactive and slowly shrinking beneath a debris cover in the absence of modern snowfall, is estimated to be more than 40 Myr. Although we agree that the maximum glacier extent was climatically controlled, we find evidence in the images to support local augmentation of accumulation from snowfall through a mechanism that does not require climate change on Mars.     

IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells

On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions. Recently a subset of T cells, distinct from T helper (T(H))1 and T(H)2 cells, producing interleukin (IL)-17 (T(H)17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation. We and others have shown that transforming growth factor (TGF)-beta and IL-6 together induce the differentiation of T(H)17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3+ regulatory T cells (T(reg) cells) or T(H)17 cells. Whereas TGF-beta induces Foxp3 and generates T(reg) cells, IL-6 inhibits the generation of T(reg) cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for T(H)17 and T(reg) cells. Here we show that IL-6-deficient (Il6-/-) mice do not develop a T(H)17 response and their peripheral repertoire is dominated by Foxp3+ T(reg) cells. However, deletion of T(reg) cells leads to the reappearance of T(H)17 cells in Il6-/- mice, suggesting an additional pathway by which T(H)17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-beta to induce T(H)17 cells in naive Il6-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a T(H)17 response.     

Genes mirror geography within Europe

Understanding the genetic structure of human populations is of fundamental interest to medical, forensic and anthropological sciences. Advances in high-throughput genotyping technology have markedly improved our understanding of global patterns of human genetic variation and suggest the potential to use large samples to uncover variation among closely spaced populations. Here we characterize genetic variation in a sample of 3,000 European individuals genotyped at over half a million variable DNA sites in the human genome. Despite low average levels of genetic differentiation among Europeans, we find a close correspondence between genetic and geographic distances; indeed, a geographical map of Europe arises naturally as an efficient two-dimensional summary of genetic variation in Europeans. The results emphasize that when mapping the genetic basis of a disease phenotype, spurious associations can arise if genetic structure is not properly accounted for. In addition, the results are relevant to the prospects of genetic ancestry testing; an individual's DNA can be used to infer their geographic origin with surprising accuracy-often to within a few hundred kilometres.     

Thermochemical flows couple the Earth's inner core growth to mantle heterogeneity

Seismic waves sampling the top 100 km of the Earth's inner core reveal that the eastern hemisphere (40 degrees E-180 degrees E) is seismically faster, more isotropic and more attenuating than the western hemisphere. The origin of this hemispherical dichotomy is a challenging problem for our understanding of the Earth as a system of dynamically coupled layers. Previously, laboratory experiments have established that thermal control from the lower mantle can drastically affect fluid flow in the outer core, which in turn can induce textural heterogeneity on the inner core solidification front. The resulting texture should be consistent with other expected manifestations of thermal mantle control on the geodynamo, specifically magnetic flux concentrations in the time-average palaeomagnetic field over the past 5 Myr, and preferred eddy locations in flows imaged below the core-mantle boundary by the analysis of historical geomagnetic secular variation. Here we show that a single model of thermochemical convection and dynamo action can account for all these effects by producing a large-scale, long-term outer core flow that couples the heterogeneity of the inner core with that of the lower mantle. The main feature of this thermochemical 'wind' is a cyclonic circulation below Asia, which concentrates magnetic field on the core-mantle boundary at the observed location and locally agrees with core flow images. This wind also causes anomalously high rates of light element release in the eastern hemisphere of the inner core boundary, suggesting that lateral seismic anomalies at the top of the inner core result from mantle-induced variations in its freezing rate.     

Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma

To survey hepatitis B virus (HBV) integration in liver cancer genomes, we conducted massively parallel sequencing of 81 HBV-positive and 7 HBV-negative hepatocellular carcinomas (HCCs) and adjacent normal tissues. We found that HBV integration is observed more frequently in the tumors (86.4%) than in adjacent liver tissues (30.7%). Copy-number variations (CNVs) were significantly increased at HBV breakpoint locations where chromosomal instability was likely induced. Approximately 40% of HBV breakpoints within the HBV genome were located within a 1,800-bp region where the viral enhancer, X gene and core gene are located. We also identified recurrent HBV integration events (in ≥ 4 HCCs) that were validated by RNA sequencing (RNA-seq) and Sanger sequencing at the known and putative cancer-related TERT, MLL4 and CCNE1 genes, which showed upregulated gene expression in tumor versus normal tissue. We also report evidence that suggests that the number of HBV integrations is associated with patient survival.     

Improvement of warm formability of Al-Mg sheet alloys containing coarse second-phase particles

Several alloying elements involving Zr,Cu,Zn and Sc were added to Al-Mg sheet alloys in order to obtain an excellent combination of high strength and good high-temperature formability.Microstructural examination showed that coarse intermetallic particles were formed in the microstructure and their amounts changed with variations of the alloying elements. During warm rolling of thermomechanical treatments prior to warm deformation,the coarse particles initiated cracks,decreasing the warm formability.For healing the crack damage and further improving the warm formability,a process of hot isothermal press was developed and optimized to the sheet alloys.With this process,the biaxial stretch formability at 350°C was improved by 22%for an aluminum alloy containing a large amount of coarse particles.     

Suppressor of cytokine signaling 1 blocks mitosis in human melanoma cells

Hypermethylation of SOCS genes is associated with many human cancers, suggesting a role as tumor suppressors. As adaptor molecules for ubiquitin ligases, SOCS proteins modulate turnover of numerous target proteins. Few SOCS targets identified so far have a direct role in cell cycle progression; the mechanism by which SOCS regulate the cell cycle thus remains largely unknown. Here we show that SOCS1 overexpression inhibits in vitro and in vivo expansion of human melanoma cells, and that SOCS1 associates specifically with Cdh1, triggering its degradation by the proteasome. Cells therefore show a G1/S transition defect, as well as a secondary blockade in mitosis and accumulation of cells in metaphase. SOCS1 expression correlated with a reduction in cyclin D/E levels and an increase in the tumor suppressor p19, as well as the CDK inhibitor p53, explaining the G1/S transition defect. As a result of Cdh1 degradation, SOCS1-expressing cells accumulated cyclin B1 and securin, as well as apparently inactive Cdc20, in mitosis. Levels of the late mitotic Cdh1 substrate Aurora A did not change. These observations comprise a hitherto unreported mechanism of SOCS1 tumor suppression, suggesting this molecule as a candidate for the design of new therapeutic strategies for human melanoma.     

High-throughput oncogene mutation profiling in human cancer

Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention.     

TRPC channel activation by extracellular thioredoxin

Mammalian homologues of Drosophila melanogaster transient receptor potential (TRP) are a large family of multimeric cation channels that act, or putatively act, as sensors of one or more chemical factor. Major research objectives are the identification of endogenous activators and the determination of cellular and tissue functions of these channels. Here we show the activation of TRPC5 (canonical TRP 5) homomultimeric and TRPC5-TRPC1 heteromultimeric channels by extracellular reduced thioredoxin, which acts by breaking a disulphide bridge in the predicted extracellular loop adjacent to the ion-selectivity filter of TRPC5. Thioredoxin is an endogenous redox protein with established intracellular functions, but it is also secreted and its extracellular targets are largely unknown. Particularly high extracellular concentrations of thioredoxin are apparent in rheumatoid arthritis, an inflammatory joint disease that disables millions of people worldwide. We show that TRPC5 and TRPC1 are expressed in secretory fibroblast-like synoviocytes from patients with rheumatoid arthritis, that endogenous TRPC5-TRPC1 channels of the cells are activated by reduced thioredoxin, and that blockade of the channels enhances secretory activity and prevents the suppression of secretion by thioredoxin. The data indicate the presence of a previously unrecognized ion-channel activation mechanism that couples extracellular thioredoxin to cell function.