A genome-wide association study of metabolic traits in human urine

We present a genome-wide association study of metabolic traits in human urine, designed to investigate the detoxification capacity of the human body. Using NMR spectroscopy, we tested for associations between 59 metabolites in urine from 862 male participants in the population-based SHIP study. We replicated the results using 1,039 additional samples of the same study, including a 5-year follow-up, and 992 samples from the independent KORA study. We report five loci with joint P values of association from 3.2 × 10(-19) to 2.1 × 10(-182). Variants at three of these loci have previously been linked with important clinical outcomes: SLC7A9 is a risk locus for chronic kidney disease, NAT2 for coronary artery disease and genotype-dependent response to drug toxicity, and SLC6A20 for iminoglycinuria. Moreover, we identify rs37369 in AGXT2 as the genetic basis of hyper-β-aminoisobutyric aciduria.     

Recognition of bacterial glycosphingolipids by natural killer T cells

Natural killer T (NKT) cells constitute a highly conserved T lymphocyte subpopulation that has the potential to regulate many types of immune responses through the rapid secretion of cytokines. NKT cells recognize glycolipids presented by CD1d, a class I-like antigen-presenting molecule. They have an invariant T-cell antigen receptor (TCR) alpha-chain, but whether this invariant TCR recognizes microbial antigens is still controversial. Here we show that most mouse and human NKT cells recognize glycosphingolipids from Sphingomonas, Gram-negative bacteria that do not contain lipopolysaccharide. NKT cells are activated in vivo after exposure to these bacterial antigens or bacteria, and mice that lack NKT cells have a marked defect in the clearance of Sphingomonas from the liver. These data suggest that NKT cells are T lymphocytes that provide an innate-type immune response to certain microorganisms through recognition by their antigen receptor, and that they might be useful in providing protection from bacteria that cannot be detected by pattern recognition receptors such as Toll-like receptor 4.     

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.     

Regulation of immunity by self-reactive T cells

A basic principle of immunology is that lymphocytes respond to foreign antigens but tolerate self tissues. For developing T cells, the ability to distinguish self from non-self is acquired in the thymus, where the majority of self-reactive cells are eliminated. Recently, however, it has become apparent that some self-reactive T cells avoid being destroyed and instead differentiate into specialized regulatory cells. This appears to be beneficial. Subpopulations of self-reactive T cells have a strong influence on self tolerance and may represent targets for therapeutic intervention to control a variety of autoimmune diseases, tumour growth and infection.     

Large-scale synthesis of a silicon photonic crystal with a complete three-dimensional bandgap near 1.5 micrometres

Photonic technology, using light instead of electrons as the information carrier, is increasingly replacing electronics in communication and information management systems. Microscopic light manipulation, for this purpose, is achievable through photonic bandgap materials, a special class of photonic crystals in which three-dimensional, periodic dielectric constant variations controllably prohibit electromagnetic propagation throughout a specified frequency band. This can result in the localization of photons, thus providing a mechanism for controlling and inhibiting spontaneous light emission that can be exploited for photonic device fabrication. In fact, carefully engineered line defects could act as waveguides connecting photonic devices in all-optical microchips, and infiltration of the photonic material with suitable liquid crystals might produce photonic bandgap structures (and hence light-flow patterns) fully tunable by an externally applied voltage. However, the realization of this technology requires a strategy for the efficient synthesis of high-quality, large-scale photonic crystals with photonic bandgaps at micrometre and sub-micrometre wavelengths, and with rationally designed line and point defects for optical circuitry. Here we describe single crystals of silicon inverse opal with a complete three-dimensional photonic bandgap centred on 1.46 microm, produced by growing silicon inside the voids of an opal template of dose-packed silica spheres that are connected by small 'necks' formed during sintering, followed by removal of the silica template. The synthesis method is simple and inexpensive, yielding photonic crystals of pure silicon that are easily integrated with existing silicon-based microelectronics.     

Fracture surface energy of the Punchbowl fault, San Andreas system

Fracture energy is a form of latent heat required to create an earthquake rupture surface and is related to parameters governing rupture propagation and processes of slip weakening. Fracture energy has been estimated from seismological and experimental rock deformation data, yet its magnitude, mechanisms of rupture surface formation and processes leading to slip weakening are not well defined. Here we quantify structural observations of the Punchbowl fault, a large-displacement exhumed fault in the San Andreas fault system, and show that the energy required to create the fracture surface area in the fault is about 300 times greater than seismological estimates would predict for a single large earthquake. If fracture energy is attributed entirely to the production of fracture surfaces, then all of the fracture surface area in the Punchbowl fault could have been produced by earthquake displacements totalling <1 km. But this would only account for a small fraction of the total energy budget, and therefore additional processes probably contributed to slip weakening during earthquake rupture.