Senescence surveillance of pre-malignant hepatocytes limits liver cancer development

Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.     

A star in a 15.2-year orbit around the supermassive black hole at the centre of the Milky Way

Many galaxies are thought to have supermassive black holes at their centres-more than a million times the mass of the Sun. Measurements of stellar velocities and the discovery of variable X-ray emission have provided strong evidence in favour of such a black hole at the centre of the Milky Way, but have hitherto been unable to rule out conclusively the presence of alternative concentrations of mass. Here we report ten years of high-resolution astrometric imaging that allows us to trace two-thirds of the orbit of the star currently closest to the compact radio source (and massive black-hole candidate) Sagittarius A*. The observations, which include both pericentre and apocentre passages, show that the star is on a bound, highly elliptical keplerian orbit around Sgr A*, with an orbital period of 15.2 years and a pericentre distance of only 17 light hours. The orbit with the best fit to the observations requires a central point mass of (3.7 +/- 1.5) x 10(6) solar masses (M(*)). The data no longer allow for a central mass composed of a dense cluster of dark stellar objects or a ball of massive, degenerate fermions.     

Near-infrared flares from accreting gas around the supermassive black hole at the Galactic Centre

Recent measurements of stellar orbits provide compelling evidence that the compact radio source Sagittarius A* (refs 4, 5) at the Galactic Centre is a 3.6-million-solar-mass black hole. Sgr A* is remarkably faint in all wavebands other than the radio region, however, which challenges current theories of matter accretion and radiation surrounding black holes. The black hole's rotation rate is not known, and therefore neither is the structure of space-time around it. Here we report high-resolution infrared observations of Sgr A* that reveal 'quiescent' emission and several flares. The infrared emission originates from within a few milliarcseconds of the black hole, and traces very energetic electrons or moderately hot gas within the innermost accretion region. Two flares exhibit a 17-minute quasi-periodic variability. If the periodicity arises from relativistic modulation of orbiting gas, the emission must come from just outside the event horizon, and the black hole must be rotating at about half of the maximum possible rate.     

Ultraviolet-radiation-induced methane emissions from meteorites and the Martian atmosphere

Almost a decade after methane was first reported in the atmosphere of Mars there is an intensive discussion about both the reliability of the observations--particularly the suggested seasonal and latitudinal variations--and the sources of methane on Mars. Given that the lifetime of methane in the Martian atmosphere is limited, a process on or below the planet's surface would need to be continuously producing methane. A biological source would provide support for the potential existence of life on Mars, whereas a chemical origin would imply that there are unexpected geological processes. Methane release from carbonaceous meteorites associated with ablation during atmospheric entry is considered negligible. Here we show that methane is produced in much larger quantities from the Murchison meteorite (a type CM2 carbonaceous chondrite) when exposed to ultraviolet radiation under conditions similar to those expected at the Martian surface. Meteorites containing several per cent of intact organic matter reach the Martian surface at high rates, and our experiments suggest that a significant fraction of the organic matter accessible to ultraviolet radiation is converted to methane. Ultraviolet-radiation-induced methane formation from meteorites could explain a substantial fraction of the most recently estimated atmospheric methane mixing ratios. Stable hydrogen isotope analysis unambiguously confirms that the methane released from Murchison is of extraterrestrial origin. The stable carbon isotope composition, in contrast, is similar to that of terrestrial microbial origin; hence, measurements of this signature in future Mars missions may not enable an unambiguous identification of biogenic methane.     

Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation

During immune responses, antibodies are selected for their ability to bind to foreign antigens with high affinity, in part by their ability to undergo homotypic bivalent binding. However, this type of binding is not always possible. For example, the small number of gp140 glycoprotein spikes displayed on the surface of the human immunodeficiency virus (HIV) disfavours homotypic bivalent antibody binding. Here we show that during the human antibody response to HIV, somatic mutations that increase antibody affinity also increase breadth and neutralizing potency. Surprisingly, the responding naive and memory B cells produce polyreactive antibodies, which are capable of bivalent heteroligation between one high-affinity anti-HIV-gp140 combining site and a second low-affinity site on another molecular structure on HIV. Although cross-reactivity to self-antigens or polyreactivity is strongly selected against during B-cell development, it is a common serologic feature of certain infections in humans, including HIV, Epstein-Barr virus and hepatitis C virus. Seventy-five per cent of the 134 monoclonal anti-HIV-gp140 antibodies cloned from six patients with high titres of neutralizing antibodies are polyreactive. Despite the low affinity of the polyreactive combining site, heteroligation demonstrably increases the apparent affinity of polyreactive antibodies to HIV.     

Extrusion Freeforming of Millimeter-Wave Electromagnetic Bandgap (EBG) Photonic Crystals

Extrusion freeforming can be used for the rapid prototyping of millimeter-wave electromagnetic bandgap (EBG) structures. In this work, an alumina-polymer paste with a relatively high volatility solvent (propanol) was used and the characteristics of the ceramic paste, particularly the rheological features are described. The advantage of high volatility solvent is that the viscosity and elastic modulus of the paste are increased sharply as the solvent evaporates. Thus, the rigidity of the extruded filament is quickly increased as a small amount of solvent evaporates. Finally, by employing this procedure, different EBG structures such as 2-D, 3-D woodpile and aperiodic structures were fabricated and their bandgaps were measured. The experimental results show that extrusion freeforming is a relatively simple and easy method to fabricate these woodpile structures with a bandgap in the 90–110 GHz region.     

Whole-genome sequencing of multiple Arabidopsis thaliana populations

The plant Arabidopsis thaliana occurs naturally in many different habitats throughout Eurasia. As a foundation for identifying genetic variation contributing to adaptation to diverse environments, a 1001 Genomes Project to sequence geographically diverse A. thaliana strains has been initiated. Here we present the first phase of this project, based on population-scale sequencing of 80 strains drawn from eight regions throughout the species' native range. We describe the majority of common small-scale polymorphisms as well as many larger insertions and deletions in the A. thaliana pan-genome, their effects on gene function, and the patterns of local and global linkage among these variants. The action of processes other than spontaneous mutation is identified by comparing the spectrum of mutations that have accumulated since A. thaliana diverged from its closest relative 10 million years ago with the spectrum observed in the laboratory. Recent species-wide selective sweeps are rare, and potentially deleterious mutations are more common in marginal populations.     

Solid Freeforming and Combinatorial Research

A view of manufacturing processes is presented in which five distinct categories are defined as casting, deformation, machining, joining, and solid freeforming. Solid freeforming is essentially biomimetic and shares problems of morphogenesis with natural processes. Our team in University of London has been exploring three mechanisms of solid freeforming. In dry powder deposition and direct ink-jet printing, the emphasis has turned to the problem of delivering a complex shape in which the three dimensional spatial arrangement of composition is delivered from the design file. In extrusion freeforming, the aim is to control microstructure at hierarchical levels also from the design file. The quest for 3-D functional gradients is satisfied by acoustic and ultrasonic dispensing and mixing of powders so that each layer can be patterned. These methods could be extended to deliver the complex patterns demanded by left-handed microwave metamaterials. Dry powder deposition and direct ink-jet printing are turning towards combinatorial methods in which multiple sample libraries are used to accelerate discovery. In turn, this paves the way for ‘autonomous research machines’ which steer their own search refinements in response to our requests for new materials. In this way, solid freeforming used for sample preparation can give an ‘arm’ to an intelligent machine so that it can conduct its own experimentation and learning; an idea that originated with Alan Turing in the late 1940s.