p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a

The CDKN2b-CDKN2a locus on chromosome 9p21 in human (chromosome 4 in mouse) is frequently lost in cancer. The locus encodes three cell cycle inhibitory proteins: p15INK4b encoded by CDKN2b, p16INK4a encoded by CDKN2a and p14ARF (p19Arf in mice) encoded by an alternative reading frame of CDKN2a (ref. 1). Whereas the tumour suppressor functions for p16INK4a and p14ARF have been firmly established, the role of p15INK4b remains ambiguous. However, many 9p21 deletions also remove CDKN2b, so we hypothesized a synergistic effect of the combined deficiency for p15INK4b, p14ARF and p16INK4a. Here we report that mice deficient for all three open reading frames (Cdkn2ab-/-) are more tumour-prone and develop a wider spectrum of tumours than Cdkn2a mutant mice, with a preponderance of skin tumours and soft tissue sarcomas (for example, mesothelioma) frequently composed of mixed cell types and often showing biphasic differentiation. Cdkn2ab-/- mouse embryonic fibroblasts (MEFs) are substantially more sensitive to oncogenic transformation than Cdkn2a mutant MEFs. Under conditions of stress, p15Ink4b protein levels are significantly elevated in MEFs deficient for p16Ink4a. Our data indicate that p15Ink4b can fulfil a critical backup function for p16Ink4a and provide an explanation for the frequent loss of the complete CDKN2b-CDKN2a locus in human tumours.     

Non-random coextinctions in phylogenetically structured mutualistic networks

The interactions between plants and their animal pollinators and seed dispersers have moulded much of Earth's biodiversity. Recently, it has been shown that these mutually beneficial interactions form complex networks with a well-defined architecture that may contribute to biodiversity persistence. Little is known, however, about which ecological and evolutionary processes generate these network patterns. Here we use phylogenetic methods to show that the phylogenetic relationships of species predict the number of interactions they exhibit in more than one-third of the networks, and the identity of the species with which they interact in about half of the networks. As a consequence of the phylogenetic effects on interaction patterns, simulated extinction events tend to trigger coextinction cascades of related species. This results in a non-random pruning of the evolutionary tree and a more pronounced loss of taxonomic diversity than expected in the absence of a phylogenetic signal. Our results emphasize how the simultaneous consideration of phylogenetic information and network architecture can contribute to our understanding of the structure and fate of species-rich communities.     

Visualizing single-molecule diffusion in mesoporous materials

Periodic mesoporous materials formed through the cooperative self-assembly of surfactants and framework building blocks can assume a variety of structures, and their widely tuneable properties make them attractive hosts for numerous applications. Because the molecular movement in the pore system is the most important and defining characteristic of porous materials, it is of interest to learn about this behaviour as a function of local structure. Generally, individual fluorescent dye molecules can be used as molecular beacons with which to explore the structure of--and the dynamics within--these porous hosts, and single-molecule fluorescence techniques provide detailed insights into the dynamics of various processes, ranging from biology to heterogeneous catalysis. However, optical microscopy methods cannot directly image the mesoporous structure of the host system accommodating the diffusing molecules, whereas transmission electron microscopy provides detailed images of the porous structure, but no dynamic information. It has therefore not been possible to 'see' how molecules diffuse in a real nanoscale pore structure. Here we present a combination of electron microscopic mapping and optical single-molecule tracking experiments to reveal how a single luminescent dye molecule travels through linear or strongly curved sections of a mesoporous channel system. In our approach we directly correlate porous structures detected by transmission electron microscopy with the diffusion dynamics of single molecules detected by optical microscopy. This opens up new ways of understanding the interactions of host and guest.     

Enhanced biological carbon consumption in a high CO2 ocean

The oceans have absorbed nearly half of the fossil-fuel carbon dioxide (CO2) emitted into the atmosphere since pre-industrial times, causing a measurable reduction in seawater pH and carbonate saturation. If CO2 emissions continue to rise at current rates, upper-ocean pH will decrease to levels lower than have existed for tens of millions of years and, critically, at a rate of change 100 times greater than at any time over this period. Recent studies have shown effects of ocean acidification on a variety of marine life forms, in particular calcifying organisms. Consequences at the community to ecosystem level, in contrast, are largely unknown. Here we show that dissolved inorganic carbon consumption of a natural plankton community maintained in mesocosm enclosures at initial CO2 partial pressures of 350, 700 and 1,050 microatm increases with rising CO2. The community consumed up to 39% more dissolved inorganic carbon at increased CO2 partial pressures compared to present levels, whereas nutrient uptake remained the same. The stoichiometry of carbon to nitrogen drawdown increased from 6.0 at low CO2 to 8.0 at high CO2, thus exceeding the Redfield carbon:nitrogen ratio of 6.6 in today's ocean. This excess carbon consumption was associated with higher loss of organic carbon from the upper layer of the stratified mesocosms. If applicable to the natural environment, the observed responses have implications for a variety of marine biological and biogeochemical processes, and underscore the importance of biologically driven feedbacks in the ocean to global change.     

PTC124 targets genetic disorders caused by nonsense mutations

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.     

Low beta diversity of herbivorous insects in tropical forests

Recent advances in understanding insect communities in tropical forests have contributed little to our knowledge of large-scale patterns of insect diversity, because incomplete taxonomic knowledge of many tropical species hinders the mapping of their distribution records. This impedes an understanding of global biodiversity patterns and explains why tropical insects are under-represented in conservation biology. Our study of approximately 500 species from three herbivorous guilds feeding on foliage (caterpillars, Lepidoptera), wood (ambrosia beetles, Coleoptera) and fruit (fruitflies, Diptera) found a low rate of change in species composition (beta diversity) across 75,000 square kilometres of contiguous lowland rainforest in Papua New Guinea, as most species were widely distributed. For caterpillars feeding on large plant genera, most species fed on multiple host species, so that even locally restricted plant species did not support endemic herbivores. Large plant genera represented a continuously distributed resource easily colonized by moths and butterflies over hundreds of kilometres. Low beta diversity was also documented in groups with differing host specificity (fruitflies and ambrosia beetles), suggesting that dispersal limitation does not have a substantial role in shaping the distribution of insect species in New Guinea lowland rainforests. Similar patterns of low beta diversity can be expected in other tropical lowland rainforests, as they are typically situated in the extensive low basins of major tropical rivers similar to the Sepik-Ramu region of New Guinea studied here.     

Strong atom-field coupling for Bose-Einstein condensates in an optical cavity on a chip

An optical cavity enhances the interaction between atoms and light, and the rate of coherent atom-photon coupling can be made larger than all decoherence rates of the system. For single atoms, this 'strong coupling regime' of cavity quantum electrodynamics has been the subject of many experimental advances. Efforts have been made to control the coupling rate by trapping the atom and cooling it towards the motional ground state; the latter has been achieved in one dimension so far. For systems of many atoms, the three-dimensional ground state of motion is routinely achieved in atomic Bose-Einstein condensates (BECs). Although experiments combining BECs and optical cavities have been reported recently, coupling BECs to cavities that are in the strong-coupling regime for single atoms has remained an elusive goal. Here we report such an experiment, made possible by combining a fibre-based cavity with atom-chip technology. This enables single-atom cavity quantum electrodynamics experiments with a simplified set-up and realizes the situation of many atoms in a cavity, each of which is identically and strongly coupled to the cavity mode. Moreover, the BEC can be positioned deterministically anywhere within the cavity and localized entirely within a single antinode of the standing-wave cavity field; we demonstrate that this gives rise to a controlled, tunable coupling rate. We study the heating rate caused by a cavity transmission measurement as a function of the coupling rate and find no measurable heating for strongly coupled BECs. The spectrum of the coupled atoms-cavity system, which we map out over a wide range of atom numbers and cavity-atom detunings, shows vacuum Rabi splittings exceeding 20 gigahertz, as well as an unpredicted additional splitting, which we attribute to the atomic hyperfine structure. We anticipate that the system will be suitable as a light-matter quantum interface for quantum information.     

Identification of stem cells in small intestine and colon by marker gene Lgr5

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above the Paneth cells in the small intestine; colon stem cells remain undefined. Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5, also known as Gpr49) was selected from a panel of intestinal Wnt target genes for its restricted crypt expression. Here, using two knock-in alleles, we reveal exclusive expression of Lgr5 in cycling columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-lacZ reporter strain, lineage-tracing experiments were performed in adult mice. The Lgr5-positive crypt base columnar cell generated all epithelial lineages over a 60-day period, suggesting that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers.