A phosphatase cascade by which rewarding stimuli control nucleosomal response

Dopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade.     

Fullerenes from aromatic precursors by surface-catalysed cyclodehydrogenation

Graphite vaporization provides an uncontrolled yet efficient means of producing fullerene molecules. However, some fullerene derivatives or unusual fullerene species might only be accessible through rational and controlled synthesis methods. Recently, such an approach has been used to produce isolable amounts of the fullerene C(60) from commercially available starting materials. But the overall process required 11 steps to generate a suitable polycyclic aromatic precursor molecule, which was then dehydrogenated in the gas phase with a yield of only about one per cent. Here we report the formation of C(60) and the triazafullerene C(57)N(3) from aromatic precursors using a highly efficient surface-catalysed cyclodehydrogenation process. We find that after deposition onto a platinum (111) surface and heating to 750 K, the precursors are transformed into the corresponding fullerene and triazafullerene molecules with about 100 per cent yield. We expect that this approach will allow the production of a range of other fullerenes and heterofullerenes, once suitable precursors are available. Also, if the process is carried out in an atmosphere containing guest species, it might even allow the encapsulation of atoms or small molecules to form endohedral fullerenes.     

Cladistic analysis of continuous modularized traits provides phylogenetic signals in Homo evolution

Evolutionary novelties in the skeleton are usually expressed as changes in the timing of growth of features intrinsically integrated at different hierarchical levels of development. As a consequence, most of the shape-traits observed across species do vary quantitatively rather than qualitatively, in a multivariate space and in a modularized way. Because most phylogenetic analyses normally use discrete, hypothetically independent characters, previous attempts have disregarded the phylogenetic signals potentially enclosed in the shape of morphological structures. When analysing low taxonomic levels, where most variation is quantitative in nature, solving basic requirements like the choice of characters and the capacity of using continuous, integrated traits is of crucial importance in recovering wider phylogenetic information. This is particularly relevant when analysing extinct lineages, where available data are limited to fossilized structures. Here we show that when continuous, multivariant and modularized characters are treated as such, cladistic analysis successfully solves relationships among main Homo taxa. Our attempt is based on a combination of cladistics, evolutionary-development-derived selection of characters, and geometric morphometrics methods. In contrast with previous cladistic analyses of hominid phylogeny, our method accounts for the quantitative nature of the traits, and respects their morphological integration patterns. Because complex phenotypes are observable across different taxonomic groups and are potentially informative about phylogenetic relationships, future analyses should point strongly to the incorporation of these types of trait.     

Mediators of vascular remodelling co-opted for sequential steps in lung metastasis

Metastasis entails numerous biological functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacological approaches, we show that the epidermal growth factor receptor ligand epiregulin, the cyclooxygenase COX2, and the matrix metalloproteinases 1 and 2, when expressed in human breast cancer cells, collectively facilitate the assembly of new tumour blood vessels, the release of tumour cells into the circulation, and the breaching of lung capillaries by circulating tumour cells to seed pulmonary metastasis. These findings reveal how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biological activities may be therapeutically targeted with specific drug combinations.     

One or more bound planets per Milky Way star from microlensing observations

Most known extrasolar planets (exoplanets) have been discovered using the radial velocity or transit methods. Both are biased towards planets that are relatively close to their parent stars, and studies find that around 17-30% (refs 4, 5) of solar-like stars host a planet. Gravitational microlensing, on the other hand, probes planets that are further away from their stars. Recently, a population of planets that are unbound or very far from their stars was discovered by microlensing. These planets are at least as numerous as the stars in the Milky Way. Here we report a statistical analysis of microlensing data (gathered in 2002-07) that reveals the fraction of bound planets 0.5-10?AU (Sun-Earth distance) from their stars. We find that 17(+6)(-9)% of stars host Jupiter-mass planets (0.3-10?M(J), where M(J) = 318?M(⊕) and M(⊕) is Earth's mass). Cool Neptunes (10-30?M(⊕)) and super-Earths (5-10?M(⊕)) are even more common: their respective abundances per star are 52(+22)(-29)% and 62(+35)(-37)%. We conclude that stars are orbited by planets as a rule, rather than the exception.     

Head swivel on the ribosome facilitates translocation by means of intra-subunit tRNA hybrid sites

The elongation cycle of protein synthesis involves the delivery of aminoacyl-transfer RNAs to the aminoacyl-tRNA-binding site (A?site) of the ribosome, followed by peptide-bond formation and translocation of the tRNAs through the ribosome to reopen the A?site. The translocation reaction is catalysed by elongation factor G (EF-G) in a GTP-dependent manner. Despite the availability of structures of various EF-G-ribosome complexes, the precise mechanism by which tRNAs move through the ribosome still remains unclear. Here we use multiparticle cryoelectron microscopy analysis to resolve two previously unseen subpopulations within Thermus thermophilus EF-G-ribosome complexes at subnanometre resolution, one of them with a partly translocated tRNA. Comparison of these substates reveals that translocation of tRNA on the 30S subunit parallels the swivelling of the 30S head and is coupled to unratcheting of the 30S body. Because the tRNA maintains contact with the peptidyl-tRNA-binding site (P?site) on the 30S head and simultaneously establishes interaction with the exit site (E?site) on the 30S platform, a novel intra-subunit 'pe/E' hybrid state is formed. This state is stabilized by domain?IV of EF-G, which interacts with the swivelled 30S-head conformation. These findings provide direct structural and mechanistic insight into the 'missing link' in terms of tRNA intermediates involved in the universally conserved translocation process.     

Sequential faulting explains the asymmetry and extension discrepancy of conjugate margins

During early extension, cold continental lithosphere thins and subsides, creating rift basins. If extension continues to final break-up, the split and greatly thinned plates subside deep below sea level to form a conjugate pair of rifted margins. Although basins and margins are ubiquitous structures, the deformation processes leading from moderately extended basins to highly stretched margins are unclear, as studies consistently report that crustal thinning is greater than extension caused by brittle faulting. This extension discrepancy might arise from differential stretching of brittle and ductile crustal layers, but that does not readily explain the typical asymmetric structure of conjugate margins-in cross-section, one margin displays gradual thinning accompanied by large faults, and the conjugate margin displays abrupt thinning but smaller-scale faulting. Whole-crust detachments, active from early in the rifting, could in theory create both thinning and asymmetry, but are mechanically problematical. Furthermore, the extension discrepancy occurs at both conjugate margins, leading to the apparent contradiction that both seem to be upper plates to a detachment fault. Alternative models propose that much brittle extension is undetected because of seismic imaging limitations caused either by subseismic-resolution faulting, invisible deformation along top-basement 100-km-scale detachments or the structural complexity of cross-cutting arrays of faults. Here we use depth-migrated seismic images to accurately measure fault extension and compare it with crustal thinning. The observations are used to create a balanced kinematic model of rifting that resolves the extension discrepancy by producing both fault-controlled crustal thinning which progresses from a rift basin to the asymmetric structure, and extreme thinning of conjugate rifted margins. Contrary to current wisdom, the observations support the idea that thinning is to a first degree explained by simple Andersonian faulting that is unambiguously visible in seismic data.     

Wnt signalling regulates adult hippocampal neurogenesis

The generation of new neurons from neural stem cells is restricted to two regions of the adult mammalian central nervous system: the subventricular zone of the lateral ventricle, and the subgranular zone of the hippocampal dentate gyrus. In both regions, signals provided by the microenvironment regulate the maintenance, proliferation and neuronal fate commitment of the local stem cell population. The identity of these signals is largely unknown. Here we show that adult hippocampal stem/progenitor cells (AHPs) express receptors and signalling components for Wnt proteins, which are key regulators of neural stem cell behaviour in embryonic development. We also show that the Wnt/beta-catenin pathway is active and that Wnt3 is expressed in the hippocampal neurogenic niche. Overexpression of Wnt3 is sufficient to increase neurogenesis from AHPs in vitro and in vivo. By contrast, blockade of Wnt signalling reduces neurogenesis from AHPs in vitro and abolishes neurogenesis almost completely in vivo. Our data show that Wnt signalling is a principal regulator of adult hippocampal neurogenesis and provide evidence that Wnt proteins have a role in adult hippocampal function.