A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain

Signalling through the receptor protein Notch, which is involved in crucial cell-fate decisions during development, requires ligand-induced cleavage of Notch. This cleavage occurs within the predicted transmembrane domain, releasing the Notch intracellular domain (NICD), and is reminiscent of gamma-secretase-mediated cleavage of beta-amyloid precursor protein (APP), a critical event in the pathogenesis of Alzheimer's disease. A deficiency in presenilin-1 (PS1) inhibits processing of APP by gamma-secretase in mammalian cells, and genetic interactions between Notch and PS1 homologues in Caenorhabditis elegans indicate that the presenilins may modulate the Notch signalling pathway. Here we report that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1. Moreover, several gamma-secretase inhibitors block this same step in Notch processing, indicating that related protease activities are responsible for cleavage within the predicted transmembrane domains of Notch and APP. Thus the targeting of gamma-secretase for the treatment of Alzheimer's disease may risk toxicity caused by reduced Notch signalling.     

Self-assembly of nanoscale cuboctahedra by coordination chemistry

Self-assembled polyhedral structures are common in biology. The coats of many viruses, for example, have a structure based on icosahedral symmetry. The preparation of synthetic polyhedral molecular assemblies represents a challenging problem, but supramolecular chemistry has now advanced to the point where the task may be addressed. Macromolecular and supramolecular entities of predefined geometric shape and with well-defined internal environments are potentially important for inclusion phenomena, molecular recognition and catalysis. Here we report the use of self-assembly of molecular units driven by coordination to transition-metal ions to prepare a cuboctahedron from 20 tridentate and bidentate subunits in a single step. The cuboctahedron is an archimedean semiregular polyhedron that combines square and triangular faces. Our self-assembled polyhedral capsules, characterized by NMR and electrospray mass spectrometry, are around 5 nanometres in diameter.     

Psychophysics: reply: Putting plaids in perspective

When we look at Anderson's Fig. 1a, or at just about anything else, we see surfaces and boundaries, contours and intersections, edges and angles. These complex, interpreted image features might well be the stimulus elements that stereo mechanisms analyse to recover depth. But are they?     

Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome

ARC syndrome (OMIM 208085) is an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity. Platelet dysfunction is common. Affected infants do not thrive and usually die in the first year of life. To elucidate the molecular basis of ARC, we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC. VPS33B encodes a homolog of the class C yeast vacuolar protein sorting gene, Vps33, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion.     

Cys-tRNACys formation and cysteine biosynthesis in methanogenic archaea: two faces of the same problem?

Aminoacyl-tRNA (transfer RNA) synthetases are essential components of the cellular translation machinery as they provide the ribosome with aminoacyl-tRNAs. Aminoacyl-tRNA synthesis is generally well understood. However, the mechanism of Cys-tRNACys formation in three methanogenic archaea ( Methanocaldococcus jannaschii, Methanothermobacter thermautotrophicus and Methanopyrus kandleri) is still unknown, since no recognizable gene for a canonical cysteinyl-tRNA synthetase could be identified in the genome sequences of these organisms. Here we review the different routes recently proposed for Cys-tRNACys formation and discuss its possible link with cysteine biosynthesis in these methanogenic archaea.     

A genetic variation map for chicken with 2.8 million single-nucleotide polymorphisms

We describe a genetic variation map for the chicken genome containing 2.8 million single-nucleotide polymorphisms (SNPs). This map is based on a comparison of the sequences of three domestic chicken breeds (a broiler, a layer and a Chinese silkie) with that of their wild ancestor, red jungle fowl. Subsequent experiments indicate that at least 90% of the variant sites are true SNPs, and at least 70% are common SNPs that segregate in many domestic breeds. Mean nucleotide diversity is about five SNPs per kilobase for almost every possible comparison between red jungle fowl and domestic lines, between two different domestic lines, and within domestic lines--in contrast to the notion that domestic animals are highly inbred relative to their wild ancestors. In fact, most of the SNPs originated before domestication, and there is little evidence of selective sweeps for adaptive alleles on length scales greater than 100 kilobases.     

Adhesion: elastocapillary coalescence in wet hair

We investigated why wet hair clumps into bundles by dunking a model brush of parallel elastic lamellae into a perfectly wetting liquid. As the brush is withdrawn, pairs of bundles aggregate successively, forming complex hierarchical patterns that depend on a balance between capillary forces and the elasticity of the lamellae. This capillary-driven self-assembly of flexible structures, which occurs in the tarsi of insects and in biomimetic adhesives but which can also damage micro-electromechanical structures or carbon nanotube 'carpets', represents a new type of coalescence process.     

A precision measurement of the mass of the top quark

The standard model of particle physics contains parameters--such as particle masses--whose origins are still unknown and which cannot be predicted, but whose values are constrained through their interactions. In particular, the masses of the top quark (M(t)) and W boson (M(W)) constrain the mass of the long-hypothesized, but thus far not observed, Higgs boson. A precise measurement of M(t) can therefore indicate where to look for the Higgs, and indeed whether the hypothesis of a standard model Higgs is consistent with experimental data. As top quarks are produced in pairs and decay in only about 10(-24) s into various final states, reconstructing their masses from their decay products is very challenging. Here we report a technique that extracts more information from each top-quark event and yields a greatly improved precision (of +/- 5.3 GeV/c2) when compared to previous measurements. When our new result is combined with our published measurement in a complementary decay mode and with the only other measurements available, the new world average for M(t) becomes 178.0 +/- 4.3 GeV/c2. As a result, the most likely Higgs mass increases from the experimentally excluded value of 96 to 117 GeV/c2, which is beyond current experimental sensitivity. The upper limit on the Higgs mass at the 95% confidence level is raised from 219 to 251 GeV/c2.     

Eight glacial cycles from an Antarctic ice core

The Antarctic Vostok ice core provided compelling evidence of the nature of climate, and of climate feedbacks, over the past 420,000 years. Marine records suggest that the amplitude of climate variability was smaller before that time, but such records are often poorly resolved. Moreover, it is not possible to infer the abundance of greenhouse gases in the atmosphere from marine records. Here we report the recovery of a deep ice core from Dome C, Antarctica, that provides a climate record for the past 740,000 years. For the four most recent glacial cycles, the data agree well with the record from Vostok. The earlier period, between 740,000 and 430,000 years ago, was characterized by less pronounced warmth in interglacial periods in Antarctica, but a higher proportion of each cycle was spent in the warm mode. The transition from glacial to interglacial conditions about 430,000 years ago (Termination V) resembles the transition into the present interglacial period in terms of the magnitude of change in temperatures and greenhouse gases, but there are significant differences in the patterns of change. The interglacial stage following Termination V was exceptionally long--28,000 years compared to, for example, the 12,000 years recorded so far in the present interglacial period. Given the similarities between this earlier warm period and today, our results may imply that without human intervention, a climate similar to the present one would extend well into the future.