Mutations in SEC63 cause autosomal dominant polycystic liver disease

Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease. We found that mutations in SEC63, encoding a component of the protein translocation machinery in the ER, also cause this disease. These findings are suggestive of a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial ER proteins in human polycystic disease.     

Meteoric smoke fallout over the Holocene epoch revealed by iridium and platinum in Greenland ice

An iridium anomaly at the Cretaceous/Tertiary boundary layer has been attributed to an extraterrestrial body that struck the Earth some 65 million years ago. It has been suggested that, during this event, the carrier of iridium was probably a micrometre-sized silicate-enclosed aggregate or the nanophase material of the vaporized impactor. But the fate of platinum-group elements (such as iridium) that regularly enter the atmosphere via ablating meteoroids remains largely unknown. Here we report a record of iridium and platinum fluxes on a climatic-cycle timescale, back to 128,000 years ago, from a Greenland ice core. We find that unexpectedly constant fallout of extraterrestrial matter to Greenland occurred during the Holocene, whereas a greatly enhanced input of terrestrial iridium and platinum masked the cosmic flux in the dust-laden atmosphere of the last glacial age. We suggest that nanometre-sized meteoric smoke particles, formed from the recondensation of ablated meteoroids in the atmosphere at altitudes >70 kilometres, are transported into the winter polar vortices by the mesospheric meridional circulation and are preferentially deposited in the polar ice caps. This implies an average global fallout of 14 +/- 5 kilotons per year of meteoric smoke during the Holocene.     

Bismuth embrittlement of copper is an atomic size effect

Embrittlement by the segregation of impurity elements to grain boundaries is one of a small number of phenomena that can lead to metallurgical failure by fast fracture. Here we settle a question that has been debated for over a hundred years: how can minute traces of bismuth in copper cause this ductile metal to fail in a brittle manner? Three hypotheses for Bi embrittlement of Cu exist: two assign an electronic effect to either a strengthening or weakening of bonds, the third postulates a simple atomic size effect. Here we report first principles quantum mechanical calculations that allow us to reject the electronic hypotheses, while supporting a size effect. We show that upon segregation to the grain boundary, the large Bi atoms weaken the interatomic bonding by pushing apart the Cu atoms at the interface. The resolution of the mechanism underlying grain boundary weakening should be relevant for all cases of embrittlement by oversize impurities.     

The massive binary companion star to the progenitor of supernova 1993J

The massive star that underwent a collapse of its core to produce supernova (SN)1993J was subsequently identified as a non-variable red supergiant star in images of the galaxy M81 taken before explosion. It showed an excess in ultraviolet and B-band colours, suggesting either the presence of a hot, massive companion star or that it was embedded in an unresolved young stellar association. The spectra of SN1993J underwent a remarkable transformation from the signature of a hydrogen-rich type II supernova to one of a helium-rich (hydrogen-deficient) type Ib. The spectral and photometric peculiarities were best explained by models in which the 13-20 solar mass supergiant had lost almost its entire hydrogen envelope to a close binary companion, producing a 'type IIb' supernova, but the hypothetical massive companion stars for this class of supernovae have so far eluded discovery. Here we report photometric and spectroscopic observations of SN1993J ten years after the explosion. At the position of the fading supernova we detect the unambiguous signature of a massive star: the binary companion to the progenitor.     

Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.     

Substrate twinning activates the signal recognition particle and its receptor

Signal sequences target proteins for secretion from cells or for integration into cell membranes. As nascent proteins emerge from the ribosome, signal sequences are recognized by the signal recognition particle (SRP), which subsequently associates with its receptor (SR). In this complex, the SRP and SR stimulate each other's GTPase activity, and GTP hydrolysis ensures unidirectional targeting of cargo through a translocation pore in the membrane. To define the mechanism of reciprocal activation, we determined the 1.9 A structure of the complex formed between these two GTPases. The two partners form a quasi-two-fold symmetrical heterodimer. Biochemical analysis supports the importance of the extensive interaction surface. Complex formation aligns the two GTP molecules in a symmetrical, composite active site, and the 3'OH groups are essential for association, reciprocal activation and catalysis. This unique circle of twinned interactions is severed twice on hydrolysis, leading to complex dissociation after cargo delivery.     

Substrate recognition strategy for botulinum neurotoxin serotype A

Clostridal neurotoxins (CNTs) are the causative agents of the neuroparalytic diseases botulism and tetanus. CNTs impair neuronal exocytosis through specific proteolysis of essential proteins called SNAREs. SNARE assembly into a low-energy ternary complex is believed to catalyse membrane fusion, precipitating neurotransmitter release; this process is attenuated in response to SNARE proteolysis. Site-specific SNARE hydrolysis is catalysed by the CNT light chains, a unique group of zinc-dependent endopeptidases. The means by which a CNT properly identifies and cleaves its target SNARE has been a subject of much speculation; it is thought to use one or more regions of enzyme-substrate interaction remote from the active site (exosites). Here we report the first structure of a CNT endopeptidase in complex with its target SNARE at a resolution of 2.1 A: botulinum neurotoxin serotype A (BoNT/A) protease bound to human SNAP-25. The structure, together with enzyme kinetic data, reveals an array of exosites that determine substrate specificity. Substrate orientation is similar to that of the general zinc-dependent metalloprotease thermolysin. We observe significant structural changes near the toxin's catalytic pocket upon substrate binding, probably serving to render the protease competent for catalysis. The novel structures of the substrate-recognition exosites could be used for designing inhibitors specific to BoNT/A.     

The central dusty torus in the active nucleus of NGC 1068

Active galactic nuclei (AGNs) display many energetic phenomena--broad emission lines, X-rays, relativistic jets, radio lobes--originating from matter falling onto a supermassive black hole. It is widely accepted that orientation effects play a major role in explaining the observational appearance of AGNs. Seen from certain directions, circum-nuclear dust clouds would block our view of the central powerhouse. Indirect evidence suggests that the dust clouds form a parsec-sized torus-shaped distribution. This explanation, however, remains unproved, as even the largest telescopes have not been able to resolve the dust structures. Here we report interferometric mid-infrared observations that spatially resolve these structures in the galaxy NGC 1068. The observations reveal warm (320 K) dust in a structure 2.1 parsec thick and 3.4 parsec in diameter, surrounding a smaller hot structure. As such a configuration of dust clouds would collapse in a time much shorter than the active phase of the AGN, this observation requires a continual input of kinetic energy to the cloud system from a source coexistent with the AGN.     

The interface between silicon and a high-k oxide

The ability of the semiconductor industry to continue scaling microelectronic devices to ever smaller dimensions (a trend known as Moore's Law) is limited by quantum mechanical effects: as the thickness of conventional silicon dioxide (SiO(2)) gate insulators is reduced to just a few atomic layers, electrons can tunnel directly through the films. Continued device scaling will therefore probably require the replacement of the insulator with high-dielectric-constant (high-k) oxides, to increase its thickness, thus preventing tunnelling currents while retaining the electronic properties of an ultrathin SiO(2) film. Ultimately, such insulators will require an atomically defined interface with silicon without an interfacial SiO(2) layer for optimal performance. Following the first reports of epitaxial growth of AO and ABO(3) compounds on silicon, the formation of an atomically abrupt crystalline interface between strontium titanate and silicon was demonstrated. However, the atomic structure proposed for this interface is questionable because it requires silicon atoms that have coordinations rarely found elsewhere in nature. Here we describe first-principles calculations of the formation of the interface between silicon and strontium titanate and its atomic structure. Our study shows that atomic control of the interfacial structure by altering the chemical environment can dramatically improve the electronic properties of the interface to meet technological requirements. The interface structure and its chemistry may provide guidance for the selection process of other high-k gate oxides and for controlling their growth.