Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy

We identified three consanguineous Austrian kindreds with 15 members affected by autosomal recessive childhood-onset severe retinal dystrophy, a genetically heterogeneous group of disorders characterized by degeneration of the photoreceptor cells. A whole-genome scan by microarray analysis of single-nucleotide polymorphisms (ref. 2) identified a founder haplotype and defined a critical interval of 1.53 cM on chromosome 14q23.3-q24.1 that contains the gene associated with this form of retinal dystrophy. RDH12 maps in this region and encodes a retinol dehydrogenase proposed to function in the visual cycle. A homozygous 677A-->G transition (resulting in Y226C) in RDH12 was present in all affected family members studied, as well as in two Austrian individuals with sporadic retinal dystrophy. We identified additional mutations in RDH12 in 3 of 89 non-Austrian individuals with retinal dystrophy: a 5-nucleotide deletion (806delCCCTG) and the transition 565C-->T (resulting in Q189X), each in the homozygous state, and 146C-->T (resulting in T49M) and 184C-->T (resulting in R62X) in compound heterozygosity. When expressed in COS-7 cells, Cys226 and Met49 variants had diminished and aberrant activity, respectively, in interconverting isomers of retinol and retinal. The severe visual impairment of individuals with mutations in RDH12 is in marked contrast to the mild visual deficiency in individuals with fundus albipunctatus caused by mutations in RDH5, encoding another retinal dehydrogenase. Our studies show that RDH12 is associated with retinal dystrophy and encodes an enzyme with a unique, nonredundant role in the photoreceptor cells.     

Invasion sequence affects predator-prey dynamics in a multi-species interaction

Ecologists seek to understand the rules that govern the assembly, coexistence and persistence of communities of interacting species. There is, however, a variety of sequences in which a multi-species community can be assembled--unlike more familiar one- and two-species systems. Ecological systems can exhibit contrasting dynamics depending on initial conditions, but studies have been focused on simple communities initiated at different densities, not on multi-species communities constructed in different sequences. Investigations of permanence and convergence in ecological communities have been concerned with the flux of whole species (presence or absence) but have not addressed the central issues concerning the dynamics exhibited by individual species in particular interactions. Here we examine data for replicated three-species systems and demonstrate that the dynamic trajectories of both a predator and its prey within the system are determined by the sequence in which it is constructed, and that for one construction-sequence alternative dynamic patterns are possible.     

Atomic structures of amyloid cross-beta spines reveal varied steric zippers

Amyloid fibrils formed from different proteins, each associated with a particular disease, contain a common cross-beta spine. The atomic architecture of a spine, from the fibril-forming segment GNNQQNY of the yeast prion protein Sup35, was recently revealed by X-ray microcrystallography. It is a pair of beta-sheets, with the facing side chains of the two sheets interdigitated in a dry 'steric zipper'. Here we report some 30 other segments from fibril-forming proteins that form amyloid-like fibrils, microcrystals, or usually both. These include segments from the Alzheimer's amyloid-beta and tau proteins, the PrP prion protein, insulin, islet amyloid polypeptide (IAPP), lysozyme, myoglobin, alpha-synuclein and beta(2)-microglobulin, suggesting that common structural features are shared by amyloid diseases at the molecular level. Structures of 13 of these microcrystals all reveal steric zippers, but with variations that expand the range of atomic architectures for amyloid-like fibrils and offer an atomic-level hypothesis for the basis of prion strains.     

Early human use of marine resources and pigment in South Africa during the Middle Pleistocene

Genetic and anatomical evidence suggests that Homo sapiens arose in Africa between 200 and 100 thousand years (kyr) ago, and recent evidence indicates symbolic behaviour may have appeared approximately 135-75 kyr ago. From 195-130 kyr ago, the world was in a fluctuating but predominantly glacial stage (marine isotope stage MIS6); much of Africa was cooler and drier, and dated archaeological sites are rare. Here we show that by approximately 164 kyr ago (+/-12 kyr) at Pinnacle Point (on the south coast of South Africa) humans expanded their diet to include marine resources, perhaps as a response to these harsh environmental conditions. The earliest previous evidence for human use of marine resources and coastal habitats was dated to approximately 125 kyr ago. Coincident with this diet and habitat expansion is an early use and modification of pigment, probably for symbolic behaviour, as well as the production of bladelet stone tool technology, previously dated to post-70 kyr ago. Shellfish may have been crucial to the survival of these early humans as they expanded their home ranges to include coastlines and followed the shifting position of the coast when sea level fluctuated over the length of MIS6.     

An intracellular P2X receptor required for osmoregulation in Dictyostelium discoideum

P2X receptors are membrane ion channels gated by extracellular ATP that are found widely in vertebrates, but not previously in microbes. Here we identify a weakly related gene in the genome of the social amoeba Dictyostelium discoideum, and show, with the use of heterologous expression in human embryonic kidney cells, that it encodes a membrane ion channel activated by ATP (30-100 muM). Site-directed mutagenesis revealed essential conservation of structure-function relations with P2X receptors of higher organisms. The receptor was insensitive to the usual P2X antagonists but was blocked by nanomolar concentrations of Cu2+ ions. In D. discoideum, the receptor was found on intracellular membranes, with prominent localization to an osmoregulatory organelle, the contractile vacuole. Targeted disruption of the gene in D. discoideum resulted in cells that were unable to regulate cell volume in hypotonic conditions. Cell swelling in these mutant cells was accompanied by a marked inhibition of contractile vacuole emptying. These findings demonstrate a new functional role for P2X receptors on intracellular organelles, in this case in osmoregulation.     

World Year of Physics: a direct test of E=mc2

One of the most striking predictions of Einstein's special theory of relativity is also perhaps the best known formula in all of science: E=mc(2). If this equation were found to be even slightly incorrect, the impact would be enormous--given the degree to which special relativity is woven into the theoretical fabric of modern physics and into everyday applications such as global positioning systems. Here we test this mass-energy relationship directly by combining very accurate measurements of atomic-mass difference, Delta(m), and of gamma-ray wavelengths to determine E, the nuclear binding energy, for isotopes of silicon and sulphur. Einstein's relationship is separately confirmed in two tests, which yield a combined result of 1-Delta(mc2)/E=(-1.4+/-4.4)x10(-7), indicating that it holds to a level of at least 0.00004%. To our knowledge, this is the most precise direct test of the famous equation yet described.     

An inhibitor of Bcl-2 family proteins induces regression of solid tumours

Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.     

Aeolian processes at the Mars Exploration Rover Meridiani Planum landing site

The martian surface is a natural laboratory for testing our understanding of the physics of aeolian (wind-related) processes in an environment different from that of Earth. Martian surface markings and atmospheric opacity are time-variable, indicating that fine particles at the surface are mobilized regularly by wind. Regolith (unconsolidated surface material) at the Mars Exploration Rover Opportunity's landing site has been affected greatly by wind, which has created and reoriented bedforms, sorted grains, and eroded bedrock. Aeolian features here preserve a unique record of changing wind direction and wind strength. Here we present an in situ examination of a martian bright wind streak, which provides evidence consistent with a previously proposed formational model for such features. We also show that a widely used criterion for distinguishing between aeolian saltation- and suspension-dominated grain behaviour is different on Mars, and that estimated wind friction speeds between 2 and 3 m s(-1), most recently from the northwest, are associated with recent global dust storms, providing ground truth for climate model predictions.