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.     

Sequencing of Aspergillus nidulans and comparative analysis with A. fumigatus and A. oryzae

The aspergilli comprise a diverse group of filamentous fungi spanning over 200 million years of evolution. Here we report the genome sequence of the model organism Aspergillus nidulans, and a comparative study with Aspergillus fumigatus, a serious human pathogen, and Aspergillus oryzae, used in the production of sake, miso and soy sauce. Our analysis of genome structure provided a quantitative evaluation of forces driving long-term eukaryotic genome evolution. It also led to an experimentally validated model of mating-type locus evolution, suggesting the potential for sexual reproduction in A. fumigatus and A. oryzae. Our analysis of sequence conservation revealed over 5,000 non-coding regions actively conserved across all three species. Within these regions, we identified potential functional elements including a previously uncharacterized TPP riboswitch and motifs suggesting regulation in filamentous fungi by Puf family genes. We further obtained comparative and experimental evidence indicating widespread translational regulation by upstream open reading frames. These results enhance our understanding of these widely studied fungi as well as provide new insight into eukaryotic genome evolution and gene regulation.     

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.     

The Lyme disease agent exploits a tick protein to infect the mammalian host

The Lyme disease agent, Borrelia burgdorferi, is maintained in a tick-mouse cycle. Here we show that B. burgdorferi usurps a tick salivary protein, Salp15 (ref. 3), to facilitate the infection of mice. The level of salp15 expression was selectively enhanced by the presence of B. burgdorferi in Ixodes scapularis, first indicating that spirochaetes might use Salp15 during transmission. Salp15 was then shown to adhere to the spirochaete, both in vitro and in vivo, and specifically interacted with B. burgdorferi outer surface protein C. The binding of Salp15 protected B. burgdorferi from antibody-mediated killing in vitro and provided spirochaetes with a marked advantage when they were inoculated into naive mice or animals previously infected with B. burgdorferi. Moreover, RNA interference-mediated repression of salp15 in I. scapularis drastically reduced the capacity of tick-borne spirochaetes to infect mice. These results show the capacity of a pathogen to use a secreted arthropod protein to help it colonize the mammalian host.     

Simulations of the formation, evolution and clustering of galaxies and quasars

The cold dark matter model has become the leading theoretical picture for the formation of structure in the Universe. This model, together with the theory of cosmic inflation, makes a clear prediction for the initial conditions for structure formation and predicts that structures grow hierarchically through gravitational instability. Testing this model requires that the precise measurements delivered by galaxy surveys can be compared to robust and equally precise theoretical calculations. Here we present a simulation of the growth of dark matter structure using 2,160(3) particles, following them from redshift z = 127 to the present in a cube-shaped region 2.230 billion lightyears on a side. In postprocessing, we also follow the formation and evolution of the galaxies and quasars. We show that baryon-induced features in the initial conditions of the Universe are reflected in distorted form in the low-redshift galaxy distribution, an effect that can be used to constrain the nature of dark energy with future generations of observational surveys of galaxies.     

Paths to understanding the genetic basis of autoimmune disease

Some people inherit an unfortunate combination of genetic sequences, such that exposure to an external trigger causes their immune response to turn on their own tissues. Although mutations in a single gene can cause autoimmunity, most autoimmune diseases are associated with several sequence variants. Marked advances in genetic resources and tools are now making it possible to identify the sequence variants that contribute to autoimmune diseases--promising a better understanding of how we normally remain tolerant of our own tissue components, and how this goes wrong in autoimmune disease.     

Prokaryotic cells of the deep sub-seafloor biosphere identified as living bacteria

Chemical analyses of the pore waters from hundreds of deep ocean sediment cores have over decades provided evidence for ongoing processes that require biological catalysis by prokaryotes. This sub-seafloor activity of microorganisms may influence the surface Earth by changing the chemistry of the ocean and by triggering the emission of methane, with consequences for the marine carbon cycle and even the global climate. Despite the fact that only about 1% of the total marine primary production of organic carbon is available for deep-sea microorganisms, sub-seafloor sediments harbour over half of all prokaryotic cells on Earth. This estimation has been calculated from numerous microscopic cell counts in sediment cores of the Ocean Drilling Program. Because these counts cannot differentiate between dead and alive cells, the population size of living microorganisms is unknown. Here, using ribosomal RNA as a target for the technique known as catalysed reporter deposition-fluorescence in situ hybridization (CARD-FISH), we provide direct quantification of live cells as defined by the presence of ribosomes. We show that a large fraction of the sub-seafloor prokaryotes is alive, even in very old (16 million yr) and deep (> 400 m) sediments. All detectable living cells belong to the Bacteria and have turnover times of 0.25-22 yr, comparable to surface sediments.