Radio-frequency scanning tunnelling microscopy

The scanning tunnelling microscope (STM) relies on localized electron tunnelling between a sharp probe tip and a conducting sample to attain atomic-scale spatial resolution. In the 25-year period since its invention, the STM has helped uncover a wealth of phenomena in diverse physical systems--ranging from semiconductors to superconductors to atomic and molecular nanosystems. A severe limitation in scanning tunnelling microscopy is the low temporal resolution, originating from the diminished high-frequency response of the tunnel current readout circuitry. Here we overcome this limitation by measuring the reflection from a resonant inductor-capacitor circuit in which the tunnel junction is embedded, and demonstrate electronic bandwidths as high as 10 MHz. This approximately 100-fold bandwidth improvement on the state of the art translates into fast surface topography as well as delicate measurements in mesoscopic electronics and mechanics. Broadband noise measurements across the tunnel junction using this radio-frequency STM have allowed us to perform thermometry at the nanometre scale. Furthermore, we have detected high-frequency mechanical motion with a sensitivity approaching approximately 15 fm Hz(-1/2). This sensitivity is on par with the highest available from nanoscale optical and electrical displacement detection techniques, and the radio-frequency STM is expected to be capable of quantum-limited position measurements.     

Charge- and size-based separation of macromolecules using ultrathin silicon membranes

Commercial ultrafiltration and dialysis membranes have broad pore size distributions and are over 1,000 times thicker than the molecules they are designed to separate, leading to poor size cut-off properties, filtrate loss within the membranes, and low transport rates. Nanofabricated membranes have great potential in molecular separation applications by offering more precise structural control, yet transport is also limited by micrometre-scale thicknesses. This limitation can be addressed by a new class of ultrathin nanostructured membranes where the membrane is roughly as thick (approximately 10 nm) as the molecules being separated, but membrane fragility and complex fabrication have prevented the use of ultrathin membranes for molecular separations. Here we report the development of an ultrathin porous nanocrystalline silicon (pnc-Si) membrane using straightforward silicon fabrication techniques that provide control over average pore sizes from approximately 5 nm to 25 nm. Our pnc-Si membranes can retain proteins while permitting the transport of small molecules at rates an order of magnitude faster than existing materials, separate differently sized proteins under physiological conditions, and separate similarly sized molecules carrying different charges. Despite being only 15 nm thick, pnc-Si membranes that are free-standing over 40,000 microm2 can support a full atmosphere of differential pressure without plastic deformation or fracture. By providing efficient, low-loss macromolecule separations, pnc-Si membranes are expected to enable a variety of new devices, including membrane-based chromatography systems and both analytical and preparative microfluidic systems that require highly efficient separations.     

Early gas stripping as the origin of the darkest galaxies in the Universe

The known galaxies most dominated by dark matter (Draco, Ursa Minor and Andromeda IX) are satellites of the Milky Way and the Andromeda galaxies. They are members of a class of faint galaxies, devoid of gas, known as dwarf spheroidals, and have by far the highest ratio of dark to luminous matter. None of the models proposed to unravel their origin can simultaneously explain their exceptional dark matter content and their proximity to a much larger galaxy. Here we report simulations showing that the progenitors of these galaxies were probably gas-dominated dwarf galaxies that became satellites of a larger galaxy earlier than the other dwarf spheroidals. We find that a combination of tidal shocks and ram pressure swept away the entire gas content of such progenitors about ten billion years ago because heating by the cosmic ultraviolet background kept the gas loosely bound: a tiny stellar component embedded in a relatively massive dark halo survived until today. All luminous galaxies should be surrounded by a few extremely dark-matter-dominated dwarf spheroidal satellites, and these should have the shortest orbital periods among dwarf spheroidals because they were accreted early.     

Placing late Neanderthals in a climatic context

Attempts to place Palaeolithic finds within a precise climatic framework are complicated by both uncertainty over the radiocarbon calibration beyond about 21,500 14C years bp and the absence of a master calendar chronology for climate events from reference archives such as Greenland ice cores or speleothems. Here we present an alternative approach, in which 14C dates of interest are mapped directly onto the palaeoclimate record of the Cariaco Basin by means of its 14C series, circumventing calendar age model and correlation uncertainties, and placing dated events in the millennial-scale climate context of the last glacial period. This is applied to different sets of dates from levels with Mousterian artefacts, presumably produced by late Neanderthals, from Gorham's Cave in Gibraltar: first, generally accepted estimates of about 32,000 14C years bp for the uppermost Mousterian levels; second, a possible extended Middle Palaeolithic occupation until about 28,000 14C years bp; and third, more contentious evidence for persistence until about 24,000 14C years bp. This study shows that the three sets translate to different scenarios on the role of climate in Neanderthal extinction. The first two correspond to intervals of general climatic instability between stadials and interstadials that characterized most of the Middle Pleniglacial and are not coeval with Heinrich Events. In contrast, if accepted, the youngest date indicates that late Neanderthals may have persisted up to the onset of a major environmental shift, which included an expansion in global ice volume and an increased latitudinal temperature gradient. More generally, our radiocarbon climatostratigraphic approach can be applied to any 'snapshot' date from discontinuous records in a variety of deposits and can become a powerful tool in evaluating the climatic signature of critical intervals in Late Pleistocene human evolution.     

A second generation human haplotype map of over 3.1 million SNPs

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.     

Genome-wide detection and characterization of positive selection in human populations

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.     

14-3-3sigma controls mitotic translation to facilitate cytokinesis

14-3-3 proteins are crucial in a wide variety of cellular responses including cell cycle progression, DNA damage checkpoints and apoptosis. One particular 14-3-3 isoform, sigma, is a p53-responsive gene, the function of which is frequently lost in human tumours, including breast and prostate cancers as a result of either hypermethylation of the 14-3-3sigma promoter or induction of an oestrogen-responsive ubiquitin ligase that specifically targets 14-3-3sigma for proteasomal degradation. Loss of 14-3-3sigma protein occurs not only within the tumours themselves but also in the surrounding pre-dysplastic tissue (so-called field cancerization), indicating that 14-3-3sigma might have an important tumour suppressor function that becomes lost early in the process of tumour evolution. The molecular basis for the tumour suppressor function of 14-3-3sigma is unknown. Here we report a previously unknown function for 14-3-3sigma as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B in a stoichiometric manner. Cells lacking 14-3-3sigma, in marked contrast to normal cells, cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells. The aberrant mitotic phenotype of 14-3-3sigma-depleted cells can be rescued by forced expression of p58 PITSLRE or by extinguishing cap-dependent translation and increasing cap-independent translation during mitosis by using rapamycin. Our findings show how aberrant mitotic translation in the absence of 14-3-3sigma impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3sigma-deficient cells may progress on the path to aneuploidy and tumorigenesis.     

Non-volcanic tremor and low-frequency earthquake swarms

Non-volcanic tremor is a weak, extended duration seismic signal observed episodically on some major faults, often in conjunction with slow slip events. Such tremor may hold the key to understanding fundamental processes at the deep roots of faults, and could signal times of accelerated slip and hence increased seismic hazard. The mechanism underlying the generation of tremor and its relationship to aseismic slip are, however, as yet unresolved. Here we demonstrate that tremor beneath Shikoku, Japan, can be explained as a swarm of small, low-frequency earthquakes, each of which occurs as shear faulting on the subduction-zone plate interface. This suggests that tremor and slow slip are different manifestations of a single process.