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Single nanometre-sized pores (nanopores) embedded in an insulating membrane are an exciting new class of nanosensors for rapid electrical detection and characterization of biomolecules. Notable examples include alpha-hemolysin protein nanopores in lipid membranes and solid-state nanopores in Si3N4. Here we report a new technique for fabricating silicon oxide nanopores with single-nanometre precision and direct visual feedback, using state-of-the-art silicon technology and transmission electron microscopy. First, a pore of 20 nm is opened in a silicon membrane by using electron-beam lithography and anisotropic etching. After thermal oxidation, the pore can be reduced to a single-nanometre when it is exposed to a high-energy electron beam. This fluidizes the silicon oxide leading to a shrinking of the small hole due to surface tension. When the electron beam is switched off, the material quenches and retains its shape. This technique dramatically increases the level of control in the fabrication of a wide range of nanodevices.

A nanopore-based device provides single-molecule detection and analytical capabilities that are achieved by electrophoretically driving molecules in solution through a nano-scale pore. The nanopore provides a highly confined space within which single nucleic acid polymers can be analyzed at high throughput by one of a variety of means, and the perfect processivity that can be enforced in a narrow pore ensures that the native order of the nucleobases in a polynucleotide is reflected in the sequence of signals that is detected. Kilobase length polymers (single-stranded genomic DNA or RNA) or small molecules (e.g., nucleosides) can be identified and characterized without amplification or labeling, a unique analytical capability that makes inexpensive, rapid DNA sequencing a possibility. Further research and development to overcome current challenges to nanopore identification of each successive nucleotide in a DNA strand offers the prospect of `third generation' instruments that will sequence a diploid mammalian genome for ~$1,000 in ~24 h.

We monitor the dynamics of superconducting vortices in the Bean state, as the system is driven to the threshold of instability by the slow ramping of an external field. Individual avalanches, containing as few as 50 vortices, are detected in real time. Thus our experiment is the superconducting analog of monitoring the granular avalanches produced by slowly dropping sand on a sandpile. The observed distribution of vortex avalanche sizes shows a power-law behavior over two decades, proving that the vortex dynamics in the Bean state is characterized by avalanches of many length scales.Some 30 years ago Bean [1] and de Gennes [2] noted the close analogy between the marginally stable state of vortices in a hard superconductor and the marginally stable slope of sand in a sandpile. We can picture building up a sandpile by slowly dropping grains on a flat surface. The slope of the pile soon reaches a certain "maximal angle of stability, " determined by a balance between gravity and intergrain frictional forces. A similar situation is present in a hard superconductor (i.e., with strong pinning).Vortices nucleate at the surface as an external magnetic field is slowly ramped. In the simplest model, due to Bean[1], the vortex density decreases linearly with distance into the superconductor. This again is due to a balance between vortex density gradients which drive vortices into the bulk and pinning forces which hamper their entry.These early analogies were invoked mainly in order to understand the static distribution of flux in a hard superconductor.More recently, interest has focused on the dynamics of systems slowly driven to the threshold of instability.A large number of diverse physical systems are characterized by such dynamics, including chargedensity waves, pinned Wigner crystals, earthquake faults, granular assemblies, and superconducting vortices. These systems have received renewed attention due to their relation to spatiotemporal dynamics, instabilities, and selforganized criticality. Sandpiles have received particularly intensive theoretical and experimental attention as a model system exhibiting such threshold dynamics.In light of the strong static analogies between sandpiles and the Bean state in hard superconductors, it is natural to ask whether there are quantitative similarities between the dynamic processes (e.g., similar avalanche size distributions) in the two systems.Here we report results of an experiment on the dynamics of vortices, which is closely analogous with those done on sandpiles. The magnetic field outside a tubular superconducting sample is ramped slowly, driving flux into the tube's outer wall. Eventually, the flux front will reach the 10-tI-~~&3 . -~gttI. 0 o C) D e Ic} 65 @o 1000 Ct 4T P 750 C, fP P P time or magnetic field FIG. 1. The voltage measured on the pickup coil as the magnetic field is ramped at 5 G/s. Frame (a) shows a 30 G segment centered at B = 7.55 kG. There are 262144 data points in this segment. The voltage trace consists of a series of many pulses, of widely varying siz...

Priapism, abnormally prolonged penile erection in the absence of sexual excitation, is associated with ischemia-mediated erectile tissue damage and subsequent erectile dysfunction. It is common among males with sickle cell disease (SCD), and SCD transgenic mice are an accepted model of the disorder. Current strategies to manage priapism suffer from a poor fundamental understanding of the molecular mechanisms underlying the disorder. Here we report that mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, displayed unexpected priapic activity. ADA enzyme therapy successfully corrected the priapic activity both in vivo and in vitro, suggesting that it was dependent on elevated adenosine levels. Further genetic and pharmacologic evidence demonstrated that A 2B adenosine receptor-mediated (A 2B R-mediated) cAMP and cGMP induction was required for elevated adenosine-induced prolonged penile erection. Finally, priapic activity in SCD transgenic mice was also caused by elevated adenosine levels and A 2B R activation. Thus, we have shown that excessive adenosine accumulation in the penis contributes to priapism through increased A 2B R signaling in both Ada -/-and SCD transgenic mice. These findings provide insight regarding the molecular basis of priapism and suggest that strategies to either reduce adenosine or block A 2B R activation may prove beneficial in the treatment of this disorder.

Uniform colloidal microspheres dispersed in a solvent will, under appropriate conditions, self-assemble into ordered crystalline structures. Using these colloidal crystals as a model system, a great variety of problems of interest to materials science, physical chemistry, and condensed-matter physics have been investigated during the past two decades. Recently, it has been demonstrated that point defects can be created in two-dimensional colloidal crystals by manipulating individual particles with optical tweezers. Direct imaging of these defects verified that their stable configurations have lower symmetry than the underlying triangular lattice, as predicted by numerical simulations for a number of two-dimensional systems. It was also observed that point defects can dissociate into pairs of well-separated dislocations, a topological excitation especially important in two dimensions. Here we use a similar experimental system to study the dynamics of mono- and di-vacancies in two-dimensional colloidal crystals. We see evidence that the excitation of point defects into dislocation pairs enhances the diffusion of di-vacancies. Moreover, the hopping of the defects does not follow a pure random walk, but exhibits surprising memory effects. We expect the results presented in this work to be relevant for explaining the dynamics of other two-dimensional systems.

SF3b is a U2 snRNP-associated protein complex essential for spliceosome assembly. Although evidence that SF3b contains the spliceosomal proteins SAPs 49, 130, 145, and 155 has accumulated, a protein-mediated association between all of these proteins has yet to be directly demonstrated. Here we report the isolation of a cDNA encoding SAP 130, which completes the cloning of the putative SF3b complex proteins. Using antibodies to SAP 130 and other putative SF3b components, we showed that SAPs 130, 145, and 155 are present in a protein complex in nuclear extracts and that these proteins associate with one another in purified U2 snRNP. Moreover, SAPs 155 and 130 interact with each other (directly or indirectly) within this complex, and SAPs 49 and 145 are known to interact directly with each other. Thus, together with prior work, our studies indicate that SAPs 49, 130, 145, and 155 are indeed components of SF3b. The Saccharomyces cerevisiae homologs of SAPs 49 and 145 are encoded by essential genes. We show here that the S. cerevisiae homologs of SAPs 130 and 155 (scSAP 130/RSE1 and scSAP 155, respectively) are also essential. Recently, the SF3b proteins were found in purified U12 snRNP, which functionally substitutes for U2 snRNP in the minor spliceosome. This high level of conservation, together with the prior observation that the SF3b proteins interact with pre-mRNA very close to the branch site, suggest that the SF3b complex plays a critical role near or at the spliceosome catalytic core.Many proteins essential for spliceosome assembly and splicing have been identified, and numerous human homologs of essential yeast splicing factors are now known (for reviews, see references 19, 20, 24, and 29). Among the best characterized of these are the components of U2 snRNP (for reviews, see references 19, 20, and 29). In mammals, functional 17S U2 snRNP can be assembled from 12S U2 snRNP and two essential splicing factors, SF3a and SF3b (5, 6). SF3a has been purified to homogeneity and contains three proteins (SF3a60, SF3a66 and SF3a120) (5, 6). SF3b has been purified through multiple chromatographic steps but has not been purified to homogeneity (5, 6). The components thought to constitute SF3b were identified by comparing purified 17S U2 snRNP and the spliceosomal complex A (for reviews see references 14 and 19). The abundant proteins common to both of these complexes are referred to as SF3b 53, 120, 150, and 160 in 17S U2 snRNP and SAPs 49, 130, 145 and 155, respectively, in the spliceosome (we use the latter nomenclature here) (2,6,19). Further evidence that at least two of these proteins are components of SF3b came from the observation that SAPs 49 and 145 interact directly with each other (7). In addition, SAPs 49, 145, and 155, as well as all three SF3a subunits, can be UV cross-linked to the region surrounding the branch site in the spliceosomal complex A (11, 12). Thus, these proteins are all located next to one another in functional spliceosomal complexes, consistent with the notion that they are present in a com...

We report the first experimental study of a model system of a two-dimensional colloidal crystal in a random pinning potential. The colloidal crystal consists of monodispersed charged polystyrene microspheres suspended in deionized aqueous media and confined near a rough charged surface. It is found that the static orientational correlation function g6(r) decays exponentially for intermediate and strong pinning, in agreement with theories. The driven depinning is dominated by thermally activated creep motion along 1D-like channels between regions with short-range order. A coexistence model is proposed for describing the observations.