Comprehensive analysis of the chromatin landscape in Drosophila melanogaster

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.     

Microwave quantum logic gates for trapped ions

Control over physical systems at the quantum level is important in fields as diverse as metrology, information processing, simulation and chemistry. For trapped atomic ions, the quantized motional and internal degrees of freedom can be coherently manipulated with laser light. Similar control is difficult to achieve with radio-frequency or microwave radiation: the essential coupling between internal degrees of freedom and motion requires significant field changes over the extent of the atoms' motion, but such changes are negligible at these frequencies for freely propagating fields. An exception is in the near field of microwave currents in structures smaller than the free-space wavelength, where stronger gradients can be generated. Here we first manipulate coherently (on timescales of 20 nanoseconds) the internal quantum states of ions held in a microfabricated trap. The controlling magnetic fields are generated by microwave currents in electrodes that are integrated into the trap structure. We also generate entanglement between the internal degrees of freedom of two atoms with a gate operation suitable for general quantum computation; the entangled state has a fidelity of 0.76(3), where the uncertainty denotes standard error of the mean. Our approach, which involves integrating the quantum control mechanism into the trapping device in a scalable manner, could be applied to quantum information processing, simulation and spectroscopy.     

Link between spin fluctuations and electron pairing in copper oxide superconductors

Although it is generally accepted that superconductivity is unconventional in the high-transition-temperature copper oxides, the relative importance of phenomena such as spin and charge (stripe) order, superconductivity fluctuations, proximity to a Mott insulator, a pseudogap phase and quantum criticality are still a matter of debate. In electron-doped copper oxides, the absence of an anomalous pseudogap phase in the underdoped region of the phase diagram and weaker electron correlations suggest that Mott physics and other unidentified competing orders are less relevant and that antiferromagnetic spin fluctuations are the dominant feature. Here we report a study of magnetotransport in thin films of the electron-doped copper oxide La(2?-?x)Ce(x)CuO(4). We show that a scattering rate that is linearly dependent on temperature--a key feature of the anomalous normal state properties of the copper oxides--is correlated with the electron pairing. We also show that an envelope of such scattering surrounds the superconducting phase, surviving to zero temperature when superconductivity is suppressed by magnetic fields. Comparison with similar behaviour found in organic superconductors strongly suggests that the linear dependence on temperature of the resistivity in the electron-doped copper oxides is caused by spin-fluctuation scattering.     

Jamming by shear

A broad class of disordered materials including foams, glassy molecular systems, colloids and granular materials can form jammed states. A jammed system can resist small stresses without deforming irreversibly, whereas unjammed systems flow under any applied stresses. The broad applicability of the Liu-Nagel jamming concept has attracted intensive theoretical and modelling interest but has prompted less experimental effort. In the Liu-Nagel framework, jammed states of athermal systems exist only above a certain critical density. Although numerical simulations for particles that do not experience friction broadly support this idea, the nature of the jamming transition for frictional grains is less clear. Here we show that jamming of frictional, disk-shaped grains can be induced by the application of shear stress at densities lower than the critical value, at which isotropic (shear-free) jamming occurs. These jammed states have a much richer phenomenology than the isotropic jammed states: for small applied shear stresses, the states are fragile, with a strong force network that percolates only in one direction. A minimum shear stress is needed to create robust, shear-jammed states with a strong force network percolating in all directions. The transitions from unjammed to fragile states and from fragile to shear-jammed states are controlled by the fraction of force-bearing grains. The fractions at which these transitions occur are statistically independent of the density. Jammed states with densities lower than the critical value have an anisotropic fabric (contact network). The minimum anisotropy of shear-jammed states vanishes as the density approaches the critical value from below, in a manner reminiscent of an order-disorder transition.     

In vivo genome editing restores haemostasis in a mouse model of haemophilia

Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells. The development of zinc finger nucleases (ZFNs) has permitted efficient genome editing in transformed and primary cells that were previously thought to be intractable to such genetic manipulation. In vitro, ZFNs have been shown to promote efficient genome editing via homology-directed repair by inducing a site-specific double-strand break (DSB) at a target locus, but it is unclear whether ZFNs can induce DSBs and stimulate genome editing at a clinically meaningful level in vivo. Here we show that ZFNs are able to induce DSBs efficiently when delivered directly to mouse liver and that, when co-delivered with an appropriately designed gene-targeting vector, they can stimulate gene replacement through both homology-directed and homology-independent targeted gene insertion at the ZFN-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of haemophilia B, and remained persistent after induced liver regeneration. Thus, ZFN-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease.     

Metabolite-enabled eradication of bacterial persisters by aminoglycosides

Bacterial persistence is a state in which a sub-population of dormant cells, or 'persisters', tolerates antibiotic treatment. Bacterial persisters have been implicated in biofilms and in chronic and recurrent infections. Despite this clinical relevance, there are currently no viable means for eradicating persisters. Here we show that specific metabolic stimuli enable the killing of both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) persisters with aminoglycosides. This potentiation is aminoglycoside-specific, it does not rely on growth resumption and it is effective in both aerobic and anaerobic conditions. It proceeds by the generation of a proton-motive force which facilitates aminoglycoside uptake. Our results demonstrate that persisters, although dormant, are primed for metabolite uptake, central metabolism and respiration. We show that aminoglycosides can be used in combination with specific metabolites to treat E. coli and S. aureus biofilms. Furthermore, we demonstrate that this approach can improve the treatment of chronic infections in a mouse urinary tract infection model. This work establishes a strategy for eradicating bacterial persisters that is based on metabolism, and highlights the importance of the metabolic environment to antibiotic treatment.     

Geochemical evidence for widespread euxinia in the later Cambrian ocean

Widespread anoxia in the ocean is frequently invoked as a primary driver of mass extinction as well as a long-term inhibitor of evolutionary radiation on early Earth. In recent biogeochemical studies it has been hypothesized that oxygen deficiency was widespread in subsurface water masses of later Cambrian oceans, possibly influencing evolutionary events during this time. Physical evidence of widespread anoxia in Cambrian oceans has remained elusive and thus its potential relationship to the palaeontological record remains largely unexplored. Here we present sulphur isotope records from six globally distributed stratigraphic sections of later Cambrian marine rocks (about 499 million years old). We find a positive sulphur isotope excursion in phase with the Steptoean Positive Carbon Isotope Excursion (SPICE), a large and rapid excursion in the marine carbon isotope record, which is thought to be indicative of a global carbon cycle perturbation. Numerical box modelling of the paired carbon sulphur isotope data indicates that these isotope shifts reflect transient increases in the burial of organic carbon and pyrite sulphur in sediments deposited under large-scale anoxic and sulphidic (euxinic) conditions. Independently, molybdenum abundances in a coeval black shale point convincingly to the transient spread of anoxia. These results identify the SPICE interval as the best characterized ocean anoxic event in the pre-Mesozoic ocean and an extreme example of oxygen deficiency in the later Cambrian ocean. Thus, a redox structure similar to those in Proterozoic oceans may have persisted or returned in the oceans of the early Phanerozoic eon. Indeed, the environmental challenges presented by widespread anoxia may have been a prevalent if not dominant influence on animal evolution in Cambrian oceans.