952 research outputs found
Enhanced charge detection of spin qubit readout via an intermediate state
We employ an intermediate excited charge state of a lateral quantum dot
device to increase the charge detection contrast during the qubit state readout
procedure, allowing us to increase the visibility of coherent qubit
oscillations. This approach amplifies the coherent oscillation magnitude but
has no effect on the detector noise resulting in an increase in the signal to
noise ratio. In this letter we apply this scheme to demonstrate a significant
enhancement of the fringe contrast of coherent Landau-Zener-Stuckleberg
oscillations between singlet S and triplet T+ two-spin states.Comment: 3 pages, 3 figure
Generation of high-purity higher-order Laguerre-Gauss beams at high laser power
We have investigated the generation of highly pure higher-order
Laguerre-Gauss (LG) beams at high laser power of order 100W, the same regime
that will be used by 2nd generation gravitational wave interferometers such as
Advanced LIGO. We report on the generation of a helical type LG33 mode with a
purity of order 97% at a power of 83W, the highest power ever reported in
literature for a higher-order LG mode.Comment: 5 pages, 6 figure
GEO 600 and the GEO-HF upgrade program: successes and challenges
The German-British laser-interferometric gravitational wave detector GEO 600
is in its 14th year of operation since its first lock in 2001. After GEO 600
participated in science runs with other first-generation detectors, a program
known as GEO-HF began in 2009. The goal was to improve the detector sensitivity
at high frequencies, around 1 kHz and above, with technologically advanced yet
minimally invasive upgrades. Simultaneously, the detector would record science
quality data in between commissioning activities. As of early 2014, all of the
planned upgrades have been carried out and sensitivity improvements of up to a
factor of four at the high-frequency end of the observation band have been
achieved. Besides science data collection, an experimental program is ongoing
with the goal to further improve the sensitivity and evaluate future detector
technologies. We summarize the results of the GEO-HF program to date and
discuss its successes and challenges
A Comparison of Noninvasive Techniques to Survey Carnivore Communities in Northeastern North America
Cryptotomography: reconstructing 3D Fourier intensities from randomly oriented single-shot diffraction patterns
We reconstructed the 3D Fourier intensity distribution of mono-disperse
prolate nano-particles using single-shot 2D coherent diffraction patterns
collected at DESY's FLASH facility when a bright, coherent, ultrafast X-ray
pulse intercepted individual particles of random, unmeasured orientations. This
first experimental demonstration of cryptotomography extended the
Expansion-Maximization-Compression (EMC) framework to accommodate unmeasured
fluctuations in photon fluence and loss of data due to saturation or background
scatter. This work is an important step towards realizing single-shot
diffraction imaging of single biomolecules.Comment: 4 pages, 4 figure
The conservation status of the world’s freshwater molluscs
With the biodiversity crisis continuing unchecked, we need to establish levels and drivers of extinction risk, and reassessments over time, to effectively allocate conservation resources and track progress towards global conservation targets. Given that threat appears particularly high in freshwaters, we assessed the extinction risk of 1428 randomly selected freshwater molluscs using the IUCN Red List Categories and Criteria, as part of the Sampled Red List Index project. We show that close to one-third of species in our sample are estimated to be threatened with extinction, with highest levels of threat in the Nearctic, Palearctic and Australasia and among gastropods. Threat levels were higher in lotic than lentic systems. Pollution (chemical and physical) and the modification of natural systems (e.g. through damming and water abstraction) were the most frequently reported threats to freshwater molluscs, with some regional variation. Given that we found little spatial congruence between species richness patterns of freshwater molluscs and other freshwater taxa, apart from crayfish, new additional conservation priority areas emerged from our study. We discuss the implications of our findings for freshwater mollusc conservation, the adequacy of a sampled approach and important next steps to estimate trends in freshwater mollusc extinction risk over time
Nrt1 and Tna1-Independent Export of NAD+ Precursor Vitamins Promotes NAD+ Homeostasis and Allows Engineering of Vitamin Production
NAD+ is both a co-enzyme for hydride transfer enzymes and a
substrate of sirtuins and other NAD+ consuming enzymes.
NAD+ biosynthesis is required for two different regimens
that extend lifespan in yeast. NAD+ is synthesized from
tryptophan and the three vitamin precursors of NAD+: nicotinic
acid, nicotinamide and nicotinamide riboside. Supplementation of yeast cells
with NAD+ precursors increases intracellular
NAD+ levels and extends replicative lifespan. Here we show
that both nicotinamide riboside and nicotinic acid are not only vitamins but are
also exported metabolites. We found that the deletion of the nicotinamide
riboside transporter, Nrt1, leads to increased export of nicotinamide riboside.
This discovery was exploited to engineer a strain to produce high levels of
extracellular nicotinamide riboside, which was recovered in purified form. We
further demonstrate that extracellular nicotinamide is readily converted to
extracellular nicotinic acid in a manner that requires intracellular
nicotinamidase activity. Like nicotinamide riboside, export of nicotinic acid is
elevated by the deletion of the nicotinic acid transporter, Tna1. The data
indicate that NAD+ metabolism has a critical extracellular
element in the yeast system and suggest that cells regulate intracellular
NAD+ metabolism by balancing import and export of
NAD+ precursor vitamins
Specialized dynamical properties of promiscuous residues revealed by simulated conformational ensembles
The ability to interact with different partners is one of the most important features in proteins. Proteins that bind a large number of partners (hubs) have been often associated with intrinsic disorder. However, many examples exist of hubs with an ordered structure, and evidence of a general mechanism promoting promiscuity in ordered proteins is still elusive. An intriguing hypothesis is that promiscuous binding sites have specific dynamical properties, distinct from the rest of the interface and pre-existing in the protein isolated state. Here, we present the first comprehensive study of the intrinsic dynamics of promiscuous residues in a large protein data set. Different computational methods, from coarse-grained elastic models to geometry-based sampling methods and to full-atom Molecular Dynamics simulations, were used to generate conformational ensembles for the isolated proteins. The flexibility and dynamic correlations of interface residues with a different degree of binding promiscuity were calculated and compared considering side chain and backbone motions, the latter both on a local and on a global scale. The study revealed that (a) promiscuous residues tend to be more flexible than nonpromiscuous ones, (b) this additional flexibility has a higher degree of organization, and (c) evolutionary conservation and binding promiscuity have opposite effects on intrinsic dynamics. Findings on simulated ensembles were also validated on ensembles of experimental structures extracted from the Protein Data Bank (PDB). Additionally, the low occurrence of single nucleotide polymorphisms observed for promiscuous residues indicated a tendency to preserve binding diversity at these positions. A case study on two ubiquitin-like proteins exemplifies how binding promiscuity in evolutionary related proteins can be modulated by the fine-tuning of the interface dynamics. The interplay between promiscuity and flexibility highlighted here can inspire new directions in protein-protein interaction prediction and design methods. © 2013 American Chemical Society
Long-Term Systemic Myostatin Inhibition via Liver-Targeted Gene Transfer in Golden Retriever Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disease affecting 1 in 3,500 newborn boys for which there is no effective treatment or cure. One novel strategy that has therapeutic potential for DMD is inhibition of myostatin, a negative regulator of skeletal muscle mass that may also promote fibrosis. Therefore, our goal in this study was to evaluate systemic myostatin inhibition in the golden retriever model of DMD (GRMD). GRMD canines underwent liver-directed gene transfer of a self-complementary adeno-associated virus type 8 vector designed to express a secreted dominant-negative myostatin peptide (n =4) and were compared with age-matched, untreated GRMD controls (n =3). Dogs were followed with serial magnetic resonance imaging (MRI) for 13 months to assess cross-sectional area and volume of skeletal muscle, then euthanized so that tissue could be harvested for morphological and histological analysis. We found that systemic myostatin inhibition resulted in increased muscle mass in GRMD dogs as assessed by MRI and confirmed at tissue harvest. We also found that hypertrophy of type IIA fibers was largely responsible for the increased muscle mass and that reductions in serum creatine kinase and muscle fibrosis were associated with long-term myostatin inhibition in GRMD. This is the first report describing the effects of long-term, systemic myostatin inhibition in a large-animal model of DMD, and we believe that the simple and effective nature of our liver-directed gene-transfer strategy makes it an ideal candidate for evaluation as a novel therapeutic approach for DMD patients
ANCHOR: a web server and database for analysis of protein–protein interaction binding pockets for drug discovery
ANCHOR is a web-based tool whose aim is to facilitate the analysis of protein–protein interfaces with regard to its suitability for small molecule drug design. To this end, ANCHOR exploits the so-called anchor residues, i.e. amino acid side-chains deeply buried at protein–protein interfaces, to indicate possible druggable pockets to be targeted by small molecules. For a given protein–protein complex submitted by the user, ANCHOR calculates the change in solvent accessible surface area (ΔSASA) upon binding for each side-chain, along with an estimate of its contribution to the binding free energy. A Jmol-based tool allows the user to interactively visualize selected anchor residues in their pockets as well as the stereochemical properties of the surrounding region such as hydrogen bonding. ANCHOR includes a Protein Data Bank (PDB) wide database of pre-computed anchor residues from more than 30 000 PDB entries with at least two protein chains. The user can query according to amino acids, buried area (SASA), energy or keywords related to indication areas, e.g. oncogene or diabetes. This database provides a resource to rapidly assess protein–protein interactions for the suitability of small molecules or fragments with bioisostere anchor analogues as possible compounds for pharmaceutical intervention. ANCHOR web server and database are freely available at http://structure.pitt.edu/anchor
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