Performance of AAV8 vectors expressing human factor IX from a hepatic-selective promoter following intravenous injection into rats

Background: Vectors based on adeno-associated virus-8 (AAV8) have shown efficiency and efficacy for liver-directed gene therapy protocols following intravascular injection, particularly in relation to haemophilia gene therapy. AAV8 has also been proposed for gene therapy targeted at skeletal and cardiac muscle, again via intravascular injection. It is important to assess vector targeting at the level of virion accumulation and transgene expression in multiple species to ascertain potential issues relating to species variation in infectivity profiles. Methods: We used AAV8 vectors expressing human factor IX (FIX) from the liver-specific LP-1 promoter and administered this virus via the intravascular route of injection into 12 week old Wistar Kyoto rats. We assessed FIX levels in serum by ELISA and transgene expression at sacrifice by immunohistochemistry using anti-FIX antibodies. Vector DNA levels in organs we determined by real time PCR. Results: Administration of 1 × 1011 or 5 × 1011 scAAV8-LP1-hFIX vector particles/rat resulted in efficient production of physiological hFIX levels, respectively in blood assessed 4 weeks post-injection. This was maintained for the 4 month duration of the study. At 4 months we observed liver persistence of vector with minimal non-hepatic distribution. Conclusion: Our results demonstrate that AAV8 is a robust vector for delivering therapeutic genes into rat liver following intravascular injection

Explanatory debugging: Supporting end-user debugging of machine-learned programs

Many machine-learning algorithms learn rules of behavior from individual end users, such as task-oriented desktop organizers and handwriting recognizers. These rules form a “program” that tells the computer what to do when future inputs arrive. Little research has explored how an end user can debug these programs when they make mistakes. We present our progress toward enabling end users to debug these learned programs via a Natural Programming methodology. We began with a formative study exploring how users reason about and correct a text-classification program. From the results, we derived and prototyped a concept based on “explanatory debugging”, then empirically evaluated it. Our results contribute methods for exposing a learned program's logic to end users and for eliciting user corrections to improve the program's predictions

The Impact of New EUV Diagnostics on CME-Related Kinematics

We present the application of novel diagnostics to the spectroscopic observation of a Coronal Mass Ejection (CME) on disk by the Extreme Ultraviolet Imaging Spectrometer (EIS) on the Hinode spacecraft. We apply a recently developed line profile asymmetry analysis to the spectroscopic observation of NOAA AR 10930 on 14-15 December 2006 to three raster observations before and during the eruption of a 1000km/s CME. We see the impact that the observer's line-of-sight and magnetic field geometry have on the diagnostics used. Further, and more importantly, we identify the on-disk signature of a high-speed outflow behind the CME in the dimming region arising as a result of the eruption. Supported by recent coronal observations of the STEREO spacecraft, we speculate about the momentum flux resulting from this outflow as a secondary momentum source to the CME. The results presented highlight the importance of spectroscopic measurements in relation to CME kinematics, and the need for full-disk synoptic spectroscopic observations of the coronal and chromospheric plasmas to capture the signature of such explosive energy release as a way of providing better constraints of CME propagation times to L1, or any other point of interest in the heliosphere.Comment: Accepted to appear in Solar Physics Topical Issue titled "Remote Sensing of the Inner Heliosphere". Manuscript has 14 pages, 5 color figures. Movies supporting the figures can be found in http://download.hao.ucar.edu/pub/mscott/papers/Weathe

Multi-site mean-field theory for cold bosonic atoms in optical lattices

We present a detailed derivation of a multi-site mean-field theory (MSMFT) used to describe the Mott-insulator to superfluid transition of bosonic atoms in optical lattices. The approach is based on partitioning the lattice into small clusters which are decoupled by means of a mean field approximation. This approximation invokes local superfluid order parameters defined for each of the boundary sites of the cluster. The resulting MSMFT grand potential has a non-trivial topology as a function of the various order parameters. An understanding of this topology provides two different criteria for the determination of the Mott insulator superfluid phase boundaries. We apply this formalism to $d$-dimensional hypercubic lattices in one, two and three dimensions, and demonstrate the improvement in the estimation of the phase boundaries when MSMFT is utilized for increasingly larger clusters, with the best quantitative agreement found for $d=3$. The MSMFT is then used to examine a linear dimer chain in which the on-site energies within the dimer have an energy separation of $\Delta$. This system has a complicated phase diagram within the parameter space of the model, with many distinct Mott phases separated by superfluid regions.Comment: 30 pages, 23 figures, accepted for publication in Phys. Rev.

Fast symplectic map tracking for the CERN Large Hadron Collider

Tracking simulations remain the essential tool for evaluating how multipolar imperfections in ring magnets restrict the domain of stable phase-space motion. In the Large Hadron Collider (LHC) at CERN, particles circulate at the injection energy, when multipole errors are most significant, for more than 10^{7} turns, but systematic tracking studies are limited to a small fraction of this total time—even on modern computers. A considerable speedup is expected by replacing element-by-element tracking with the use of a symplectified one-turn map. We have applied this method to the realistic LHC lattice, version 6, and report here our results for various map orders, with special emphasis on precision and speed

Critiquing Variational Theories of the Anderson-Hubbard Model: Real-Space Self-Consistent Hartree-Fock Solutions

A simple and commonly employed approximate technique with which one can examine spatially disordered systems when strong electronic correlations are present is based on the use of real-space unrestricted self-consistent Hartree-Fock wave functions. In such an approach the disorder is treated exactly while the correlations are treated approximately. In this report we critique the success of this approximation by making comparisons between such solutions and the exact wave functions for the Anderson-Hubbard model. Due to the sizes of the complete Hilbert spaces for these problems, the comparisons are restricted to small one-dimensional chains, up to ten sites, and a 4x4 two-dimensional cluster, and at 1/2 filling these Hilbert spaces contain about 63,500 and 166 million states, respectively. We have completed these calculations both at and away from 1/2 filling. This approximation is based on a variational approach which minimizes the Hartree-Fock energy, and we have completed comparisons of the exact and Hartree-Fock energies. However, in order to assess the success of this approximation in reproducing ground-state correlations we have completed comparisons of the local charge and spin correlations, including the calculation of the overlap of the Hartree-Fock wave functions with those of the exact solutions. We find that this approximation reproduces the local charge densities to quite a high accuracy, but that the local spin correlations, as represented by , are not as well represented. In addition to these comparisons, we discuss the properties of the spin degrees of freedom in the HF approximation, and where in the disorder-interaction phase diagram such physics may be important

Solar Atmospheric Oscillations and the Chromospheric Magnetic Topology

We investigate the oscillatory properties of the quiet solar chromosphere in relation to the underlying photosphere, with particular regard to the effects of the magnetic topology. We perform a Fourier analysis on a sequence of line-of-sight velocities measured simultaneously in a photospheric (Fe I 709.0 nm) and a chromospheric line (Ca II 854.2 nm). The velocities were obtained from full spectroscopic data acquired at high spatial resolution with the Interferometric BIdimensional Spectrometer (IBIS). The field of view encompasses a full supergranular cell, allowing us to discriminate between areas with different magnetic characteristics. We show that waves with frequencies above the acoustic cut-off propagate from the photosphere to upper layers only in restricted areas of the quiet Sun. A large fraction of the quiet chromosphere is in fact occupied by ``magnetic shadows'', surrounding network regions, that we identify as originating from fibril-like structures observed in the core intensity of the Ca II line. We show that a large fraction of the chromospheric acoustic power at frequencies below the acoustic cut-off, residing in the proximity of the magnetic network elements, directly propagates from the underlying photosphere. This supports recent results arguing that network magnetic elements can channel low-frequency photospheric oscillations into the chromosphere, thus providing a way to input mechanical energy in the upper layers.Comment: 4 pages, 3 figure, A&A Letters in pres

Neural mechanisms of resistance to peer influence in early adolescence

During the shift from a parent-dependent child to a fully autonomous adult, peers take on a significant role in shaping the adolescent’s behaviour. Peer-derived influences are not always positive, however. Here we explore neural correlates of inter-individual differences in the probability of resisting peer influence in early adolescence. Using functional magnetic-resonance imaging (fMRI), we found striking differences between 10-year old children with high and low resistance to peer influence in their brain activity during observation of angry hand-movements and angry facial expressions: compared with subjects with low resistance to peer influence, individuals with high resistance showed a highly coordinated brain activity in neural systems underlying perception of action and decision making. These findings suggest that the probability of resisting peer influence depends on neural interactions during observation of emotion-laden actions

Comparison of H alpha synoptic charts with the large-scale solar magnetic field as observed at Stanford

Two methods of observing the neutral line of the large-scale photospheric magnetic field are compared: (1) neutral line positions inferred from H alpha photographs and (2) observations of the photospheric magnetic field made with low spatial resolution (3 arc min.) and high sensitivity using the Stanford magnetograph. The comparison is found to be very favorable