1,283 research outputs found

    FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents.

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    Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge. GBM survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome

    Quantitative clinical neurological testing--II : Some statistical considerations of a battery of tests

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    A battery of clinical neurological tests was evaluated statistically. In one experiment eight medical students were studied to obtain information on the reproducibility of four observers, eight repeated examinations, and four time periods of day. To obtain learning and fatigue effects another experiment using ten medical students was carried out. The results from this study for these particular groups indicate: 1. 1. That different examiners, such as neurologists and physical therapists, may be trained to obtain comparable results using the quantitative tests of the battery of clinical neurological tests.2. 2. That the level of neurological function obtained using these neurological tests does not vary significantly during the four stated periods of the day.3. 3. That the level of neurological function does not differ significantly when the battery of neurological tests was administered on four consecutive days.4. 4. It is doubtful that a significant learning trend exists when these neurological tests are administered on four consecutive days.5. 5. That the weekly means of most of the neurological tests which involve many repetitions of the same action at each examination are significantly larger for the second week.6. 6. The neurological tests of five repeated trials, e.g., gap strength, and the tests of four reduced trials, e.g., speed of hand, may be used as useful measures of two types of fatigue.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32043/1/0000086.pd

    Superconductors with Magnetic Impurities: Instantons and Sub-gap States

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    When subject to a weak magnetic impurity potential, the order parameter and quasi-particle energy gap of a bulk singlet superconductor are suppressed. According to the conventional mean-field theory of Abrikosov and Gor'kov, the integrity of the energy gap is maintained up to a critical concentration of magnetic impurities. In this paper, a field theoretic approach is developed to critically analyze the validity of the mean field theory. Using the supersymmetry technique we find a spatially homogeneous saddle-point that reproduces the Abrikosov-Gor'kov theory, and identify instanton contributions to the density of states that render the quasi-particle energy gap soft at any non-zero magnetic impurity concentration. The sub-gap states are associated with supersymmetry broken field configurations of the action. An analysis of fluctuations around these configurations shows how the underlying supersymmetry of the action is restored by zero modes. An estimate of the density of states is given for all dimensionalities. To illustrate the universality of the present scheme we apply the same method to study `gap fluctuations' in a normal quantum dot coupled to a superconducting terminal. Using the same instanton approach, we recover the universal result recently proposed by Vavilov et al. Finally, we emphasize the universality of the present scheme for the description of gap fluctuations in d-dimensional superconducting/normal structures.Comment: 18 pages, 9 eps figure

    ASTEC -- the Aarhus STellar Evolution Code

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    The Aarhus code is the result of a long development, starting in 1974, and still ongoing. A novel feature is the integration of the computation of adiabatic oscillations for specified models as part of the code. It offers substantial flexibility in terms of microphysics and has been carefully tested for the computation of solar models. However, considerable development is still required in the treatment of nuclear reactions, diffusion and convective mixing.Comment: Astrophys. Space Sci, in the pres

    Isometric Sliced Inverse Regression for Nonlinear Manifolds Learning

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    [[abstract]]Sliced inverse regression (SIR) was developed to find effective linear dimension-reduction directions for exploring the intrinsic structure of the high-dimensional data. In this study, we present isometric SIR for nonlinear dimension reduction, which is a hybrid of the SIR method using the geodesic distance approximation. First, the proposed method computes the isometric distance between data points; the resulting distance matrix is then sliced according to K-means clustering results, and the classical SIR algorithm is applied. We show that the isometric SIR (ISOSIR) can reveal the geometric structure of a nonlinear manifold dataset (e.g., the Swiss roll). We report and discuss this novel method in comparison to several existing dimension-reduction techniques for data visualization and classification problems. The results show that ISOSIR is a promising nonlinear feature extractor for classification applications.[[incitationindex]]SCI[[booktype]]紙本[[booktype]]電子

    Stability of the monoclinic phase in the ferroelectric perovskite PbZr(1-x)TixO3

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    Recent structural studies of ferroelectric PbZr(1-x)TixO3 (PZT) with x= 0.48, have revealed a new monoclinic phase in the vicinity of the morphotropic phase boundary (MPB), previously regarded as the the boundary separating the rhombohedral and tetragonal regions of the PZT phase diagram. In the present paper, the stability region of all three phases has been established from high resolution synchrotron x-ray powder diffraction measurements on a series of highly homogeneous samples with 0.42 <=x<= 0.52. At 20K the monoclinic phase is stable in the range 0.46 <=x<= 0.51, and this range narrows as the temperature is increased. A first-order phase transition from tetragonal to rhombohedral symmetry is observed only for x= 0.45. The MPB, therefore, corresponds not to the tetragonal-rhombohedral phase boundary, but instead to the boundary between the tetragonal and monoclinic phases for 0.46 <=x<= 0.51. This result provides important insight into the close relationship between the monoclinic phase and the striking piezoelectric properties of PZT; in particular, investigations of poled samples have shown that the monoclinic distortion is the origin of the unusually high piezoelectric response of PZT.Comment: REVTeX file, 7 figures embedde

    A tetragonal-to-monoclinic phase transition in a ferroelectric perovskite: the structure of PbZr(0.52)Ti(0.48)O3

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    The perovskite-like ferroelectric system PbZr(1-x)Ti(x)O3 (PZT) has a nearly vertical morphotropic phase boundary (MPB) around x=0.45-0.50. Recent synchrotron x-ray powder diffraction measurements by Noheda et al. [Appl. Phys. Lett. 74, 2059 (1999)] have revealed a new monoclinic phase between the previously-established tetragonal and rhombohedral regions. In the present work we describe a Rietveld analysis of the detailed structure of the tetragonal and monoclinic PZT phases on a sample with x= 0.48 for which the lattice parameters are respectively: at= 4.044 A, ct= 4.138 A, at 325 K, and am= 5.721 A, bm= 5.708 A, cm= 4.138 A, beta= 90.496 deg., at 20K. In the tetragonal phase the shifts of the atoms along the polar [001] direction are similar to those in PbTiO3 but the refinement indicates that there are, in addition, local disordered shifts of the Pb atoms of ~0.2 A perpendicular to the polar axis.. The monoclinic structure can be viewed as a condensation along one of the directions of the local displacements present in the tetragonal phase. It equally well corresponds to a freezing-out of the local displacements along one of the directions recently reported by Corker et al.[J. Phys. Condens. Matter 10, 6251 (1998)] for rhombohedral PZT. The monoclinic structure therefore provides a microscopic picture of the MPB region in which one of the "locally" monoclinic phases in the "average" rhombohedral or tetragonal structures freezes out, and thus represents a bridge between these two phases.Comment: REVTeX, 7 figures. Modifications after referee's suggestion: new figure (figure 5), comments in 2nd para. (Sect.III) and in 2nd & 3rd para. (Sect. IV-a), in the abstract: "...of ~0.2 A perpendicular to the polar axis.

    Piecewise Approximate Bayesian Computation: fast inference for discretely observed Markov models using a factorised posterior distribution

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    Many modern statistical applications involve inference for complicated stochastic models for which the likelihood function is difficult or even impossible to calculate, and hence conventional likelihood-based inferential techniques cannot be used. In such settings, Bayesian inference can be performed using Approximate Bayesian Computation (ABC). However, in spite of many recent developments to ABC methodology, in many applications the computational cost of ABC necessitates the choice of summary statistics and tolerances that can potentially severely bias the estimate of the posterior. We propose a new “piecewise” ABC approach suitable for discretely observed Markov models that involves writing the posterior density of the parameters as a product of factors, each a function of only a subset of the data, and then using ABC within each factor. The approach has the advantage of side-stepping the need to choose a summary statistic and it enables a stringent tolerance to be set, making the posterior “less approximate”. We investigate two methods for estimating the posterior density based on ABC samples for each of the factors: the first is to use a Gaussian approximation for each factor, and the second is to use a kernel density estimate. Both methods have their merits. The Gaussian approximation is simple, fast, and probably adequate for many applications. On the other hand, using instead a kernel density estimate has the benefit of consistently estimating the true piecewise ABC posterior as the number of ABC samples tends to infinity. We illustrate the piecewise ABC approach with four examples; in each case, the approach offers fast and accurate inference
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