Oncogenic Gain of Function in Glioblastoma Is Linked to Mutant p53 Amyloid Oligomers.

Tumor-associated p53 mutations endow cells with malignant phenotypes, including chemoresistance. Amyloid-like oligomers of mutant p53 transform this tumor suppressor into an oncogene. However, the composition and distribution of mutant p53 oligomers are unknown and the mechanism involved in the conversion is sparse. Here, we report accumulation of a p53 mutant within amyloid-like p53 oligomers in glioblastoma-derived cells presenting a chemoresistant gain-of-function phenotype. Statistical analysis from fluorescence fluctuation spectroscopy, pressure-induced measurements, and thioflavin T kinetics demonstrates the distribution of oligomers larger than the active tetrameric form of p53 in the nuclei of living cells and the destabilization of native-drifted p53 species that become amyloid. Collectively, these results provide insights into the role of amyloid-like mutant p53 oligomers in the chemoresistance phenotype of malignant and invasive brain tumors and shed light on therapeutic options to avert cancer

The Wasteland of Random Supergravities

We show that in a general \cal{N} = 1 supergravity with N \gg 1 scalar fields, an exponentially small fraction of the de Sitter critical points are metastable vacua. Taking the superpotential and Kahler potential to be random functions, we construct a random matrix model for the Hessian matrix, which is well-approximated by the sum of a Wigner matrix and two Wishart matrices. We compute the eigenvalue spectrum analytically from the free convolution of the constituent spectra and find that in typical configurations, a significant fraction of the eigenvalues are negative. Building on the Tracy-Widom law governing fluctuations of extreme eigenvalues, we determine the probability P of a large fluctuation in which all the eigenvalues become positive. Strong eigenvalue repulsion makes this extremely unlikely: we find P \propto exp(-c N^p), with c, p being constants. For generic critical points we find p \approx 1.5, while for approximately-supersymmetric critical points, p \approx 1.3. Our results have significant implications for the counting of de Sitter vacua in string theory, but the number of vacua remains vast.Comment: 39 pages, 9 figures; v2: fixed typos, added refs and clarification

The Conformal Anomaly of M5-Branes

We show that the conformal anomaly for N M5-branes grows like $N^3$. The method we employ relates Coulomb branch interactions in six dimensions to interactions in four dimensions using supersymmetry. This leads to a relation between the six-dimensional conformal anomaly and the conformal anomaly of N=4 Yang-Mills. Along the way, we determine the structure of the four derivative interactions for the toroidally compactified (2,0) theory, while encountering interesting novelties in the structure of the six derivative interactions.Comment: 38 pages, LaTeX; references adde

Six-dimensional (1,0) effective action of F-theory via M-theory on Calabi-Yau threefolds

The six-dimensional effective action of F-theory compactified on a singular elliptically fibred Calabi-Yau threefold is determined by using an M-theory lift. The low-energy data are derived by comparing a circle reduction of a general six-dimensional (1,0) gauged supergravity theory with the effective action of M-theory on the resolved Calabi-Yau threefold. The derivation includes six-dimensional tensor multiplets for which the (anti-) self-duality constraints are imposed on the level of the five-dimensional action. The vector sector of the reduced theory is encoded by a non-standard potential due to the Green-Schwarz term in six dimensions. This Green-Schwarz term also contains higher curvature couplings which are considered to establish the full map between anomaly coefficients and geometry. F-/M-theory duality is exploited by moving to the five-dimensional Coulomb branch after circle reduction and integrating out massive vector multiplets and matter hypermultiplets. The associated fermions then generate additional Chern-Simons couplings at one-loop. Further couplings involving the graviphoton are induced by quantum corrections due to excited Kaluza-Klein modes. On the M-theory side integrating out massive fields corresponds to resolving the singularities of the Calabi-Yau threefold, and yields intriguing relations between six-dimensional anomalies and classical topology.Comment: 55 pages, v2: typos corrected, discussion of loop corrections improve

An inhibitory pull-push circuit in frontal cortex.

Push-pull is a canonical computation of excitatory cortical circuits. By contrast, we identify a pull-push inhibitory circuit in frontal cortex that originates in vasoactive intestinal polypeptide (VIP)-expressing interneurons. During arousal, VIP cells rapidly and directly inhibit pyramidal neurons; VIP cells also indirectly excite these pyramidal neurons via parallel disinhibition. Thus, arousal exerts a feedback pull-push influence on excitatory neurons-an inversion of the canonical push-pull of feedforward input

Seiberg duality for Chern-Simons quivers and D-brane mutations

Chern-Simons quivers for M2-branes at Calabi-Yau singularities are best understood as the low energy theory of D2-branes on a dual type IIA background. We show how the D2-brane point of view naturally leads to three dimensional Seiberg dualities for Chern-Simons quivers with chiral matter content: They arise from a change of brane basis (or mutation), in complete analogy with the better known Seiberg dualities for D3-brane quivers. This perspective reproduces the known rules for Seiberg dualities in Chern-Simons-Yang-Mills theories with unitary gauge groups. We provide explicit examples of dual theories for the quiver dual to the Y^{p,q}(CP^2) geometries. We also comment on the string theory derivation of CS quivers dual to massive type IIA geometries.Comment: 32 pages+appendix; v2: added a referenc

Decompactifications and Massless D-Branes in Hybrid Models

A method of determining the mass spectrum of BPS D-branes in any phase limit of a gauged linear sigma model is introduced. A ring associated to monodromy is defined and one considers K-theory to be a module over this ring. A simple but interesting class of hybrid models with Landau-Ginzburg fibres over CPn are analyzed using special Kaehler geometry and D-brane probes. In some cases the hybrid limit is an infinite distance in moduli space and corresponds to a decompactification. In other cases the hybrid limit is at a finite distance and acquires massless D-branes. An example studied appears to correspond to a novel theory of supergravity with an SU(2) gauge symmetry where the gauge and gravitational couplings are necessarily tied to each other.Comment: PDF-LaTeX, 34 pages, 2 mps figure

Non-abelian Action for Multiple Five-Branes with Self-Dual Tensors

We construct an action for non-abelian 2-form in 6-dimensions. Our action consists of a non-abelian generalization of the abelian action of Perry and Schwarz for a single five-brane. It admits a self-duality equation on the field strength as the equation of motion. It has a modified 6d Lorentz symmetry. On dimensional reduction on a circle, our action gives the standard 5d Yang-Mills action plus higher order corrections. Based on these properties, we propose that our theory describes the gauge sector of multiple M5-branes in flat space.Comment: LaTeX, 26 pages. v2: improved discussion of Lorentz symmetry. ref added. v3: add comments in the discussion section on the inclusion of scalar fields and supersymmetry; title changed to a more suitable one; version published in JHE

On instantons as Kaluza-Klein modes of M5-branes

Instantons and W-bosons in 5d maximally supersymmetric Yang-Mills theory arise from a circle compactification of the 6d (2,0) theory as Kaluza-Klein modes and winding self-dual strings, respectively. We study an index which counts BPS instantons with electric charges in Coulomb and symmetric phases. We first prove the existence of unique threshold bound state of (noncommutative) U(1) instantons for any instanton number, and also show that charged instantons in the Coulomb phase correctly give the degeneracy of SU(2) self-dual strings. By studying SU(N) self-dual strings in the Coulomb phase, we find novel momentum-carrying degrees on the worldsheet. The total number of these degrees equals the anomaly coefficient of SU(N) (2,0) theory. We finally show that our index can be used to study the symmetric phase of this theory, and provide an interpretation as the superconformal index of the sigma model on instanton moduli space.Comment: 54 pages, 2 figures. v2: references added, figure improved, added comments on self-dual string anomaly, added new materials on the symmetric phase index, other minor correction

Development of a decision support tool to facilitate primary care management of patients with abnormal liver function tests without clinically apparent liver disease [HTA03/38/02]. Abnormal Liver Function Investigations Evaluation (ALFIE)

Liver function tests (LFTs) are routinely performed in primary care, and are often the gateway to further invasive and/or expensive investigations. Little is known of the consequences in people with an initial abnormal liver function (ALF) test in primary care and with no obvious liver disease. Further investigations may be dangerous for the patient and expensive for Health Services. The aims of this study are to determine the natural history of abnormalities in LFTs before overt liver disease presents in the population and identify those who require minimal further investigations with the potential for reduction in NHS costs