Corner contributions to holographic entanglement entropy

The entanglement entropy of three-dimensional conformal field theories contains a universal contribution coming from corners in the entangling surface. We study these contributions in a holographic framework and, in particular, we consider the effects of higher curvature interactions in the bulk gravity theory. We find that for all of our holographic models, the corner contribution is only modified by an overall factor but the functional dependence on the opening angle is not modified by the new gravitational interactions. We also compare the dependence of the corner term on the new gravitational couplings to that for a number of other physical quantities, and we show that the ratio of the corner contribution over the central charge appearing in the two-point function of the stress tensor is a universal function for all of the holographic theories studied here. Comparing this holographic result to the analogous functions for free CFT's, we find fairly good agreement across the full range of the opening angle. However, there is a precise match in the limit where the entangling surface becomes smooth, i.e., the angle approaches $\pi$, and we conjecture the corresponding ratio is a universal constant for all three-dimensional conformal field theories. In this paper, we expand on the holographic calculations in our previous letter arXiv:1505.04804, where this conjecture was first introduced.Comment: 62 pages, 6 figures, 1 table; v2: minor modifications to match published version, typos fixe

Computer Aided Identification of Small Molecules Disrupting uPAR/α5β1- Integrin Interaction: A New Paradigm for Metastasis Prevention

Disseminated dormant cancer cells can resume growth and eventually form overt metastases, but the underlying molecular mechanism responsible for this change remains obscure. We previously established that cell surface interaction between urokinase receptor (uPAR) and alpha5beta1-integrin initiates a sequel of events, involving MAPK-ERK activation that culminates in progressive cancer growth. We also identified the site on uPAR that binds alpha5beta1-integrin. Disruption of uPAR/integrin interaction blocks ERK activation and forces cancer cells into dormancy.Using a target structure guided computation docking we identified 68 compounds from a diversity library of 13,000 small molecules that were predicted to interact with a previously identified integrin-binding site on uPAR. Of these 68 chemical hits, ten inhibited ERK activation in a cellular assay and of those, 2 compounds, 2-(Pyridin-2-ylamino)-quinolin-8-ol and, 2,2'-(methylimino)di (8-quinolinol) inhibited ERK activation by disrupting the uPAR/integrins interaction. These two compounds, when applied in vivo, inhibited ERK activity and tumor growth and blocked metastases of a model head and neck carcinoma.We showed that interaction between two large proteins (uPAR and alpha5beta1-integrin) can be disrupted by a small molecule leading to profound downstream effects. Because this interaction occurs in cells with high uPAR expression, a property almost exclusive to cancer cells, we expect a new therapy based on these lead compounds to be cancer cell specific and minimally toxic. This treatment, rather than killing disseminated metastatic cells, should induce a protracted state of dormancy and prevent overt metastases

Using metadynamics to explore complex free-energy landscapes

Metadynamics is an atomistic simulation technique that allows, within the same framework, acceleration of rare events and estimation of the free energy of complex molecular systems. It is based on iteratively \u2018filling\u2019 the potential energy of the system by a sum of Gaussians centred along the trajectory followed by a suitably chosen set of collective variables (CVs), thereby forcing the system to migrate from one minimum to the next. The power of metadynamics is demonstrated by the large number of extensions and variants that have been developed. The first scope of this Technical Review is to present a critical comparison of these variants, discussing their advantages and disadvantages. The effectiveness of metadynamics, and that of the numerous alternative methods, is strongly influenced by the choice of the CVs. If an important variable is neglected, the resulting estimate of the free energy is unreliable, and predicted transition mechanisms may be qualitatively wrong. The second scope of this Technical Review is to discuss how the CVs should be selected, how to verify whether the chosen CVs are sufficient or redundant, and how to iteratively improve the CVs using machine learning approaches

Enhanced and effective conformational sampling of protein molecular systems for their free energy landscapes

Protein folding and protein–ligand docking have long persisted as important subjects in biophysics. Using multicanonical molecular dynamics (McMD) simulations with realistic expressions, i.e., all-atom protein models and an explicit solvent, free-energy landscapes have been computed for several systems, such as the folding of peptides/proteins composed of a few amino acids up to nearly 60 amino-acid residues, protein–ligand interactions, and coupled folding and binding of intrinsically disordered proteins. Recent progress in conformational sampling and its applications to biophysical systems are reviewed in this report, including descriptions of several outstanding studies. In addition, an algorithm and detailed procedures used for multicanonical sampling are presented along with the methodology of adaptive umbrella sampling. Both methods control the simulation so that low-probability regions along a reaction coordinate are sampled frequently. The reaction coordinate is the potential energy for multicanonical sampling and is a structural identifier for adaptive umbrella sampling. One might imagine that this probability control invariably enhances conformational transitions among distinct stable states, but this study examines the enhanced conformational sampling of a simple system and shows that reasonably well-controlled sampling slows the transitions. This slowing is induced by a rapid change of entropy along the reaction coordinate. We then provide a recipe to speed up the sampling by loosening the rapid change of entropy. Finally, we report all-atom McMD simulation results of various biophysical systems in an explicit solvent

The Interleukin-6 inflammation pathway from cholesterol to aging – Role of statins, bisphosphonates and plant polyphenols in aging and age-related diseases

We describe the inflammation pathway from Cholesterol to Aging. Interleukin 6 mediated inflammation is implicated in age-related disorders including Atherosclerosis, Peripheral Vascular Disease, Coronary Artery Disease, Osteoporosis, Type 2 Diabetes, Dementia and Alzheimer's disease and some forms of Arthritis and Cancer. Statins and Bisphosphonates inhibit Interleukin 6 mediated inflammation indirectly through regulation of endogenous cholesterol synthesis and isoprenoid depletion. Polyphenolic compounds found in plants, fruits and vegetables inhibit Interleukin 6 mediated inflammation by direct inhibition of the signal transduction pathway. Therapeutic targets for the control of all the above diseases should include inhibition of Interleukin-6 mediated inflammation