VDNA: The virtual DNA plug-in for VMD

Summary: The DNA inter base pair step parameters (Tilt, Roll, Twist, Shift, Slide, Rise) are a standard internal coordinate representation of DNA. In the absence of bend and shear, it is relatively easy to mentally visualize how Twist and Rise generate the familiar double helix. More complex structures do not readily yield to such intuition. For this reason, we developed a plug-in for VMD that accepts a set of mathematical expressions as input and generates a coarse-grained model of DNA as output. This feature of VDNA appears to provide a unique approach to DNA modeling. Predefined expressions include: linear, sheared, bent and circular DNA, and models of the nucleosome superhelix, chromatin, thermal motion and nucleosome unwrapping

Impact of Deleterious Mutations on Structure, Function and Stability of Serum/Glucocorticoid Regulated Kinase 1: A Gene to Diseases Correlation.

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a Ser/Thr protein kinase involved in regulating cell survival, growth, proliferation, and migration. Its elevated expression and dysfunction are reported in breast, prostate, hepatocellular, lung adenoma, and renal carcinomas. We have analyzed the SGK1 mutations to explore their impact at the sequence and structure level by utilizing state-of-the-art computational approaches. Several pathogenic and destabilizing mutations were identified based on their impact on SGK1 and analyzed in detail. Three amino acid substitutions, K127M, T256A, and Y298A, in the kinase domain of SGK1 were identified and incorporated structurally into original coordinates of SGK1 to explore their time evolution impact using all-atom molecular dynamic (MD) simulations for 200 ns. MD results indicate substantial conformational alterations in SGK1, thus its functional loss, particularly upon T256A mutation. This study provides meaningful insights into SGK1 dysfunction upon mutation, leading to disease progression, including cancer, and neurodegeneration

Mutation Symmetries in BPS Quiver Theories: Building the BPS Spectra

We study the basic features of BPS quiver mutations in 4D $\mathcal{N}=2$ supersymmetric quantum field theory with $G=ADE$ gauge symmetries.\ We show, for these gauge symmetries, that there is an isotropy group $\mathcal{G}_{Mut}^{G}$ associated to a set of quiver mutations capturing information about the BPS spectra. In the strong coupling limit, it is shown that BPS chambers correspond to finite and closed groupoid orbits with an isotropy symmetry group $\mathcal{G}_{strong}^{G}$ isomorphic to the discrete dihedral groups $Dih_{2h_{G}}$ contained in Coxeter$(G)$ with $$ the Coxeter number of G. These isotropy symmetries allow to determine the BPS spectrum of the strong coupling chamber; and give another way to count the total number of BPS and anti-BPS states of $\mathcal{N}=2$ gauge theories. We also build the matrix realization of these mutation groups $\mathcal{G}_{strong}^{G}$ from which we read directly the electric-magnetic charges of the BPS and anti-BPS states of $\mathcal{N}=2$ QFT$_{4}$ as well as their matrix intersections. We study as well the quiver mutation symmetries in the weak coupling limit and give their links with infinite Coxeter groups. We show amongst others that $\mathcal{G}_{weak}^{su_{2}}$ is contained in ${GL}({2,}\mathbb{Z})$; and isomorphic to the infinite Coxeter ${I_{2}^{\infty}}$. Other issues such as building $\mathcal{G}$ and $\mathcal{G}_{weak}^{su_{3}}$ are also studied.Comment: LaTeX, 98 pages, 18 figures, Appendix I on groupoids adde

On unitary subsectors of polycritical gravities

We study higher-derivative gravity theories in arbitrary space-time dimension d with a cosmological constant at their maximally critical points where the masses of all linearized perturbations vanish. These theories have been conjectured to be dual to logarithmic conformal field theories in the (d-1)-dimensional boundary of an AdS solution. We determine the structure of the linearized perturbations and their boundary fall-off behaviour. The linearized modes exhibit the expected Jordan block structure and their inner products are shown to be those of a non-unitary theory. We demonstrate the existence of consistent unitary truncations of the polycritical gravity theory at the linearized level for odd rank.Comment: 22 pages. Added references, rephrased introduction slightly. Published versio

Lysophosphatidic Acid-Induced Transcriptional Profile Represents Serous Epithelial Ovarian Carcinoma and Worsened Prognosis

BACKGROUND:Lysophosphatidic acid (LPA) governs a number of physiologic and pathophysiological processes. Malignant ascites fluid is rich in LPA, and LPA receptors are aberrantly expressed by ovarian cancer cells, implicating LPA in the initiation and progression of ovarian cancer. However, there is an absence of systematic data critically analyzing the transcriptional changes induced by LPA in ovarian cancer. METHODOLOGY AND PRINCIPAL FINDINGS:In this study, gene expression profiling was used to examine LPA-mediated transcription by exogenously adding LPA to human epithelial ovarian cancer cells for 24 h to mimic long-term stimulation in the tumor microenvironment. The resultant transcriptional profile comprised a 39-gene signature that closely correlated to serous epithelial ovarian carcinoma. Hierarchical clustering of ovarian cancer patient specimens demonstrated that the signature is associated with worsened prognosis. Patients with LPA-signature-positive ovarian tumors have reduced disease-specific and progression-free survival times. They have a higher frequency of stage IIIc serous carcinoma and a greater proportion is deceased. Among the 39-gene signature, a group of seven genes associated with cell adhesion recapitulated the results. Out of those seven, claudin-1, an adhesion molecule and phenotypic epithelial marker, is the only independent biomarker of serous epithelial ovarian carcinoma. Knockdown of claudin-1 expression in ovarian cancer cells reduces LPA-mediated cellular adhesion, enhances suspended cells and reduces LPA-mediated migration. CONCLUSIONS:The data suggest that transcriptional events mediated by LPA in the tumor microenvironment influence tumor progression through modulation of cell adhesion molecules like claudin-1 and, for the first time, report an LPA-mediated expression signature in ovarian cancer that predicts a worse prognosis

The effect of S-substitution at the O6-guanine site on the structure and dynamics of a DNA oligomer containing a G:T mismatch

The effect of S-substitution on the O6 guanine site of a 13-mer DNA duplex containing a G:T mismatch is studied using molecular dynamics. The structure, dynamic evolution and hydration of the S-substituted duplex are compared with those of a normal duplex, a duplex with Ssubstitution on guanine, but no mismatch and a duplex with just a G:T mismatch. The S-substituted mismatch leads to cell death rather than repair. One suggestion is that the G:T mismatch recognition protein recognises the S-substituted mismatch (GS:T) as G:T. This leads to a cycle of futile repair ending in DNA breakage and cell death. We find that some structural features of the helix are similar for the duplex with the G:T mismatch and that with the S-substituted mismatch, but differ from the normal duplex, notably the helical twist. These differences arise from the change in the hydrogen-bonding pattern of the base pair. However a marked feature of the S-substituted G:T mismatch duplex is a very large opening. This showed considerable variability. It is suggested that this enlarged opening would lend support to an alternative model of cell death in which the mismatch protein attaches to thioguanine and activates downstream damage-response pathways. Attack on the sulphur by reactive oxygen species, also leading to cell death, would also be aided by the large, variable opening

Geometric measure of quantum discord and the geometry of a class of two-qubit states

We investigate the geometric picture of the level surfaces of quantum entanglement and geometric measure of quantum discord (GMQD) of a class of X-states, respectively. This pictorial approach provides us a direct understanding of the structure of entanglement and GMQD. The dynamic evolution of GMQD under two typical kinds of quantum decoherence channels is also investigated. It is shown that there exists a class of initial states for which the GMQD is not destroyed by decoherence in a finite time interval. Furthermore, we establish a factorization law between the initial and final GMQD, which allows us to infer the evolution of entanglement under the influences of the environment.Comment: 10 pages, 4 figures, comments are welcom

Modeling DNA Structure, Elasticity and Deformations at the Base-pair Level

We present a generic model for DNA at the base-pair level. We use a variant of the Gay-Berne potential to represent the stacking energy between neighboring base-pairs. The sugar-phosphate backbones are taken into account by semi-rigid harmonic springs with a non-zero spring length. The competition of these two interactions and the introduction of a simple geometrical constraint leads to a stacked right-handed B-DNA-like conformation. The mapping of the presented model to the Marko-Siggia and the Stack-of-Plates model enables us to optimize the free model parameters so as to reproduce the experimentally known observables such as persistence lengths, mean and mean squared base-pair step parameters. For the optimized model parameters we measured the critical force where the transition from B- to S-DNA occurs to be approximately $140{pN}$. We observe an overstretched S-DNA conformation with highly inclined bases that partially preserves the stacking of successive base-pairs.Comment: 15 pages, 25 figures. submitted to PR

Spontaneous Creation of Inflationary Universes and the Cosmic Landscape

We study some gravitational instanton solutions that offer a natural realization of the spontaneous creation of inflationary universes in the brane world context in string theory. Decoherence due to couplings of higher (perturbative) modes of the metric as well as matter fields modifies the Hartle-Hawking wavefunction for de Sitter space. Generalizing this new wavefunction to be used in string theory, we propose a principle in string theory that hopefully will lead us to the particular vacuum we live in, thus avoiding the anthropic principle. As an illustration of this idea, we give a phenomenological analysis of the probability of quantum tunneling to various stringy vacua. We find that the preferred tunneling is to an inflationary universe (like our early universe), not to a universe with a very small cosmological constant (i.e., like today's universe) and not to a 10-dimensional uncompactified de Sitter universe. Such preferred solutions are interesting as they offer a cosmological mechanism for the stabilization of extra dimensions during the inflationary epoch.Comment: 52 pages, 7 figures, 1 table. Added discussion on supercritical string vacua, added reference

Classical Inhomogeneities in String Cosmology

We generalize previous work on inhomogeneous pre-big bang cosmology by including the effect of non-trivial moduli and antisymmetric-tensor/axion fields. The general quasi-homogeneous asymptotic solution---as one approaches the big bang singularity from perturbative initial data---is given and its range of validity is discussed, allowing us to give a general quantitative estimate of the amount of inflation obtained during the perturbative pre-big bang era. The question of determining early-time ``attractors'' for generic pre-big bang cosmologies is also addressed, and a motivated conjecture is advanced. We also discuss S-duality-related features of the solutions, and speculate on the way an asymptotic T-duality symmetry may act on moduli space as one approaches the big bang.Comment: 32 pages, Revtex, 1 figure included, epsfig.sty needed; one reference adde