SIRT6 Promotes COX-2 Expression and Acts as an Oncogene in Skin Cancer

SIRT6 is a SIR2 family member that regulates multiple molecular pathways involved in metabolism, genomic stability, and aging. It has been proposed previously that SIRT6 is a tumor suppressor in cancer. Here, we challenge this concept by presenting evidence that skin-specific deletion of SIRT6 in the mouse inhibits skin tumorigenesis. SIRT6 promoted expression of COX-2 by repressing AMPK signaling, thereby increasing cell proliferation and survival in the skin epidermis. SIRT6 expression in skin keratinocytes was increased by exposure to UVB light through activation of the AKT pathway. Clinically, we found that SIRT6 was upregulated in human skin squamous cell carcinoma. Taken together, our results provide evidence that SIRT6 functions as an oncogene in the epidermis and suggest greater complexity to its role in epithelial carcinogenesis. (C) 2014 AACR.

CINCINNATA in Antirrhinum majus directly modulates genes involved in cytokinin and auxin signaling

Mutations in the CINCINNATA (CIN) gene in Antirrhinum majus and its orthologs in Arabidopsis result in crinkly leaves as a result of excess growth towards the leaf margin. CIN homologs code for TCP (TEOSINTE-BRANCHED 1, CYCLOIDEA, PROLIFERATING CELL FACTOR 1 AND 2) transcription factors and are expressed in a broad zone in a growing leaf distal to the proliferation zone where they accelerate cell maturation. Although a few TCP targets are known, the functional basis of CIN-mediated leaf morphogenesis remains unclear. We compared the global transcription profiles of wild-type and the cin mutant of A. majus to identify the targets of CIN. We cloned and studied the direct targets using RNA in situ hybridization, DNA-protein interaction, chromatin immunoprecipitation and reporter gene analysis. Many of the genes involved in the auxin and cytokinin signaling pathways showed altered expression in the cin mutant. Further, we showed that CIN binds to genomic regions and directly promotes the transcription of a cytokinin receptor homolog HISTIDINE KINASE 4 (AmHK4) and an IAA3/SHY2 (INDOLE-3-ACETIC ACID INDUCIBLE 3/SHORT HYPOCOTYL 2) homolog in A. majus. Our results suggest that CIN limits excess cell proliferation and maintains the flatness of the leaf surface by directly modulating the hormone pathways involved in patterning cell proliferation and differentiation during leaf growth. 10.1111/(ISSN)1469-8137

Logarithmic corrections to extremal black hole entropy in N=2, 4 and 8 supergravity

We compute the logarithmic correction to black hole entropy about exponentially suppressed saddle points of the Quantum Entropy Function corresponding to Z(N) orbifolds of the near horizon geometry of the extremal black hole under study. By carefully accounting for zero mode contributions we show that the logarithmic contributions for quarter-BPS black holes in N = 4 supergravity and one-eighth BPS black holes in N = 8 supergravity perfectly match with the prediction from the microstate counting. We also find that the logarithmic contribution for half-BPS black holes in N = 2 supergravity depends non-trivially on the Z(N) orbifold. Our analysis draws heavily on the results we had previously obtained for heat kernel coefficients on Z(N) orbifolds of spheres and hyperboloids in arXiv:1311.6286 and we also propose a generalization of the Plancherel formula to Z(N) orbifolds of hyperboloids to an expression involving the Harish-Chandra character of sl (2, R), a result which is of possible mathematical interest.

Humanized antibody neutralizing 2009 pandemic H1N1 virus

The 2009 pandemic H1N1 S-OIV (swine origin influenza A virus) caused noticeable morbidity and mortality worldwide. In addition to vaccine and antiviral drug therapy, the use of influenza virus neutralizing monoclonal antibodies (MAbs) for treatment purposes is a viable alternative. We previously reported the isolation of a high affinity, potently neutralizing murine MAb MA2077 against 2009 pandemic H1N1 virus. We describe here the humanization of MA2077 and its expression in a mammalian cell line. Six complementarity-determining regions (CDRs) of MA2077 were grafted onto the human germline variable regions; along with six and eight back mutations in the framework of heavy and light chains, respectively, pertaining to the vernier zone and interchain packing residues to promote favorable CDR conformation and facilitate antigen binding. The full length humanized antibody, 2077Hu2, expressed in CHO-K1 cells, showed high affinity to hemagglutinin protein (K-D = 0.75 +/- 0.32 nM) and potent neutralization of pandemic H1N1 virus (IC50 = 0.17 mu g/mL), with marginally higher IC50 as compared to MA2077 (0.08 mu g/mL). In addition, 2077Hu2 also retained the epitope specificity for the ``Sa'' antigenic site on pandemic HA. To the best of our knowledge, this is the first report of a humanized neutralizing antibody against pandemic H1N1 virus.

Oxygen potentials and phase equilibria in the system Ca-Co-O and thermodynamic properties of Ca3Co2O6 and Ca3Co4O9.163

Oxygen potentials established by the equilibrium between three condensed phases, CaOss+CoOss+ Ca3Co2O6 and CoOss+Ca3Co2O6+Ca3CO3.93+O-alpha(9.36-delta), are measured as a function of temperature using solid-state electrochemical cells incorporating yttria-stabilized zirconia as the electrolyte and pure oxygen as the reference electrode. Cation non-stoichiometry and oxygen non-stoichiometry in Ca3Co3.93+alpha O9.36-delta are determined using different techniques under defined conditions. Decomposition temperatures and thermodynamic properties of Ca3Co2O6 and Ca3Co4O9.163 are calculated from the results. The standard entropy and enthalpy of formation of Ca3Co2O6 at 298.15 K are evaluated. Using thermodynamic data from this study and auxiliary information from the literature, phase diagram for the ternary system Ca-Co-O is computed. Isothermal sections at representative temperatures are displayed to demonstrate the evolution of phase relations with temperature. (C) 2014 Elsevier Inc. All rights reserved.

Phase Diagram Study of Succinonitrile-Vanillin Organic Alloy System

Phase diagram studies of succinonitrile-vanillin system show the formation of 2:1 congruent melting type compound. Crystallization velocities of pure components, succinonitrile-vanillin complex, and two eutectics have been determined at different undercoolings. On the basis of heat of fusion measurements, excess thermodynamic functions have been calculated. Microstructural studies revealed that impurities modify the morphology. FTIR spectral studies and computer simulation have shown the existence of hydrogen bonding in the eutectics and the congruent melting compound. On the basis of experimental results, the mechanism of formation of eutectics and its solidification behavior are discussed.

PECVD grown SiC cantilevers with Dry and Wet Release

Cantilevers made out of PECVD grown SiC films are reported here. The cantilevers were realized in two different methods isotropic etch (Dry release) and combination of wet etch and critical point dry release. The dry release process for Silicon isotropic etch results in excellent etch selectivity against SiC, to provide released structures. The optimized wet release process is able to overcome stiction issues to provide excellent SiC cantilevers.

Stress Engineering using Si3N4 for stiction free release of SOI beams

We report on the effect of thin silicon nitride (Si3N4) induced tensile stress on the structural release of 200nm thick SOI beam, in the surface micro-machining process. A thin (20nm / 100nm) LPCVD grown Si3N4 is shown to significantly enhance the yield of released beam in wet release technique. This is especially prominent with increase in beam length, where the beams have higher tendency for stiction. We attribute this yield enhancement to the nitride induced tensile stress, as verified by buckling tendency and resonance frequency data obtained from optical profilometry and laser doppler vibrometry.

Logarithmic corrections to twisted indices from the quantum entropy function

We compute logarithmic corrections to the twisted index B-6(g) in four-dimensional N = 4 and N = 8 string theories using the framework of the Quantum Entropy Function. We find that these vanish, matching perfectly with the large-charge expansion of the corresponding microscopic expressions.

Heat kernels on the AdS(2) cone and logarithmic corrections to extremal black hole entropy

We develop new techniques to efficiently evaluate heat kernel coefficients for the Laplacian in the short-time expansion on spheres and hyperboloids with conical singularities. We then apply these techniques to explicitly compute the logarithmic contribution to black hole entropy from an N = 4 vector multiplet about a Z(N) orbifold of the near-horizon geometry of quarter-BPS black holes in N = 4 supergravity. We find that this vanishes, matching perfectly with the prediction from the microstate counting. We also discuss possible generalisations of our heat kernel results to higher-spin fields over ZN orbifolds of higher-dimensional spheres and hyperboloids.

Genome-wide methylation profiling identifies an essential role of reactive oxygen species in pediatric glioblastoma multiforme and validates a methylome specific for H3 histone family 3A with absence of G-CIMP/isocitrate dehydrogenase 1 mutation

Background. Pediatric glioblastoma multiforme (GBM) is rare, and there is a single study, a seminal discovery showing association of histone H3.3 and isocitrate dehydrogenase (IDH) 1 mutation with a DNA methylation signature. The present study aims to validate these findings in an independent cohort of pediatric GBM, compare it with adult GBM, and evaluate the involvement of important functionally altered pathways. Methods. Genome-wide methylation profiling of 21 pediatric GBM cases was done and compared with adult GBM data (GSE22867). We performed gene mutation analysis of IDH1 and H3 histone family 3A (H3F3A), status evaluation of glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and Gene Ontology analysis. Experimental evaluation of reactive oxygen species (ROS) association was also done. Results. Distinct differences were noted between methylomes of pediatric and adult GBM. Pediatric GBM was characterized by 94 hypermethylated and 1206 hypomethylated cytosine-phosphate-guanine (CpG) islands, with 3 distinct clusters, having a trend to prognostic correlation. Interestingly, none of the pediatric GBM cases showed G-CIMP/IDH1 mutation. Gene Ontology analysis identified ROS association in pediatric GBM, which was experimentally validated. H3F3A mutants (36.4%; all K27M) harbored distinct methylomes and showed enrichment of processes related to neuronal development, differentiation, and cell-fate commitment. Conclusions. Our study confirms that pediatric GBM has a distinct methylome compared with that of adults. Presence of distinct clusters and an H3F3A mutation-specific methylome indicate existence of epigenetic subgroups within pediatric GBM. Absence of IDH1/G-CIMP status further indicates that findings in adult GBM cannot be simply extrapolated to pediatric GBM and that there is a strong need for identification of separate prognostic markers. A possible role of ROS in pediatric GBM pathogenesis is demonstrated for the first time and needs further evaluation.

Novel multimeric IL-1 receptor antagonist for the treatment of rheumatoid arthritis

Protein therapeutics targeting inflammatory mediators have shown great promise for the treatment of autoimmunities such as rheumatoid arthritis (RA). However, a significant challenge in this area has been their low in vivo stability and consequently their severely compromised therapeutic efficacy. One such therapeutic molecule IL-1 receptor antagonist (IL-1ra), used in the treatment of rheumatoid arthritis, has displayed only modest efficacy in human clinical trials owing to its short biological half-life. Herein, we report a novel approach to conglomerate individual protein entities into a drug depot by incorporation of an amyloidogenic motif Lys-Phe-Phe-Glu (KFFE) thereby dramatically improving their systemic persistence and in turn their therapeutic efficacy in a mice model of autoimmune arthritis. (C) 2014 Elsevier Ltd. All rights reserved.

Dielectric elastomers: Asymptotically-correct three-dimensional displacement field

Asymptotically-accurate dimensional reduction from three to two dimensions and recovery of 3-D displacement field of non-prestretched dielectric hyperelastic membranes are carried out using the Variational Asymptotic Method (VAM) with moderate strains and very small ratio of the membrane thickness to its shortest wavelength of the deformation along the plate reference surface chosen as the small parameters for asymptotic expansion. Present work incorporates large deformations (displacements and rotations), material nonlinearity (hyperelasticity), and electrical effects. It begins with 3-D nonlinear electroelastic energy and mathematically splits the analysis into a one-dimensional (1-D) through-the-thickness analysis and a 2-D nonlinear plate analysis. Major contribution of this paper is a comprehensive nonlinear through-the-thickness analysis which provides a 2-D energy asymptotically equivalent of the 3-D energy, a 2-D constitutive relation between the 2-D generalized strain and stress tensors for the plate analysis and a set of recovery relations to express the 3-D displacement field. Analytical expressions are derived for warping functions and stiffness coefficients. This is the first attempt to integrate an analytical work on asymptotically-accurate nonlinear electro-elastic constitutive relation for compressible dielectric hyperelastic model with a generalized finite element analysis of plates to provide 3-D displacement fields using VAM. A unified software package `VAMNLM' (Variational Asymptotic Method applied to Non-Linear Material models) was developed to carry out 1-D non-linear analysis (analytical), 2-D non-linear finite element analysis and 3-D recovery analysis. The applicability of the current theory is demonstrated through an actuation test case, for which distribution of 3-D displacements are provided. (C) 2014 Elsevier Ltd. All rights reserved.

Water Dispersible, Positively and Negatively Charged MoS2 Nanosheets: Surface Chemistry and the Role of Surfactant Binding

Stable aqueous dispersions of atomically thin layered MoS2 nanosheets have been obtained by sonication in the presence of ionic surfactants. The dispersions are stabilized by electrostatic repulsion between the sheets, and we show that the sign of the charge on the MoS2 nanosheets, either positive or negative, can be can be controlled by the choice of the surfactant. Using techniques from solution NMR, we show that the surfactant chains are weakly bound to the MoS2 sheets and undergo rapid exchange with free surfactant chains present in the dispersion. In situ nuclear Overhauser effect spectroscopic measurements provide direct evidence that the surfactant chains lie flat, arranged randomly on the basal plane of the MoS2 nanosheets with their charged headgroup exposed. These results provide a chemical perspective for understanding the stability of these inorganic nanosheets in aqueous dispersions and the origin of the charge on the sheets.