Instantons and Killing spinors

We investigate instantons on manifolds with Killing spinors and their cones. Examples of manifolds with Killing spinors include nearly Kaehler 6-manifolds, nearly parallel G_2-manifolds in dimension 7, Sasaki-Einstein manifolds, and 3-Sasakian manifolds. We construct a connection on the tangent bundle over these manifolds which solves the instanton equation, and also show that the instanton equation implies the Yang-Mills equation, despite the presence of torsion. We then construct instantons on the cones over these manifolds, and lift them to solutions of heterotic supergravity. Amongst our solutions are new instantons on even-dimensional Euclidean spaces, as well as the well-known BPST, quaternionic and octonionic instantons.Comment: 40 pages, 2 figures v2: author email addresses and affiliations adde

Kinetics and activation of phospholipase C by P2Y purinergic agonists and guanine nucleotides

Membranes prepared from [3H]inositol-labeled turkey erythrocytes express a phospholipase C that is markedly stimulated by stable analogs of GTP (Harden, T. K., Stephens, L., Hawkins, P. T., and Downes, C. P. (1987) J. Biol. Chem. 262, 9057-9061). We now report that P2-purinergic receptor-mediated regulation of the enzyme occurs in the membrane preparation. The order of potency of a series of ATP and ADP analogs for stimulation of inositol phosphate formation, i.e. 2-methylthioadenosine 5'-triphosphate (2MeSATP) greater than adenosine 5'-O-(2-thiodiphosphate) greater than adenosine 5'-O-(3-thiotriphosphate) greater than ATP greater than 5'-adenylyl imidodiphosphate approximately ADP greater than alpha, beta-methyleneadenosine 5'-triphosphate greater than beta, gamma-methyleneadenosine 5'-triphosphate, was consistent with that for the P2Y-purinergic receptor subtype. Agonist-stimulated effects were completely dependent on the presence of guanine nucleotide. Activation of phospholipase C by guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) occurred with a considerable time lag. The rate of activation followed first order kinetics and was markedly increased by increasing concentrations of a P2Y receptor agonist; in contrast, the rate of activation at a fixed agonist concentration was independent of guanine nucleotide concentration. Addition of guanosine 5'-O-(2-thiodiphosphate) (GDP beta S) prior to addition of agonist and GTP, 5'-guanylyl imidodiphosphate (Gpp(NH)p), or GTP gamma S blocked in a concentration-dependent manner the stimulatory effect of guanine nucleotide. GDP beta S, added subsequent to preactivation of membranes with 2MeSATP and GTP gamma S or Gpp(NH)p had only small inhibitory effects on the rate of inositol phosphate production observed over the subsequent 10 min. In contrast, addition of GDP beta S to GTP-preactivated membranes resulted in a rapid return of enzyme activity to the basal state within 60 s. Taken together, the data are consistent with the idea that P2Y receptor activation increases the rate of exchange of GTP and GTP analogs for GDP on the relevant guanine nucleotide regulatory protein. Once the active enzymic species is formed, hydrolysis of guanine nucleotide reverts the enzyme to the inactive state

Matrix Models for Supersymmetric Chern-Simons Theories with an ADE Classification

We consider N=3 supersymmetric Chern-Simons (CS) theories that contain product U(N) gauge groups and bifundamental matter fields. Using the matrix model of Kapustin, Willett and Yaakov, we examine the Euclidean partition function of these theories on an S^3 in the large N limit. We show that the only such CS theories for which the long range forces between the eigenvalues cancel have quivers which are in one-to-one correspondence with the simply laced affine Dynkin diagrams. As the A_n series was studied in detail before, in this paper we compute the partition function for the D_4 quiver. The D_4 example gives further evidence for a conjecture that the saddle point eigenvalue distribution is determined by the distribution of gauge invariant chiral operators. We also see that the partition function is invariant under a generalized Seiberg duality for CS theories.Comment: 20 pages, 3 figures; v2 refs added; v3 conventions in figure 3 altered, version to appear in JHE

The ABCDEF's of Matrix Models for Supersymmetric Chern-Simons Theories

We consider N = 3 supersymmetric Chern-Simons gauge theories with product unitary and orthosymplectic groups and bifundamental and fundamental fields. We study the partition functions on an S^3 by using the Kapustin-Willett-Yaakov matrix model. The saddlepoint equations in a large N limit lead to a constraint that the long range forces between the eigenvalues must cancel; the resulting quiver theories are of affine Dynkin type. We introduce a folding/unfolding trick which lets us, at the level of the large N matrix model, (i) map quivers with orthosymplectic groups to those with unitary groups, and (ii) obtain non-simply laced quivers from the corresponding simply laced quivers using a Z_2 outer automorphism. The brane configurations of the quivers are described in string theory and the folding/unfolding is interpreted as the addition/subtraction of orientifold and orbifold planes. We also relate the U(N) quiver theories to the affine ADE quiver matrix models with a Stieltjes-Wigert type potential, and derive the generalized Seiberg duality in 2 + 1 dimensions from Seiberg duality in 3 + 1 dimensions.Comment: 30 pages, 5 figure

Heterotic Sigma Models with N=2 Space-Time Supersymmetry

We study the non-linear sigma model realization of a heterotic vacuum with N=2 space-time supersymmetry. We examine the requirements of (0,2) + (0,4) world-sheet supersymmetry and show that a geometric vacuum must be described by a principal two-torus bundle over a K3 manifold.Comment: 20 pages, uses xy-pic; v3: typos corrected, reference added, discussion of constraints on Hermitian form modifie

Exploring Curved Superspace

We systematically analyze Riemannian manifolds M that admit rigid supersymmetry, focusing on four-dimensional N=1 theories with a U(1)_R symmetry. We find that M admits a single supercharge, if and only if it is a Hermitian manifold. The supercharge transforms as a scalar on M. We then consider the restrictions imposed by the presence of additional supercharges. Two supercharges of opposite R-charge exist on certain fibrations of a two-torus over a Riemann surface. Upon dimensional reduction, these give rise to an interesting class of supersymmetric geometries in three dimensions. We further show that compact manifolds admitting two supercharges of equal R-charge must be hyperhermitian. Finally, four supercharges imply that M is locally isometric to M_3 x R, where M_3 is a maximally symmetric space.Comment: 39 pages; minor change

Baryonic symmetries and M5 branes in the AdS_4/CFT_3 correspondence

We study U(1) symmetries dual to Betti multiplets in the AdS_4/CFT_3 correspondence for M2 branes at Calabi-Yau four-fold singularities. Analysis of the boundary conditions for vector fields in AdS_4 allows for a choice where wrapped M5 brane states carrying non-zero charge under such symmetries can be considered. We begin by focusing on isolated toric singularities without vanishing six-cycles, and study in detail the cone over Q^{111}. The boundary conditions considered are dual to a CFT where the gauge group is U(1)^2 x SU(N)^4. We find agreement between the spectrum of gauge-invariant baryonic-type operators in this theory and wrapped M5 brane states. Moreover, the physics of vacua in which these symmetries are spontaneously broken precisely matches a dual gravity analysis involving resolutions of the singularity, where we are able to match condensates of the baryonic operators, Goldstone bosons and global strings. We also argue more generally that theories where the resolutions have six-cycles are expected to receive non-perturbative corrections from M5 brane instantons. We give a general formula relating the instanton action to normalizable harmonic two-forms, and compute it explicitly for the Q^{222} example. The holographic interpretation of such instantons is currently unclear.Comment: 92 pages, 10 figure

DNA immunization as a technology platform for monoclonal antibody induction

To combat the threat of many emerging infectious diseases, DNA immunization offers a unique and powerful approach to the production of high-quality monoclonal antibodies (mAbs) against various pathogens. Compared with traditional protein-based immunization approaches, DNA immunization is efficient for testing novel immunogen designs, does not require the production or purification of proteins from a pathogen or the use of recombinant protein technology and is effective at generating mAbs against conformation-sensitive targets. Although significant progress in the use of DNA immunization to generate mAbs has been made over the last two decades, the literature does not contain an updated summary of this experience. The current review provides a comprehensive analysis of the literature, including our own work, describing the use of DNA immunization to produce highly functional mAbs, in particular, those against emerging infectious diseases. Critical factors such as immunogen design, delivery approach, immunization schedule, use of immune modulators and the role of final boost immunization are discussed in detail

Epithelial to Mesenchymal Transition Is Mechanistically Linked with Stem Cell Signatures in Prostate Cancer Cells

Current management of patients diagnosed with prostate cancer (PCa) is very effective; however, tumor recurrence with Castrate Resistant Prostate Cancer (CRPC) and subsequent metastasis lead to poor survival outcome, suggesting that there is a dire need for novel mechanistic understanding of tumor recurrence, which would be critical for designing novel therapies. The recurrence and the metastasis of PCa are tightly linked with the biology of prostate cancer stem cells or cancer-initiating cells that is reminiscent of the acquisition of Epithelial to Mesenchymal Transition (EMT) phenotype. Increasing evidence suggests that EMT-type cells share many biological characteristics with cancer stem-like cells.In this study, we found that PCa cells with EMT phenotype displayed stem-like cell features characterized by increased expression of Sox2, Nanog, Oct4, Lin28B and/or Notch1, consistent with enhanced clonogenic and sphere (prostasphere)-forming ability and tumorigenecity in mice, which was associated with decreased expression of miR-200 and/or let-7 family. Reversal of EMT by re-expression of miR-200 inhibited prostasphere-forming ability of EMT-type cells and reduced the expression of Notch1 and Lin28B. Down-regulation of Lin28B increased let-7 expression, which was consistent with repressed self-renewal capability.These results suggest that miR-200 played a pivotal role in linking the characteristics of cancer stem-like cells with EMT-like cell signatures in PCa. Selective elimination of cancer stem-like cells by reversing the EMT phenotype to Mesenchymal-Epithelial Transition (MET) phenotype using novel agents would be useful for the prevention of tumor recurrence especially by eliminating those cells that are the "Root Cause" of tumor development and recurrence

The Na(+)–H(+ )exchanger-1 induces cytoskeletal changes involving reciprocal RhoA and Rac1 signaling, resulting in motility and invasion in MDA-MB-435 cells

INTRODUCTION: An increasing body of evidence shows that the tumour microenvironment is essential in driving neoplastic progression. The low serum component of this microenvironment stimulates motility/invasion in human breast cancer cells via activation of the Na(+)–H(+ )exchanger (NHE) isoform 1, but the signal transduction systems that underlie this process are still poorly understood. We undertook the present study to elucidate the role and pattern of regulation by the Rho GTPases of this serum deprivation-dependent activation of both NHE1 and subsequent invasive characteristics, such as pseudopodia and invadiopodia protrusion, directed cell motility and penetration of normal tissues. METHODS: The present study was performed in a well characterized human mammary epithelial cell line representing late stage metastatic progression, MDA-MB-435. The activity of RhoA and Rac1 was modified using their dominant negative and constitutively active mutants and the activity of NHE1, cell motility/invasion, F-actin content and cell shape were measured. RESULTS: We show for the first time that serum deprivation induces NHE1-dependent morphological and cytoskeletal changes in metastatic cells via a reciprocal interaction of RhoA and Rac1, resulting in increased chemotaxis and invasion. Deprivation changed cell shape by reducing the amount of F-actin and inducing the formation of leading edge pseudopodia. Serum deprivation inhibited RhoA activity and stimulated Rac1 activity. Rac1 and RhoA were antagonistic regulators of both basal and stimulated tumour cell NHE1 activity. The regulation of NHE1 activity by RhoA and Rac1 in both conditions was mediated by an alteration in intracellular proton affinity of the exchanger. Interestingly, the role of each of these G-proteins was reversed during serum deprivation; basal NHE1 activity was regulated positively by RhoA and negatively by Rac1, whereas RhoA negatively and Rac1 positively directed the stimulation of NHE1 during serum deprivation. Importantly, the same pattern of RhoA and Rac1 regulation found for NHE1 activity was observed in both basal and serum deprivation dependent increases in motility, invasion and actin cytoskeletal organization. CONCLUSION: Our findings suggest that the reported antagonistic roles of RhoA and Rac1 in cell motility/invasion and cytoskeletal organization may be due, in part, to their concerted action on NHE1 activity as a convergence point