Induction of Epidermal Growth Factor Receptor Expression by Epstein-Barr Virus Latent Membrane Protein 1 C-Terminal-Activating Region 1 Is Mediated by NF- B p50 Homodimer/Bcl-3 Complexes

The Epstein-Barr virus (EBV) is associated with the development of numerous malignancies, including the epithelial malignancy nasopharyngeal carcinoma (NPC). The viral oncoprotein latent membrane protein 1 (LMP1) is expressed in almost all EBV-associated malignancies and has profound effects on gene expression. LMP1 acts as a constitutively active tumor necrosis factor receptor and activates multiple forms of the NF-κB family of transcription factors. LMP1 has two domains that both activate NF-κB. In epithelial cells, LMP1 C-terminal activating region 1 (CTAR1) uniquely activates p50/p50-, p50/p52-, and p65-containing complexes while CTAR2 activates canonical p50/p65 complexes. CTAR1 also uniquely upregulates the epidermal growth factor receptor (EGFR). In NPC, NF-κB p50/p50 homodimers and the transactivator Bcl-3 were detected on the EGFR promoter. In this study, the role of NF-κB p50 and Bcl-3 in LMP1-mediated upregulation of EGFR was analyzed. In LMP1-CTAR1-expressing cells, chromatin immunoprecipitation detected p50 and Bcl-3 on the NF-κB consensus sites within the egfr promoter. Transient overexpression of p50 and Bcl-3 increased EGFR expression, confirming the regulation of EGFR by these factors. Treatment with p105/p50 siRNA effectively reduced p105/p50 levels but unexpectedly increased Bcl-3 expression and levels of p50/Bcl-3 complexes, resulting in increased EGFR expression. These data suggest that induction of p50/p50/Bcl-3 complexes by LMP1 CTAR1 mediates LMP1-induced EGFR upregulation and that formation of the p50/p50/Bcl-3 complex is negatively regulated by the p105 precursor. The distinct forms of NF-κB that are induced by LMP1 CTAR1 likely activate distinct cellular genes

Identification of Epstein-Barr Virus RK-BARF0-Interacting Proteins and Characterization of Expression Pattern

The Epstein-Barr virus (EBV) BamHI A transcripts are a family of transcripts that are differentially spliced and can be detected in multiple EBV-associated malignancies. Several of the transcripts may encode proteins. One transcript of interest, RK-BARF0, is proposed to encode a 279-amino-acid protein with a possible endoplasmic reticulum-targeting sequence. In this study, the properties of RK-BARF0 were examined through identification of cellular-interacting proteins through yeast two-hybrid analysis and characterization of its expression in EBV-infected cells and tumors. In addition to the interaction previously identified with cellular Notch, it was determined that RK-BARF0 also bound cellular human I-mfa domain-containing protein (HIC), epithelin, and scramblase. An interaction between RK-BARF0 and Notch or epithelin induced proteasome-dependent degradation of Notch and epithelin but not of HIC or scramblase. Low levels of endogenous Notch expression in EBV-positive cell lines may correlate with RK-BARF0 expression. However, a screen of EBV-positive cell lines and tumors with an affinity-purified α-RK-BARF0 antiserum did not consistently detect RK-BARF0. These data suggest that while RK-BARF0 may have important cellular functions during EBV infection, and while the phenotype of EBV-positive cells suggest its expression, RK-BARF0 levels may be too low to detect

Study of multi black hole and ring singularity apparent horizons

We study critical black hole separations for the formation of a common apparent horizon in systems of $N$ - black holes in a time symmetric configuration. We study in detail the aligned equal mass cases for $N=2,3,4,5$, and relate them to the unequal mass binary black hole case. We then study the apparent horizon of the time symmetric initial geometry of a ring singularity of different radii. The apparent horizon is used as indicative of the location of the event horizon in an effort to predict a critical ring radius that would generate an event horizon of toroidal topology. We found that a good estimate for this ring critical radius is $20/(3\pi) M$. We briefly discuss the connection of this two cases through a discrete black hole 'necklace' configuration.Comment: 31 pages, 21 figure

Numerical relativity with characteristic evolution, using six angular patches

The characteristic approach to numerical relativity is a useful tool in evolving gravitational systems. In the past this has been implemented using two patches of stereographic angular coordinates. In other applications, a six-patch angular coordinate system has proved effective. Here we investigate the use of a six-patch system in characteristic numerical relativity, by comparing an existing two-patch implementation (using second-order finite differencing throughout) with a new six-patch implementation (using either second- or fourth-order finite differencing for the angular derivatives). We compare these different codes by monitoring the Einstein constraint equations, numerically evaluated independently from the evolution. We find that, compared to the (second-order) two-patch code at equivalent resolutions, the errors of the second-order six-patch code are smaller by a factor of about 2, and the errors of the fourth-order six-patch code are smaller by a factor of nearly 50.Comment: 12 pages, 5 figures, submitted to CQG (special NFNR issue

Generic effective source for scalar self-force calculations

A leading approach to the modelling of extreme mass ratio inspirals involves the treatment of the smaller mass as a point particle and the computation of a regularized self-force acting on that particle. In turn, this computation requires knowledge of the regularized retarded field generated by the particle. A direct calculation of this regularized field may be achieved by replacing the point particle with an effective source and solving directly a wave equation for the regularized field. This has the advantage that all quantities are finite and require no further regularization. In this work, we present a method for computing an effective source which is finite and continuous everywhere, and which is valid for a scalar point particle in arbitrary geodesic motion in an arbitrary background spacetime. We explain in detail various technical and practical considerations that underlie its use in several numerical self-force calculations. We consider as examples the cases of a particle in a circular orbit about Schwarzschild and Kerr black holes, and also the case of a particle following a generic time-like geodesic about a highly spinning Kerr black hole. We provide numerical C code for computing an effective source for various orbital configurations about Schwarzschild and Kerr black holes.Comment: 24 pages, 7 figures, final published versio

BSSN in Spherical Symmetry

The BSSN (Baumgarte-Shapiro-Shibata-Nakamura) formulation of the Einstein evolution equations is written in spherical symmetry. These equations can be used to address a number of technical and conceptual issues in numerical relativity in the context of a single Schwarzschild black hole. One of the benefits of spherical symmetry is that the numerical grid points can be tracked on a Kruskal--Szekeres diagram. Boundary conditions suitable for puncture evolution of a Schwarzschild black hole are presented. Several results are shown for puncture evolution using a fourth--order finite difference implementation of the equations.Comment: This is the final version to be published in CQG. It contains much more information and detail than the original versio

Are moving punctures equivalent to moving black holes?

When simulating the inspiral and coalescence of a binary black-hole system, special care needs to be taken in handling the singularities. Two main techniques are used in numerical-relativity simulations: A first and more traditional one ``excises'' a spatial neighbourhood of the singularity from the numerical grid on each spacelike hypersurface. A second and more recent one, instead, begins with a ``puncture'' solution and then evolves the full 3-metric, including the singular point. In the continuum limit, excision is justified by the light-cone structure of the Einstein equations and, in practice, can give accurate numerical solutions when suitable discretizations are used. However, because the field variables are non-differentiable at the puncture, there is no proof that the moving-punctures technique is correct, particularly in the discrete case. To investigate this question we use both techniques to evolve a binary system of equal-mass non-spinning black holes. We compare the evolution of two curvature 4-scalars with proper time along the invariantly-defined worldline midway between the two black holes, using Richardson extrapolation to reduce the influence of finite-difference truncation errors. We find that the excision and moving-punctures evolutions produce the same invariants along that worldline, and thus the same spacetimes throughout that worldline's causal past. This provides convincing evidence that moving-punctures are indeed equivalent to moving black holes.Comment: 4 pages, 3 eps color figures; v2 = major revisions to introduction & conclusions based on referee comments, but no change in analysis or result

Initial Data and Coordinates for Multiple Black Hole Systems

We present here an alternative approach to data setting for spacetimes with multiple moving black holes generalizing the Kerr-Schild form for rotating or non-rotating single black holes to multiple moving holes. Because this scheme preserves the Kerr-Schild form near the holes, it selects out the behaviour of null rays near the holes, may simplify horizon tracking, and may prove useful in computational applications. For computational evolution, a discussion of coordinates (lapse function and shift vector) is given which preserves some of the properties of the single-hole Kerr-Schild form

Black Hole--Scalar Field Interactions in Spherical Symmetry

We examine the interactions of a black hole with a massless scalar field using a coordinate system which extends ingoing Eddington-Finkelstein coordinates to dynamic spherically symmetric-spacetimes. We avoid problems with the singularity by excising the region of the black hole interior to the apparent horizon. We use a second-order finite difference scheme to solve the equations. The resulting program is stable and convergent and will run forever without problems. We are able to observe quasi-normal ringing and power-law tails as well an interesting nonlinear feature.Comment: 16 pages, 26 figures, RevTex, to appear in Phys. Rev.

A template bank for gravitational waveforms from coalescing binary black holes: non-spinning binaries

Gravitational waveforms from the inspiral and ring-down stages of the binary black hole coalescences can be modelled accurately by approximation/perturbation techniques in general relativity. Recent progress in numerical relativity has enabled us to model also the non-perturbative merger phase of the binary black-hole coalescence problem. This enables us to \emph{coherently} search for all three stages of the coalescence of non-spinning binary black holes using a single template bank. Taking our motivation from these results, we propose a family of template waveforms which can model the inspiral, merger, and ring-down stages of the coalescence of non-spinning binary black holes that follow quasi-circular inspiral. This two-dimensional template family is explicitly parametrized by the physical parameters of the binary. We show that the template family is not only \emph{effectual} in detecting the signals from black hole coalescences, but also \emph{faithful} in estimating the parameters of the binary. We compare the sensitivity of a search (in the context of different ground-based interferometers) using all three stages of the black hole coalescence with other template-based searches which look for individual stages separately. We find that the proposed search is significantly more sensitive than other template-based searches for a substantial mass-range, potentially bringing about remarkable improvement in the event-rate of ground-based interferometers. As part of this work, we also prescribe a general procedure to construct interpolated template banks using non-spinning black hole waveforms produced by numerical relativity.Comment: A typo fixed in Eq.(B11