Deregulation of HDAC5 by Viral Interferon Regulatory Factor 3 Plays an Essential Role in Kaposi's Sarcoma-Associated Herpesvirus-Induced Lymphangiogenesis.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi's sarcoma (KS), which is one of the most common HIV-associated neoplasms. The endothelium is the thin layer of squamous cells where vascular blood endothelial cells (BECs) line the interior surface of blood vessels and lymphatic endothelial cells (LECs) are in direct contact with lymphatic vessels. The KS lesions contain a prominent compartment of neoplastic spindle morphology cells that are closely related to LECs. Furthermore, while KSHV can infect both LECs and BECs in vitro, its infection activates genetic programming related to lymphatic endothelial cell fate, suggesting that lymphangiogenic pathways are involved in KSHV infection and malignancy. Here, we report for the first time that viral interferon regulatory factor 3 (vIRF3) is readily detected in over 40% of KS lesions and that vIRF3 functions as a proangiogenic factor, inducing hypersprouting formation and abnormal growth in a LEC-specific manner. Mass spectrometry analysis revealed that vIRF3 interacted with histone deacetylase 5 (HDAC5), which is a signal-responsive regulator for vascular homeostasis. This interaction blocked the phosphorylation-dependent cytosolic translocation of HDAC5 and ultimately altered global gene expression in LECs but not in BECs. Consequently, vIRF3 robustly induced spindle morphology and hypersprouting formation of LECs but not BECs. Finally, KSHV infection led to the hypersprouting formation of LECs, whereas infection with a ΔvIRF3 mutant did not do so. Collectively, our data indicate that vIRF3 alters global gene expression and induces a hypersprouting formation in an HDAC5-binding-dependent and LEC-specific manner, ultimately contributing to KSHV-associated pathogenesis.IMPORTANCE Several lines of evidences indicate that KSHV infection of LECs induces pathological lymphangiogenesis and that the results resemble KS-like spindle morphology. However, the underlying molecular mechanism remains unclear. Here, we demonstrated that KSHV vIRF3 is readily detected in over 40% of various KS lesions and functions as a potent prolymphangiogenic factor by blocking the phosphorylation-dependent cytosolic translocation of HDAC5, which in turn modulates global gene expression in LECs. Consequently, vIRF3-HDAC5 interaction contributes to virus-induced lymphangiogenesis. The results of this study suggest that KSHV vIRF3 plays a crucial role in KSHV-induced malignancy

A Class of Topological Actions

We review definitions of generalized parallel transports in terms of Cheeger-Simons differential characters. Integration formulae are given in terms of Deligne-Beilinson cohomology classes. These representations of parallel transport can be extended to situations involving distributions as is appropriate in the context of quantized fields.Comment: 41 pages, no figure

Realistic Equations of State for the Primeval Universe

Early universe equations of state including realistic interactions between constituents are built up. Under certain reasonable assumptions, these equations are able to generate an inflationary regime prior to the nucleosynthesis period. The resulting accelerated expansion is intense enough to solve the flatness and horizon problems. In the cases of curvature parameter \kappa equal to 0 or +1, the model is able to avoid the initial singularity and offers a natural explanation for why the universe is in expansion.Comment: 32 pages, 5 figures. Citations added in this version. Accepted EPJ

Conservation laws and scattering for de Sitter classical particles

Starting from an intrinsic geometric characterization of de Sitter timelike and lightlike geodesics we give a new description of the conserved quantities associated with classical free particles on the de Sitter manifold. These quantities allow for a natural discussion of classical pointlike scattering and decay processes. We also provide an intrinsic definition of energy of a classical de Sitter particle and discuss its different expressions in various local coordinate systems and their relations with earlier definitions found in the literature.Comment: 25 pages, 1 figur

Cosmic acceleration from second order gauge gravity

We construct a phenomenological theory of gravitation based on a second order gauge formulation for the Lorentz group. The model presents a long-range modification for the gravitational field leading to a cosmological model provided with an accelerated expansion at recent times. We estimate the model parameters using observational data and verify that our estimative for the age of the Universe is of the same magnitude than the one predicted by the standard model. The transition from the decelerated expansion regime to the accelerated one occurs recently (at $\sim9.3\;Gyr$).Comment: RevTex4 15 pages, 1 figure. Accepted for publication in Astrophysics & Space Scienc

Does Quantum Mechanics Clash with the Equivalence Principle - and Does it Matter?

With an eye on developing a quantum theory of gravity, many physicists have recently searched for quantum challenges to the equivalence principle of general relativity. However, as historians and philosophers of science are well aware, the principle of equivalence is not so clear. When clarified, we think quantum tests of the equivalence principle won't yield much. The problem is that the clash/not-clash is either already evident or guaranteed not to exist. Nonetheless, this work does help teach us what it means for a theory to be geometric.Comment: 12 page

Extended High-Ionization Nuclear Emission-Line Region in the Seyfert Galaxy NGC 4051

We present an optical spectroscopic analysis of the well-known Seyfert galaxy NGC 4051. The high-ionization nuclear emission-line region (HINER) traced by [Fe X]6374 is found to be spatially extended to a radius of 3a rcseconds (150 pc) west and southwest from the nucleus; NGC 4051 is the third example which has an extended HINER. The nuclear spectrum shows that the flux of [Fe X]6374 is stronger than that of [Fe VII] 6087 in our observation. This property cannot be interpreted in terms of a simple one-zone photoionization model. In order to understand what happens in the nuclear region in NGC 4051, we investigate the physical condition of the nuclear emission-line region in detail using new photoionization models in which the following three emission-line components are taken into account; (1) optically thick, ionization-bounded clouds; (2) optically thin, matter-bounded clouds; and (3) a contamination component which emits H$\alpha$ and H$\beta$ lines. Here the observed extended HINER is considered to be associated with the low-density, matter-bounded clouds. Candidates of the contamination component are either the broad-line region (BLR) or nuclear star forming regions or both. The complexity of the excitation condition found in NGC 4051 can be consistently understood if we take account of these contamination components.Comment: 16 pages, including figures. To Appear in the Astronomical Journal February 2000 Issu

Interacting Constituents in Cosmology

Universe evolution, as described by Friedmann's equations, is determined by source terms fixed by the choice of pressure $\times$ energy-density equations of state $p(\rho)$. The usual approach in Cosmology considers equations of state accounting only for kinematic terms, ignoring the contribution from the interactions between the particles constituting the source fluid. In this work the importance of these neglected terms is emphasized. A systematic method, based on the Statistical Mechanics of real fluids, is proposed to include them. A toy-model is presented which shows how such interaction terms can engender significant cosmological effects.Comment: 24 pages, 6 figures. It includes results presented in "Cosmic Acceleration from Elementary Interactions" [arXiv:gr-qc/0512135]. Citations added in v.

Lie algebroid cohomology and Lie algebroid extensions

We consider the extension problem for Lie algebroids over schemes over a field. Given a locally free Lie algebroid Q over a scheme X, and a coherent sheaf of Lie OX-algebras L, we determine the obstruction to the existence of extensions 0\u2192L\u2192E\u2192Q\u21920, and classify the extensions in terms of a suitable Lie algebroid hypercohomology group. In the preliminary sections we study free Lie algebroids and recall some basic facts about Lie algebroid hypercohomology

Topology at the Planck Length

A basic arbitrariness in the determination of the topology of a manifold at the Planck length is discussed. An explicit example is given of a `smooth' change in topology from the 2-sphere to the 2-torus through a sequence of noncommuting geometries. Applications are considered to the theory of D-branes within the context of the proposed $M$(atrix) theory.Comment: Orsay Preprint 97/34, 17 pages, Late