Kidney podocytes and their slit diaphragms form the final barrier to urinary protein loss. This explains why podocyte injury is typically associated with nephrotic syndrome. The present study uncovered an unanticipated novel role for costimulatory molecule B7-1 in podocytes as an inducible modifier of glomerular permselectivity. B7-1 in podocytes was found in genetic, drug-induced, immune-mediated, and bacterial toxin-induced experimental kidney diseases with nephrotic syndrome. The clinical significance of our results is underscored by the observation that podocyte expression of B7-1 correlated with the severity of human lupus nephritis. In vivo, exposure to low-dose LPS rapidly upregulates B7-1 in podocytes of WT and SCID mice, leading to nephrotic-range proteinuria. Mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, suggesting a link between podocyte B7-1 expression and proteinuria. LPS signaling through toll-like receptor-4 reorganized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes led to reorganization of vital slit diaphragm proteins. In summary, upregulation of B7-1 in podocytes may contribute to the pathogenesis of proteinuria by disrupting the glomerular filter and provides a novel molecular target to tackle proteinuric kidney diseases. Our findings suggest a novel function for B7-1 in danger signaling by nonimmune cells. 1390The Nonstandard abbreviations used: foot process (FP); glomerular basement membrane (GBM); puromycin aminonucleoside (PAN); slit diaphragm (SD); toll-like receptor (TLR).

Transforming growth factor-␤ (TGF-␤) signaling proceeds from the cell membrane to the nucleus through the cooperation of the type I and II serine/threonine kinase receptors and their downstream SMAD effectors. Although various regulatory proteins affecting TGF-␤-mediated events have been described, relatively little is known about receptor interactions at the level of the plasma membrane. Caveolae are cholesterol-rich membrane microdomains that, along with their marker protein caveolin-1 (Cav-1), have been implicated in the compartmentalization and regulation of certain signaling events. Here, we demonstrate that specific components of the TGF-␤ cascade are associated with caveolin-1 in caveolae and that Cav-1 interacts with the Type I TGF-␤ receptor. Additionally, Cav-1 is able to suppress TGF-␤-mediated phosphorylation of Smad-2 and subsequent downstream events. We localize the Type I TGF-␤ receptor interaction to the scaffolding domain of Cav-1 and show that it occurs in a physiologically relevant time frame, acting to rapidly dampen signaling initiated by the TGF-␤ receptor complex.

No-scale models arise in many compactifications of string theory and supergravity, the most prominent recent example being type IIB flux compactifications. Focussing on the case where the no-scale field is a single unstabilized volume modulus (radion), we analyse the general form of supergravity loop corrections that affect the no-scale structure of the Kähler potential. These corrections contribute to the 4d scalar potential of the radion in a way that is similar to the Casimir effect. We discuss the interplay of this loop effect with string-theoretic α ′ corrections and its possible role in the stabilization of the radion.

Kidney podocytes and their slit diaphragms form the final barrier to urinary protein loss. This explains why podocyte injury is typically associated with nephrotic syndrome. The present study uncovered an unanticipated novel role for costimulatory molecule B7-1 in podocytes as an inducible modifier of glomerular permselectivity. B7-1 in podocytes was found in genetic, drug-induced, immune-mediated, and bacterial toxin–induced experimental kidney diseases with nephrotic syndrome. The clinical significance of our results is underscored by the observation that podocyte expression of B7-1 correlated with the severity of human lupus nephritis. In vivo, exposure to low-dose LPS rapidly upregulates B7-1 in podocytes of WT and SCID mice, leading to nephrotic-range proteinuria. Mice lacking B7-1 are protected from LPS-induced nephrotic syndrome, suggesting a link between podocyte B7-1 expression and proteinuria. LPS signaling through toll-like receptor-4 reorganized the podocyte actin cytoskeleton in vitro, and activation of B7-1 in cultured podocytes led to reorganization of vital slit diaphragm proteins. In summary, upregulation of B7-1 in podocytes may contribute to the pathogenesis of proteinuria by disrupting the glomerular filter and provides a novel molecular target to tackle proteinuric kidney diseases. Our findings suggest a novel function for B7-1 in danger signaling by nonimmune cells

The Kosterlitz-Thouless phase transition is described by the nonperturbative renormalization flow of the two dimensional ϕ 4 -model. The observation of essential scaling demonstrates that the flow equation incorporates nonperturbative effects which have previously found an alternative description in terms of vortices. The duality between the linear and nonlinear σ-model gives a unified description of the long distance behaviour for O(N )-models in arbitrary dimension d. We compute critical exponents in first order in the derivative expansion. FhThe Kosterlitz-Thouless phase transition [1] may describe the critical behaviour of various two dimensional systems. It poses a challenge to our theoretical understanding due to several uncommon features. The low temperature phase exhibits a massless Goldstone boson like excitation despite the fact that the global U (1) symmetry is not spontaneously broken by a standard order parameter. In this phase the critical exponents depend on the temperature. In the high temperature phase the approach to the transition is not governed by critical exponents but rather by essential scaling. Modern nonperturbative renormalization group methods have described the characteristic properties of the low temperature phase qualitatively [2]. In this letter we extend this analysis to the essential scaling in the high temperature phase and provide for a quantitatively accurate discussion of the low temperature phase. We present a universal renormalization group description of models with O(N ) symmetry in arbritrary dimension.We employ the concept of the effective average action Γ k [3], which equals the effective action Γ apart from the fact that in the former only fluctuations with momenta larger than k are included. For large momentum scales Γ k therefore equals some appropriately regularized microscopic action while for k = 0 we have Γ 0 = Γ. Thus Γ k interpolates between microscopic and macroscopic scales. Since Γ is the generating functional for the 1PI correlation functions it specifies directly the quantities of interest like the correlation length ξ = m −1 R . The flow of Γ k is obeys an exact renormalization group equation [3],Here Γ (2) k is the second functional derivative, ∂ t denotes the logarithmic derivative k · ∂/∂k and the trace (in momentum space) reads Tr = N a=1 d d q/(2π) d . The cutoff R k (q 2 ) suppresses the low momentum modes. We use a cutoff of the formwhere the wave function renormalization Z k will be fixed later. In order to solve equation (1) numerically one has to truncate the most general form of Γ k . We introduce dimensionless, renormalized fields,φ a = Z 1/2 k k (2−d)/2 ϕ a , ρ = (1/2)φ aφa and parametrize Γ k in first order in a derivative expansion byThe flow of Γ k is then given by the flow of the quantities u, z andỹ which are dimensionless and depend only on the O(N )-invariantρ and on k. We denote by κ the running minimum of the potential u k (ρ) and fix Z k by requiring z k (κ) = 1.The partial differential equations [3-5]

We propose a general class of five-dimensional soft-wall models with AdS metric near the ultraviolet brane and four-dimensional Poincaré invariance, where the infrared scale is determined dynamically. A large UV/IR hierarchy can be generated without any fine-tuning, thus solving the electroweak/Planck scale hierarchy problem. Generically, the spectrum of fluctuations is discrete with a level spacing (mass gap) provided by the inverse length of the wall, similar to RS1 models with Standard Model fields propagating in the bulk. Moreover two particularly interesting cases arise. They can describe: (a) a theory with a continuous spectrum above the mass gap which can model unparticles corresponding to operators of a CFT where the conformal symmetry is broken by a mass gap, and; (b) a theory with a discrete spectrum provided by linear Regge trajectories as in AdS/QCD models.

We have computed one-loop bulk and brane mass renormalization effects in a five-dimensional gauge theory compactified on the M_4 \times S^1/Z_2 orbifold, where an arbitrary gauge group G is broken by the orbifold action to its subgroup H. The space-time components of the gauge boson zero modes along the H generators span the gauge theory on the orbifold fixed point branes while the zero modes of the higher-dimensional components of the gauge bosons along the G/H generators play the role of Higgs fields with respect to the gauge group H. No quadratic divergences in the mass renormalization of the gauge and Higgs fields are found either in the bulk or on the branes. All brane effects for the Higgs field masses vanish (only wave function renormalization effects survive) while bulk effects are finite and can trigger, depending on the fermionic content of the theory, spontaneous Hosotani breaking of the brane gauge group H. For the gauge fields we do find logarithmic divergences corresponding to mass renormalization of their heavy Kaluza-Klein modes. Two-loop brane effects for Higgs field masses are expected from wave function renormalization brane effects inserted into finite bulk mass corrections.Comment: 31 pages, uses axodraw.sty and mcite.st

We elaborate on a recently proposed mechanism to suppress large contributions to the electroweak precision observables in five dimensional (5D) warped models, without the need for an extended 5D gauge sector. The main ingredient is a modification of the AdS metric in the vicinity of the infrared (IR) brane corresponding to a strong deviation from conformality in the IR of the 4D holographic dual. We compute the general low energy effective theory of the 5D warped Standard Model, emphasizing additional IR contributions to the wave function renormalization of the light Higgs mode. We also derive expressions for the S and T parameters as a function of a generic 5D metric and zero-mode wave functions. We give an approximate formula for the mass of the radion that works even for strong deviation from the AdS background. We proceed to work out the details of an explicit model and derive bounds for the first KK masses of the various bulk fields. The radion is the lightest new particle although its mass is already at about 1/3 of the mass of the lightest resonances, the KK states of the gauge bosons. We examine carefully various issues that can arise for extreme choices of parameters such as the possible reintroduction of the hierarchy problem, the onset of nonperturbative physics due to strong IR curvature or the creation of new hierarchies near the Planck scale. We conclude that a KK scale of 1 TeV is compatible with all these constraints.