The HIV Matrix Protein p17 Subverts Nuclear Receptors Expression and Induces a STAT1-Dependent Proinflammatory Phenotype in Monocytes

BACKGROUND: Long-term remission of HIV-1 disease can be readily achieved by combinations of highly effective antiretroviral therapy (HAART). However, a residual persistent immune activation caused by circulating non infectious particles or viral proteins is observed under HAART and might contribute to an higher risk of non-AIDS pathologies and death in HIV infected persons. A sustained immune activation supports lipid dysmetabolism and increased risk for development of accelerated atehrosclerosis and ischemic complication in virologically suppressed HIV-infected persons receiving HAART. AIM: While several HIV proteins have been identified and characterized for their ability to maintain immune activation, the role of HIV-p17, a matrix protein involved in the viral replication, is still undefined. RESULTS: Here, we report that exposure of macrophages to recombinant human p17 induces the expression of proinflammatory and proatherogenic genes (MCP-1, ICAM-1, CD40, CD86 and CD36) while downregulating the expression of nuclear receptors (FXR and PPARγ) that counter-regulate the proinflammatory response and modulate lipid metabolism in these cells. Exposure of macrophage cell lines to p17 activates a signaling pathway mediated by Rack-1/Jak-1/STAT-1 and causes a promoter-dependent regulation of STAT-1 target genes. These effects are abrogated by sera obtained from HIV-infected persons vaccinated with a p17 peptide. Ligands for FXR and PPARγ counteract the effects of p17. CONCLUSIONS: The results of this study show that HIV p17 highjacks a Rack-1/Jak-1/STAT-1 pathway in macrophages, and that the activation of this pathway leads to a simultaneous dysregulation of immune and metabolic functions. The binding of STAT-1 to specific responsive elements in the promoter of PPARγ and FXR and MCP-1 shifts macrophages toward a pro-atherogenetic phenotype characterized by high levels of expression of the scavenger receptor CD36. The present work identifies p17 as a novel target in HIV therapy and grounds the development of anti-p17 small molecules or vaccines

New constraint on the existence of the mu+-> e+ gamma decay

The analysis of a combined data set, totaling 3.6 \times 10^14 stopped muons on target, in the search for the lepton flavour violating decay mu^+ -> e^+ gamma is presented. The data collected by the MEG experiment at the Paul Scherrer Institut show no excess of events compared to background expectations and yield a new upper limit on the branching ratio of this decay of 5.7 \times 10^-13 (90% confidence level). This represents a four times more stringent limit than the previous world best limit set by MEG.Comment: 5 pages, 3 figures, a version accepted in Phys. Rev. Let

MEG Upgrade Proposal

We propose the continuation of the MEG experiment to search for the charged lepton flavour violating decay (cLFV) \mu \to e \gamma, based on an upgrade of the experiment, which aims for a sensitivity enhancement of one order of magnitude compared to the final MEG result, down to the $6 \times 10^{-14}$ level. The key features of this new MEG upgrade are an increased rate capability of all detectors to enable running at the intensity frontier and improved energy, angular and timing resolutions, for both the positron and photon arms of the detector. On the positron-side a new low-mass, single volume, high granularity tracker is envisaged, in combination with a new highly segmented, fast timing counter array, to track positron from a thinner stopping target. The photon-arm, with the largest liquid xenon (LXe) detector in the world, totalling 900 l, will also be improved by increasing the granularity at the incident face, by replacing the current photomultiplier tubes (PMTs) with a larger number of smaller photosensors and optimizing the photosensor layout also on the lateral faces. A new DAQ scheme involving the implementation of a new combined readout board capable of integrating the diverse functions of digitization, trigger capability and splitter functionality into one condensed unit, is also under development. We describe here the status of the MEG experiment, the scientific merits of the upgrade and the experimental methods we plan to use.Comment: A. M. Baldini and T. Mori Spokespersons. Research proposal submitted to the Paul Scherrer Institute Research Committee for Particle Physics at the Ring Cyclotron. 131 Page

The MEG detector for μ+→e+γ{\mu}+\to e+{\gamma} decay search

The MEG (Mu to Electron Gamma) experiment has been running at the Paul Scherrer Institut (PSI), Switzerland since 2008 to search for the decay \meg\ by using one of the most intense continuous $\mu^+$ beams in the world. This paper presents the MEG components: the positron spectrometer, including a thin target, a superconducting magnet, a set of drift chambers for measuring the muon decay vertex and the positron momentum, a timing counter for measuring the positron time, and a liquid xenon detector for measuring the photon energy, position and time. The trigger system, the read-out electronics and the data acquisition system are also presented in detail. The paper is completed with a description of the equipment and techniques developed for the calibration in time and energy and the simulation of the whole apparatus.Comment: 59 pages, 90 figure

Measurement of the radiative decay of polarized muons in the MEG experiment

We studied the radiative muon decay $\mu^+ \to e^+\nu\bar{\nu}\gamma$ by using for the first time an almost fully polarized muon source. We identified a large sample (~13000) of these decays in a total sample of 1.8x10^14 positive muon decays collected in the MEG experiment in the years 2009--2010 and measured the branching ratio B($\mu^+ \to e^+\nu\bar{\nu}\gamma$) = (6.03+-0.14(stat.)+-0.53(sys.))x10^-8 for E_e > 45 MeV and E_{\gamma} > 40 MeV, consistent with the Standard Model prediction. The precise measurement of this decay mode provides a basic tool for the timing calibration, a normalization channel, and a strong quality check of the complete MEG experiment in the search for $\mu^+ \to e^+\gamma$ process.Comment: 8 pages, 7 figures. Added an introduction to NLO calculation which was recently calculated. Published versio

Gas Distribution and Monitoring for the Drift Chamber of the MEG-II Experiment

The reconstruction of the positron trajectory in the MEG-II experiment searching for the $\mu^+ \to e^+ \gamma$ decay uses a cylindrical drift chamber operated with a helium-isobutane gas mixture. A stable performance of the detector in terms of its electron drift properties, avalanche multiplication, and with a gas mixture of controlled composition and purity has to be provided and continuously monitored. In this paper we describe the strategies adopted to meet the requirements imposed by the target sensitivity of MEG-II, including the construction and commissioning of a small chamber for an online monitoring of the gas quality.Comment: 12 pages, 6 figures, submitted to Journal of Instrumentatio

Evidence for the η_b(1S) Meson in Radiative Υ(2S) Decay

We have performed a search for the η_b(1S) meson in the radiative decay of the Υ(2S) resonance using a sample of 91.6 × 10^6 Υ(2S) events recorded with the BABAR detector at the PEP-II B factory at the SLAC National Accelerator Laboratory. We observe a peak in the photon energy spectrum at E_γ = 609.3^(+4.6)_(-4.5)(stat)±1.9(syst) MeV, corresponding to an η_b(1S) mass of 9394.2^(+4.8)_(-4.9)(stat) ± 2.0(syst) MeV/c^2. The branching fraction for the decay Υ(2S) → γη_b(1S) is determined to be [3.9 ± 1.1(stat)^(+1.1)_(-0.9)(syst)] × 10^(-4). We find the ratio of branching fractions B[Υ(2S) → γη_b(1S)]/B[Υ(3S) → γη_b(1S)]= 0.82 ± 0.24(stat)^(+0.20)_(-0.19)(syst)

The measuring systems of the wire tension for the MEG II Drift Chamber by means of the resonant frequency technique

The ultra-low mass Cylindrical Drift Chamber designed for the MEG experiment upgrade is a challenging apparatus made of 1728 phi = 20 micron gold plated tungsten sense wires, 7680 phi = 40 micron and 2496 phi = 50 micron silver plated aluminum field wires. Because of electrostatic stability requirements all the wires have to be stretched at mechanical tensions of about 25, 19 and 29 g respectively which must be controlled at a level better than 0.5 g. This chamber is presently in acquisition, but during its construction about 100 field wires broke, because of chemical corrosion induced by the atmospheric humidity. On the basis of the experience gained with this chamber we decided to build a new one, equipped with a different type of wires less sensitive to corrosion. The choice of the new wire required a deep inspection of its characteristics and one of the main tools for doing this is a system for measuring the wire tension by means of the resonant frequency technique, which is described in this paper. The system forces the wires to oscillate by applying a sinusoidal signal at a known frequency, and then measures the variation of the capacitance between a wire and a common ground plane as a function of the external signal frequency. We present the details of the measuring system and the results obtained by scanning the mechanical tensions of two samples of MEG II CDCH wires and discuss the possible improvements of the experimental apparatus and of the measuring technique.Comment: Ten pages, twelve figures, to be submitted to Nuclear Instruments and Methods

Discovery That Theonellasterol a Marine Sponge Sterol Is a Highly Selective FXR Antagonist That Protects against Liver Injury in Cholestasis

Background: The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated genes and biological functions. Principal Findings: Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic FXR agonists on FXR-regulated genes, including SHP, OSTa, BSEP and MRP4. A proof-of-concept study carried out to investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed to rescue from liver injury and downregulated the expression of MRP4. Conclusions: FXR antagonism in vivo results in a positive modulation of MRP4 expression in the liver and is a feasible strategy to target obstructive cholestasis