574 research outputs found
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
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 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 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 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() =
(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 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 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
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