Hepatitis C virus production requires apolipoprotein A-I and affects its association with nascent low-density lipoproteins

Background/aims The life cycle of hepatitis C virus (HCV) is intimately linked to the lipid metabolism of the host. In particular, HCV exploits the metabolic machinery of the lipoproteins in several steps of its life cycle such as circulation in the bloodstream, cell attachment and entry, assembly and release of viral particles. However, the details of how HCV interacts with and influences the metabolism of the host lipoproteins are not well understood. A study was undertaken to investigate whether HCV directly affects the protein composition of host circulating lipoproteins. Methods A proteomic analysis of circulating very low-, low- and high-density lipoproteins (VLDL, LDL and HDL), isolated from either in-treatment naive HCV-infected patients or healthy donors (HD), was performed using two-dimensional gel electrophoresis and tandem mass spectrometry (MALDI-TOF/TOF). The results obtained were further investigated using in vitro models of HCV infection and replication. Results A decreased level of apolipoprotein A-I (apoA-I) was found in the LDL fractions of HCV-infected patients. This result was confirmed by western blot and ELISA analysis. HCV cellular models (JFH1 HCV cell culture system (HCVcc) and HCV subgenomic replicons) showed that the decreased apoA-I/LDL association originates from hepatic biogenesis rather than lipoprotein catabolism occurring in the circulation, and is not due to a downregulation of the apoA-I protein concentration. The sole non-structural viral proteins were sufficient to impair the apoA-I/LDL association. Functional evidence was obtained for involvement of apoA-I in the viral life cycle such as RNA replication and virion production. The specific siRNA-mediated downregulation of apoA-I led to a reduction in both HCV RNA and viral particle levels in culture. Conclusions This study shows that HCV induces lipoprotein structural modification and that its replication and production are linked to the host lipoprotein metabolism, suggesting apoA-I as a new possible target for antiviral therapy

PEN: a low energy test of lepton universality

Allowed charged $\pi$ meson decays are characterized by simple dynamics, few available decay channels, mainly into leptons, and extremely well controlled radiative and loop corrections. In that sense, pion decays represent a veritable triumph of the standard model (SM) of elementary particles and interactions. This relative theoretical simplicity makes charged pion decays a sensitive means for testing the underlying symmetries and the universality of weak fermion couplings, as well as for studying pion structure and chiral dynamics. Even after considerable recent improvements, experimental precision is lagging far behind that of the theoretical description for pion decays. We review the current state of experimental study of the pion electronic decay $\pi^+ \to e^+\nu_e(\gamma)$, or $\pi_{e2(\gamma)}$, where the $(\gamma)$ indicates inclusion and explicit treatment of radiative decay events. We briefly review the limits on non-SM processes arising from the present level of experimental precision in $\pi_{e2(\gamma)}$ decays. Focusing on the PEN experiment at the Paul Scherrer Institute (PSI), Switzerland, we examine the prospects for further improvement in the near term.Comment: 11 pages, 5 figures; paper presented at the XIII International Conference on Heavy Quarks and Leptons, 22-27 May 2016, Blacksburg, Virginia, US

PEN experiment: a precise measurement of the pi+ -> e+ nu decay branching fraction

A new measurement of $B_{\pi e2}$, the $\pi^+ \to e^+\nu(\gamma)$ decay branching ratio, is currently under way at the Paul Scherrer Institute. The present experimental result on $B_{\pi e2}$ constitutes the most accurate test of lepton universality available. The accuracy, however, still lags behind the theoretical precision by over an order of magnitude. Because of the large helicity suppression of the $\pi_{e2}$ decay, its branching ratio is susceptible to significant contributions from new physics, making this decay a particularly suitable subject of study.Comment: 4 pages, 3 figures, talk given at the Tenth Conference on the Intersections of Particle and Nuclear Physics (CIPANP 2009), La Jolla/San Diego, CA, 26-31 May 2009; to appear in Proceedings to be published by the American Institute of Physic

Neutron Beta Decay Studies with Nab

Precision measurements in neutron beta decay serve to determine the coupling constants of beta decay and allow for several stringent tests of the standard model. This paper discusses the design and the expected performance of the Nab spectrometer.Comment: Submitted to Proceedings of the Conference CIPANP12, St.Petersburg, Florida, May 201

Early targets of miR-34a in neuroblastoma

Several genes encoding for proteins involved in proliferation, invasion, and apoptosis are known to be direct miR-34a targets. Here, we used proteomics to screen for targets of miR-34a in neuroblastoma (NBL), a childhood cancer that originates from precursor cells of the sympathetic nervous system. We examined the effect of miR-34a overexpression using a tetracycline inducible system in two NBL cell lines (SHEP and SH-SY5Y) at early time points of expression (6, 12, and 24 h). Proteome analysis using post-metabolic labeling led to the identification of 2,082 proteins, and among these 186 were regulated (112 proteins down-regulated and 74 up-regulated). Prediction of miR-34a targets via bioinformatics showed that 32 transcripts held miR-34a seed sequences in their 3′-UTR. By combining the proteomics data with Kaplan Meier geneexpression studies, we identified seven new gene products (ALG13, TIMM13, TGM2, ABCF2, CTCF, Ki67, and LYAR) that were correlated with worse clinical outcomes. These were further validated in vitro by 3′-UTR seed sequence regulation. In addition, Michigan Molecular Interactions searches indicated that together these proteins affect signaling pathways that regulate cell cycle and proliferation, focal adhesions, and other cellular properties that overall enhance tumor progression (including signaling pathways such as TGF-β, WNT, MAPK, and FAK). In conclusion, proteome analysis has here identified early targets of miR-34a with relevance to NBL tumorigenesis. Along with the results of previous studies, our data strongly suggest miR-34a as a useful tool for improving the chance of therapeutic success with NBL

H-Prune through GSK-3β interaction sustains canonical WNT/β-catenin signaling enhancing cancer progression in NSCLC.

H-Prune hydrolyzes short-chain polyphosphates (PPase activity) together with an hitherto cAMP-phosphodiesterase (PDE), the latest influencing different human cancers by its overexpression. H-Prune promotes cell migration in cooperation with glycogen synthase kinase-3 (Gsk-3β). Gsk-3β is a negative regulator of canonical WNT/β-catenin signaling. Here, we investigate the role of Gsk-3β/h-Prune complex in the regulation of WNT/β-catenin signaling, demonstrating the h-Prune capability to activate WNT signaling also in a paracrine manner, through Wnt3a secretion. In vivo study demonstrates that h-Prune silencing inhibits lung metastasis formation, increasing mouse survival. We assessed h-Prune levels in peripheral blood of lung cancer patients using ELISA assay, showing that h-Prune is an early diagnostic marker for lung cancer. Our study dissects out the mechanism of action of h-Prune in tumorigenic cells and also sheds light on the identification of a new therapeutic target in non-small-cell lung cancer

First Observation of PP-odd γ\gamma Asymmetry in Polarized Neutron Capture on Hydrogen

We report the first observation of the parity-violating 2.2 MeV gamma-ray asymmetry $A^{np}_\gamma$ in neutron-proton capture using polarized cold neutrons incident on a liquid parahydrogen target at the Spallation Neutron Source at Oak Ridge National Laboratory. $A^{np}_\gamma$ isolates the $\Delta I=1$, \mbox{$^{3}S_{1}\rightarrow {^{3}P_{1}}$} component of the weak nucleon-nucleon interaction, which is dominated by pion exchange and can be directly related to a single coupling constant in either the DDH meson exchange model or pionless EFT. We measured $A^{np}_\gamma = [-3.0 \pm 1.4 (stat) \pm 0.2 (sys)]\times 10^{-8}$, which implies a DDH weak $\pi NN$ coupling of $h_{\pi}^{1} = [2.6 \pm 1.2(stat) \pm 0.2(sys)] \times 10^{-7}$ and a pionless EFT constant of $C^{^{3}S_{1}\rightarrow ^{3}P_{1}}/C_{0}=[-7.4 \pm 3.5 (stat) \pm 0.5 (sys)] \times 10^{-11}$ MeV$^{-1}$. We describe the experiment, data analysis, systematic uncertainties, and the implications of the result.Comment: 6 pages, 5 figure

Precise Measurement of pi+ -> e+ nu Branching Ratio

The PEN Collaboration is conducting a new measurement of the pi+ -> e+ nu branching ratio at the Paul Scherrer Institute, with the goal uncertainty of delta B/B(pie2)=5E-4 or lower. At present, the combined accuracy of all published pie2 decay measurements lags behind the theoretical calculation by a factor of 40. In this contribution we report on the PEN detector configuration and its performance during two development runs done in 2007 and 2008.Comment: pdflatex, 11 pages, 5 figures, to be published in "Progress in High-Energy Physics and Nuclear Safety", NATO Science for Peace Series: B - Physics and Biophysic