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

C7 is expressed on endothelial cells as a trap for the assembling terminal complement complex and may exert anti-inflammatory function

We describe a novel localization of C7 as a membrane-bound molecule on endothelial cells (ECs). Data obtained by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot analysis, Northern blot analysis, and mass spectrometry revealed that membrane- associated C7 (mC7) was indistinguish-able from soluble C7 and was associated with vimentin on the cell surface. mC7 interacted with the other late complement components to form membrane-bound TCC (mTCC). Unlike the soluble SC5b-9, mTCC failed to stimulate ECs to express adhesion molecules, to secrete IL-8, and to induce albumin leakage through a monolayer of ECs, and more importantly protected ECs from the proinflammatory effect of SC5b-9. Our data disclose the possibility of a novel role of mC7 that acts as a trap for the late complement components to control excessive inflammation induced by SC5b-9. \ua9 2009 by The American Society of Hematology

Repurposing of the Antiepileptic Drug Levetiracetam to Restrain Neuroendocrine Prostate Cancer and Inhibit Mast Cell Support to Adenocarcinoma

A relevant fraction of castration-resistant prostate cancers (CRPC) evolve into fatal neuroendocrine (NEPC) tumors in resistance to androgen deprivation and/or inhibitors of androgen receptor pathway. Therefore, effective drugs against both CRPC and NEPC are needed. We have previously described a dual role of mast cells (MCs) in prostate cancer, being capable to promote adenocarcinoma but also to restrain NEPC. This finding suggests that a molecule targeting both MCs and NEPC cells could be effective against prostate cancer. Using an in silico drug repurposing approach, here we identify the antiepileptic drug levetiracetam as a potential candidate for this purpose. We found that the protein target of levetiracetam, SV2A, is highly expressed by both NEPC cells and MCs infiltrating prostate adenocarcinoma, while it is low or negligible in adenocarcinoma cells. In vitro, levetiracetam inhibited the proliferation of NEPC cells and the degranulation of MCs. In mice bearing subcutaneous tumors levetiracetam was partially active on both NEPC and adenocarcinoma, the latter effect due to the inhibition of MMP9 release by MCs. Notably, in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice subjected to surgical castration to mimic androgen deprivation therapy, levetiracetam reduced onset and frequency of both high grade prostatic intraepithelial neoplasia, adenocarcinoma and NEPC, thus increasing the number of cured mice showing only signs of tumor regression. Our results demonstrate that levetiracetam can directly restrain NEPC development after androgen deprivation, and that it can also block adenocarcinoma progression through the inhibition of some MCs functions. These findings open the possibility of further testing levetiracetam for the therapy of prostate cancer or of MC-mediated diseases

Preliminary results from EMERSITO, the rapid response network for site effect studies

On May 20, 2012, at 02:03 UTC, a ML 5.9 reverse-fault earthquake occurred in the Emilia-Romagna region, northern Italy, at a hypocentral depth of 6.3 km (http://iside.rm. ingv.it/), close to the cities of Modena and Ferrara in the plain of the Po River. The epicenter was near the village of Finale Emilia where macroseismic intensity was assessed at 7 EMS98 [Tertulliani et al. 2012, this issue], while the closest accelerometric station, MRN, located less than 20 km west-ward at Mirandola (Figure 1) recorded peaks of ground accelerations of about 300 cm/s2 (www.protezionecivile.gov.it/resources/ cms/documents/Report_DPC_1_Emilia_EQSd.pdf ). The mainshock triggered liquefaction phenomena a few kilometers eastwards of the epicenter, around the village of San Carlo. On the same day, two other shocks of ML 5.1 followed (02:07, 13:18 GMT; http://iside.rm.ingv.it/). On May 29, 2012, at 07:00 UTC another ML 5.8 earthquake hit the region (http://iside.rm.ingv.it/), with the epicenter close to the village of Mirandola (Figure 1). Three other strong aftershocks occurred afterwards, of ML 5.3 (May 29, at 10:55), ML 5.2 (May 29, at 11:00) and ML 5.1 ( June 3, at 19:20). For a detailed description of the seismic sequence, see Moretti et al. [2012], Scognamiglio et al. [2012], and Massa et al. [2012], in this issue. The Emilia seismic sequence resulted in 25 casualties, several of whom were among the workers in the many factories that collapsed during working hours, and there was extensive damage to monuments, public buildings, industrial sites, and private homes. The Po Plain region that was struck by the 2012 Emilia seismic sequence is a very large E-W trending syntectonic alluvial basin, which covers about 45,000 km2. It is surrounded by the Alps to the north and the Apennines to the south, and it is filled with Plio-Pleistocene terrigenous sediments and Holocene deposits, with depths varying from a few hundred meters up to several kilometers. The epicentral area was located south of the Po River, corresponding to the active front of the northern Apennines thrust belt (north-vergence), which is composed of buried folds and thrust faults that locally produce structural highs (Figure 1), and are known as Pieghe Emiliane and Ferraresi [Pieri and Groppi 1981]. The top of this limestone and marl bedrock rises to ca. 100 m from the surface and has been derived locally from borehole logs. The seismic response of this ca. 150-m-deep soft cover was investigated using weak-motion events and microtremors recorded in a borehole by Margheriti et al. [2000]. The occurrence of the May 2012 seismic sequence made it possible to study the seismic response under near-field conditions. These studies are aimed at providing tools to reduce the impact of future earthquakes on the local communities. In addition to the amplification due to one-dimensional (1D) resonance, it is well known that seismic responses of deep sedimentary basins are affected by 2D and 3D effects (e.g., wave diffraction, conversion at the basin edges, trapping and focusing of energy within the soil volume). Evidence of basin-induced surface waves and edge effects have been observed in many basins worldwide; e.g., the Osaka basin in Japan [e.g., Kawase 1996, Pitarka et al. 1998], various southern California basins [Graves et al. 1998, Day et al. 2008], and the Parkway basin in New Zealand [Chávez-García et al. 1999]. In Italy, good examples of site amplification in alluvial basins can be found for the Gubbio, Città di Castello, L'Aquila and Fucino basins [ Bordoni et al. 2003, Bindi et al. 2009, Cara et al. 2011, Milana et al. 2011]. Therefore, the day after the mainshock, the INGV rapidresponse network for site effects, called EMERSITO, planned the experiments presented in this report. EMERSITO put together independent research groups from several territorial centers of the Istituto Nazionale di Geofisica e Vulcanologia (INGV; National Institute of Geophysics and Volcanology) who agree to collaborate spontaneously and on the basis of a data archiving and sharing policy. They then deployed their seismic equipment in the epicentral area, building on the experience of the 2009 L'Aquila earthquake [Di Giulio et al. 2011, Margheriti et al. 2011, Milana et al. 2011]. The deployment was planned also in collaboration with the geological survey of the Regione Emilia Romagna (Servizio Geologico e Sismico e dei Suoli) and the University of Modena, as well as being in the framework of SISMIKO [Moretti et al. 2012]. As a result of this effort, since May 22, three linear arrays have been deployed (Figure 1), with a total of 22 sites instrumented, 16 of them equipped with both velocimeters and accelerometers. These arrays recorded most of the aftershock sequence, including the MW 5.8 May 29, 2012, 07:00 earthquake. The continuous recordings will be archived into the EIDA database (http://eida.rm.ingv.it/) under restricted access. The aim of this report is to describe the experiments performed by the EMERSITO team, as well as the main features of the recorded earthquakes. A preliminary insight in the site response of the investigated area within the context of the geological structure of the Po Plain is also given

Marked increase in etravirine and saquinavir plasma concentrations during atovaquone/proguanil prophylaxis

The case of a 32-year-old Caucasian female with multi-drug resistant HIV-1 subtype B infection treated with a salvage regimen including maraviroc, raltegravir, etravirine and unboosted saquinavir who started atovaquone/proguanil prophylaxis, is reported. The potential interactions between atovaquone/proguanil and these anti-retroviral drugs are investigated. Pharmacokinetic analyses documented a marked increase in etravirine and saquinavir plasma concentrations (+55% and +274%, respectively), but not in raltegravir and maraviroc plasma concentrations. The evidence that atovaquone/proguanil significantly interacts with etravirine and saquinavir, but not with raltegravir and maraviroc, suggests that the mechanism of interaction is related to cytochrome P450

Evaluation of site effects in the Aterno river valley (Central Italy) from aftershocks of the 2009 L'Aquila earthquake

A temporary network of 33 seismic stations was deployed in the area struck by the 6th April 2009, Mw 6.3, L’Aquila earthquake (central Italy), with the aim to investigate the site amplification within the Aterno river Valley. The seismograms of 18 earthquakes recorded by 14 of the 33 stations were used to evaluate the average horizontal to vertical spectral ratio (HVSR) for each site and the standard horizontal spectral ratio (SSR) between a site and a reference station. The obtained results have been compared to the geological and geophysical information in order to explain the resonance frequencies and the amplification levels with respect to surface geology of the valley. The result indicate that there is no uniform pattern of amplification, due to the complex geologic setting, as the thickness and degree of cementation of the deposits is highly variable. As consequence, a large number of the local site response is observed, therefore it is very difficult to elaborate a unique model that can explain such a variability of the amplification.Published697-7154.1. Metodologie sismologiche per l'ingegneria sismicaJCR Journalpartially_ope

Evaluation of the local site effects in the upper and middle Aterno valley

In the months following the April 6th, 2009, L’Aquila earthquake, several Italian and foreign research institutions installed dozens of seismic stations to monitor more than 100 localities with the aim of studying the local site effects in the epicentral area (upper and middle Aterno valley). The stations (accelerometers and velocimeters) have been deployed inside or very close to the inhabited areas. Among the investigated sites there are Onna, where almost the totality of the buildings collapsed, and the historic centre of L’Aquila, both towns suffering many casualties. The preliminary results for the examined sites show an extreme variability of ground motion and significant amplification for the most damaged localities.In press4.1. Metodologie sismologiche per l'ingegneria sismicaN/A or not JCRope

Rapid response to the earthquake emergency of May 2012 in the Po Plain, northern Italy

No abstrac

Observation of flow angle and flow magnitude fluctuations in Pb-Pb collisions at sNN=5.02TeV at the CERN Large Hadron Collider

This Letter reports on the first measurements of transverse momentum dependent flow angle n and flow magnitude vn fluctuations determined using new four-particle correlators. The measurements are performed for various centralities in Pb–Pb collisions at a center-of-mass energy per nucleon pair of √s NN = 5.02 TeV with ALICE at the CERN Large Hadron Collider. Both flow angle and flow magnitude fluctuations are observed in the presented centrality ranges and are strongest in the most central collisions and for a transverse momentum pT > 2 GeV/c. Comparison with theoretical models, including iEBE-VISHNU, MUSIC, and AMPT, show that the measurements exhibit unique sensitivities to the initial state of heavy-ion collisions

First measurement of Ωc 0 production in pp collisions at s=13 TeV

The inclusive production of the charm–strange baryon Omega_c^0 is measured for the first time via its hadronic decay into Omega-pi+ at midrapidity (|y|<0.5) in proton–proton (pp) collisions at the centre-of-mass energy sqrt(s) = 13 TeV with the ALICE detector at the LHC. The transverse momentum (pT) differential cross section multiplied by the branching ratio is presented in the interval 2 < pT < 12 GeV/c . The pT dependence of the Omega_C^0-baryon production relative to the prompt D^0-meson and to the prompt Csi_C^0-baryon production is compared to various models that take different hadronisation mechanisms into consideration. In the measured pT interval, the ratio of the pT-integrated cross sections of Omega_c^0 and prompt Lambda_c^+ baryons multiplied by the Omega- pi+ branching ratio is found to be larger by a factor of about 20 with a significance of about 4σ when compared to e+e- collisions