Ion mobility discontinuities in superfluid helium: A test of the Huang-Olinto theory

A new method has been developed for making sensitive differential measurements of ion mobilities in liquid helium. Using this method, it has been possible to make a definitive test of the part of the Huang-Olinto theory intended to explain discontinuities in ion mobilities in superfluid helium. The theory has been found to be incorrect

Seismic anisotropy beneath southern Iberia from SKS splitting

International audienceSeismic anisotropy of the south Iberian upper mantle is investigated using shear-wave splitting of SKS phases. We analyzed teleseismic events recorded by sixteen permanent broadband stations installed on the southern Iberian Peninsula and in northern Africa, and we determined fast polarization directions phi, and delay times delta t between fast and slow components. The area of investigation extends across two important geological structures in the Variscan Iberian Peninsula: the Variscan Iberian Massif in its center, and the Gibraltar arc in the Southeast, that represents the most westerly Alpine belt in the western Mediterranean. Shear-wave splitting measurements from stations in the Betic domain show homogeneous ENE-WSW fast directions nearly parallel to the trend of the mountain belt, and smooth spatial variations. Stations in the North, toward the southern part of the Variscan Iberian Massif show homogeneous fast directions however trending NS to NE-SW, different from those recorded in the Betic. These observations may reflect a post-Hercynian (Variscan) deformation of the Ossa-Morena zone, related to the main stages in the tectonic evolution of this part, namely transpressional stage, transtensional stage and shortening episode, or a deformation related to the posterior Alpine orogeny. Along the Gibraltar arc, we observe a smoothly varying phi trend changing from ENE-WSW in the Eastern Betics to NS in the area of Gibraltar and Ceuta, following more or less the general trend of the mountain belt around the Alboran Sea, and the coastline. Since a similar rotation is also visible in results from Pn anisotropy, this suggests that the anisotropy is vertically coherent starting from just below the Moho. Comparing the anisotropy pattern expected from various geodynamic models with the observed SKS splitting suggests that the anisotropy is best explained by a model of slab rollback, rather than by delamination models

Morphology of the tropopause layer and lower stratosphere above a tropical cyclone : a case study on cyclone Davina (1999)

During the APE-THESEO mission in the Indian Ocean the Myasishchev Design Bureau stratospheric research aircraft M55 Geophysica performed a flight over and within the inner core region of tropical cyclone Davina. Measurements of total water, water vapour, temperature, aerosol backscattering, ozone and tracers were made and are discussed here in comparison with the averages of those quantities acquired during the campaign time frame. Temperature anomalies in the tropical tropopause layer (TTL), warmer than average in the lower part and colder than average in the upper TTL were observed. Ozone was strongly reduced compared to its average value, and thick cirrus decks were present up to the cold point, sometimes topped by a layer of very dry air. Evidence for meridional transport of trace gases in the stratosphere above the cyclone was observed and perturbed water distribution in the TTL was documented. The paper discuss possible processes of dehydration induced by the cirrus forming above the cyclone, and change in the chemical tracer and water distribution in the lower stratosphere 400–430 K due to meridional transport from the mid-latitudes and link with Davina. Moreover it compares the data prior and after the cyclone passage to discuss its actual impact on the atmospheric chemistry and thermodynamics

Inhibition of Akt signaling in hepatoma cells induces apoptotic cell death independent of Akt activation status

Cataloged from PDF version of article.The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is involved in cell survival and anti-apoptotic signaling. Akt has been shown to be constitutively expressed in a variety of human tumors including hepatocellular carcinoma (HCC). In this report we analyzed the status of Akt pathway in three HCC cell lines, and tested cytotoxic effects of Akt pathway inhibitors LY294002, Wortmannin and Inhibitor VIII. In Mahlavu human hepatoma cells Akt was constitutively activated, as demonstrated by its Ser473 phosphorylation, downstream hyperphosphorylation of BAD on Ser136, and by a specific cell-free kinase assay. In contrast, Huh7 and HepG2 did not show hyperactivation when tested by the same criteria. Akt enzyme hyperactivation in Mahlavu was associated with a loss of PTEN protein expression. Akt signaling was inhibited by the upstream kinase inhibitors, LY294002, Wortmannin, as well as by the specific Akt Inhibitor VIII in all three hepatoma cell lines. Cytotoxicity assays with Akt inhibitors in the same cell lines indicated that they were all sensitive, but with different IC50 values as assayed by RT-CES. We also demonstrated that the cytotoxic effect was through apoptotic cell death. Our findings provide evidence for its constitutive activation in one HCC cell line, and that HCC cell lines, independent of their Akt activation status respond to Akt inhibitors by apoptotic cell death. Thus, Akt inhibition may be considered as an attractive therapeutic intervention in liver cancer. © Springer Science+Business Media, LLC 2010

Improving nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway

Background: Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with nelarabine. Methods: The effectiveness of nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings. Results: Treatment with nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of nelarabine transporters or metabolic activators. We then studied the combination of nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples. Conclusions: These findings indicate that nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients

Electron/pion separation with an Emulsion Cloud Chamber by using a Neural Network

We have studied the performance of a new algorithm for electron/pion separation in an Emulsion Cloud Chamber (ECC) made of lead and nuclear emulsion films. The software for separation consists of two parts: a shower reconstruction algorithm and a Neural Network that assigns to each reconstructed shower the probability to be an electron or a pion. The performance has been studied for the ECC of the OPERA experiment [1]. The $e/\pi$ separation algorithm has been optimized by using a detailed Monte Carlo simulation of the ECC and tested on real data taken at CERN (pion beams) and at DESY (electron beams). The algorithm allows to achieve a 90% electron identification efficiency with a pion misidentification smaller than 1% for energies higher than 2 GeV

SCH 48973: a Potent, Broad-Spectrum, Antienterovirus Compound.

SCH 48973 is a novel molecule with potent, selective, antienterovirus activity. In assays of the cytopathic effect against five picornaviruses, SCH 48973 had antiviral activity (50% inhibitory concentrations [IC50s]) of 0.02 to 0.11 microg/ml, with no detectable cytotoxicity at 50 microg/ml. SCH 48973 inhibited 80% of 154 recent human enterovirus isolates at an IC50 of 0.9 microg/ml. The antiviral activity of SCH 48973 is derived from its specific interaction with viral capsid, as confirmed by competition binding studies. The affinity constant (Ki) for SCH 48973 binding to poliovirus was 8.85 x 10(-8) M. In kinetic studies, a maximum of approximately 44 molecules of SCH 48973 were bound to poliovirus capsid. SCH 48973 demonstrated efficacy in a murine poliovirus model of enterovirus disease. SCH 48973 increased the survival of infected mice when it was administered orally at dosages of 3 to 20 mg/kg of body weight/day. Oral administration of SCH 48973 also reduced viral titers in the brains of infected mice. On the basis of its in vitro and in vivo profiles, SCH 48973 represents a potential candidate for therapeutic intervention against enterovirus infections

Simulation of the CMS Resistive Plate Chambers

The Resistive Plate Chamber (RPC) muon subsystem contributes significantly to the formation of the trigger decision and reconstruction of the muon trajectory parameters. Simulation of the RPC response is a crucial part of the entire CMS Monte Carlo software and directly influences the final physical results. An algorithm based on the parametrization of RPC efficiency, noise, cluster size and timing for every strip has been developed. Experimental data obtained from cosmic and proton-proton collisions at $\sqrt{s}=7$ TeV have been used for determination of the parameters. A dedicated validation procedure has been developed. A good agreement between the simulated and experimental data has been achieved.Comment: to be published in JINS

Synergistic cytotoxic effects of bortezomib and CK2 inhibitor CX-4945 in acute lymphoblastic leukemia: turning offthe prosurvival ER chaperone BIP/Grp78 and turning on the proapoptotic NF-κB

The proteasome inhibitor bortezomib is a new targeted treatment option for refractory or relapsed acute lymphoblastic leukemia (ALL) patients. However, a limited efficacy of bortezomib alone has been reported. A terminal pro-apoptotic endoplasmic reticulum (ER) stress/unfolded protein response (UPR) is one of the several mechanisms of bortezomib-induced apoptosis. Recently, it has been documented that UPR disruption could be considered a selective anti-leukemia therapy. CX- 4945, a potent casein kinase (CK) 2 inhibitor, has been found to induce apoptotic cell death in T-ALL preclinical models, via perturbation of ER/UPR pathway. In this study, we analyzed in T- and B-ALL preclinical settings, the molecular mechanisms of synergistic apoptotic effects observed after bortezomib/CX-4945 combined treatment. We demonstrated that, adding CX-4945 after bortezomib treatment, prevented leukemic cells from engaging a functional UPR in order to buffer the bortezomibmediated proteotoxic stress in ER lumen. We documented that the combined treatment decreased pro-survival ER chaperon BIP/Grp78 expression, via reduction of chaperoning activity of Hsp90. Bortezomib/CX-4945 treatment inhibited NF-κB signaling in T-ALL cell lines and primary cells from T-ALL patients, but, intriguingly, in B-ALL cells the drug combination activated NF-κB p65 pro-apoptotic functions. In fact in B-cells, the combined treatment induced p65-HDAC1 association with consequent repression of the anti-apoptotic target genes, Bcl-xL and XIAP. Exposure to NEMO (IKKγ)-binding domain inhibitor peptide reduced the cytotoxic effects of bortezomib/CX-4945 treatment. Overall, our findings demonstrated that CK2 inhibition could be useful in combination with bortezomib as a novel therapeutic strategy in both T- and B-ALL