The rna-binding ubiquitin ligase mex3a affects glioblastoma tumorigenesis by inducing ubiquitylation and degradation of rig-i

Glioblastoma multiforme (GB) is the most malignant primary brain tumor in humans, with an overall survival of approximatively 15 months. The molecular heterogeneity of GB, as well as its rapid progression, invasiveness and the occurrence of drug-resistant cancer stem cells, limits the efficacy of the current treatments. In order to develop an innovative therapeutic strategy, it is mandatory to identify and characterize new molecular players responsible for the GB malignant phenotype. In this study, the RNA-binding ubiquitin ligase MEX3A was selected from a gene expression analysis performed on publicly available datasets, to assess its biological and still-unknown activity in GB tumorigenesis. We find that MEX3A is strongly up-regulated in GB specimens, and this correlates with very low protein levels of RIG-I, a tumor suppressor involved in differentiation, apoptosis and innate immune response. We demonstrate that MEX3A binds RIG-I and induces its ubiquitylation and proteasome-dependent degradation. Further, the genetic depletion of MEX3A leads to an increase of RIG-I protein levels and results in the suppression of GB cell growth. Our findings unveil a novel molecular mechanism involved in GB tumorigenesis and suggest MEX3A and RIG-I as promising therapeutic targets in GB

Shake table testing of a tuned mass damper inerter (Tmdi)-equipped structure and nonlinear dynamic modeling under harmonic excitations

This paper presents preliminary experimental results from a novel shaking table testing campaign investigating the dynamic response of a two-degree-of-freedom (2DOF) physical specimen with a grounded inerter under harmonic base excitation and contributes a nonlinear dynamic model capturing the behavior of the test specimen. The latter consists of a primary mass connected to the ground through a high damping rubber isolator (HDRI) and a secondary mass connected to the primary mass through a second HDRI. Further, a flywheel-based rack-and-pinion inerter prototype device is used to connect the secondary mass to the ground. The resulting specimen resembles the tuned mass damper inerter (TMDI) configuration with grounded inerter analytically defined and numerically assessed by the authors in a number of previous publications. Physical specimens with three different inerter coefficients are tested on the shake table under sine-sweep excitation with three different amplitudes. Experimental frequency response functions (FRFs) are derived manifesting a softening nonlinear behavior of the specimens and enhanced vibration suppression with increased inerter coefficient. Further, a 2DOF parametric nonlinear model of the specimen is established accounting for non-ideal inerter device behavior and its potential to characterize experimental response time-histories, FRFs, and force-displacement relationships of the HDRIs and of the inerter is verified

Late Holocene landscape change history related to the Alpine Fault determined from drowned forests in Lake Poerua, Westland, New Zealand

Lake Poerua is a small, shallow lake that abuts the scarp of the Alpine Fault on the West Coast of New Zealand’s South Island. Radiocarbon dates from drowned podocarp trees on the lake floor, a sediment core from a rangefront alluvial fan, and living tree ring ages have been used to deduce the late Holocene history of the lake. Remnant drowned stumps of kahikatea (Dacrycarpus dacrydioides) at 1.7–1.9m water depth yield a preferred time-ofdeath age at 1766–1807 AD, while a dryland podocarp and kahikatea stumps at 2.4–2.6m yield preferred time-of-death ages of ca. 1459–1626 AD. These age ranges are matched to, but offset from, the timings of Alpine Fault rupture events at ca. 1717 AD, and either ca. 1615 or 1430 AD. Alluvial fan detritus dated from a core into the toe of a rangefront alluvial fan, at an equivalent depth to the maximum depth of the modern lake (6.7 m), yields a calibrated age of AD 1223–1413. This age is similar to the timing of an earlier Alpine Fault rupture event at ca. 1230AD±50 yr. Kahikatea trees growing on rangefront fans give ages of up to 270 yr, which is consistent with alluvial fan aggradation following the 1717AD earthquake. The elevation levels of the lake and fan imply a causal and chronological link between lake-level rise and Alpine Fault rupture. The results of this study suggest that the growth of large, coalescing alluvial fans (Dry and Evans Creek fans) originating from landslides within the rangefront of the Alpine Fault and the rise in the level of Lake Poerua may occur within a decade or so of large Alpine Fault earthquakes that rupture adjacent to this area. These rises have in turn drowned lowland forests that fringed the lake. Radiocarbon chronologies built using OxCal show that a series of massive landscape changes beginning with fault rupture, followed by landsliding, fan sedimentation and lake expansion. However, drowned Kahikatea trees may be poor candidates for intimately dating these events, as they may be able to tolerate water for several decades after metre-scale lake level rises have occurred

The phosphodiesterase 5 inhibitor sildenafil decreases the proinflammatory chemokine IL-8 in diabetic cardiomyopathy: in vivo and in vitro evidence

Purpose: Interleukin (IL)-8 is a proinflammatory C-X-C chemokine involved in inflammation underling cardiac diseases, primary or in comorbid condition, such diabetic cardiomyopathy (DCM). The phosphodiesterase type 5 inhibitor sildenafil can ameliorate cardiac conditions by counteracting inflammation. The study aim is to evaluate the effect of sildenafil on serum IL-8 in DCM subjects vs. placebo, and on IL-8 release in human endothelial cells (Hfaec) and peripheral blood mononuclear cells (PBMC) under inflammatory stimuli. Methods: IL-8 was quantified: in sera of (30) DCM subjects before (baseline) and after sildenafil (100 mg/day, 3-months) vs. (16) placebo and (15) healthy subjects, by multiplatform array; in supernatants from inflammation-challenged cells after sildenafil (1 µM), by ELISA. Results: Baseline IL-8 was higher in DCM vs. healthy subjects (149.14 ± 46.89 vs. 16.17 ± 5.38 pg/ml, p < 0.01). Sildenafil, not placebo, significantly reduced serum IL-8 (23.7 ± 5.9 pg/ml, p < 0.05 vs. baseline). Receiver operating characteristic (ROC) curve for IL-8 was 0.945 (95% confidence interval of 0.772 to 1.0, p < 0.01), showing good capacity of discriminating the response in terms of drug-induced IL-8 decrease (sensitivity of 0.93, specificity of 0.90). Sildenafil significantly decreased IL-8 protein release by inflammation-induced Hfaec and PBMC and downregulated IL-8 mRNA in PBMC, without affecting cell number or PDE5 expression. Conclusion: Sildenafil might be suggested as potential novel pharmacological tool to control DCM progression through IL-8 targeting at systemic and cellular level

a hysteretic absorber to mitigate vibrations of rail noise barriers

Noise barriers for high-speed train lines are subject to strong vibrations due to fluid pressure generated by moving trains. The barriers, generally made of steel cantilever beams, suffer fatigue. For their safety, it is necessary to adopt more resistant solutions or reduce their vibration, as is applied in this study. Following the fundamental work by Den Hartog on viscoelastic tuned mass dampers, later contributions on vibration mitigation have shown a variety of phenomena exhibited by a primary structure connected to a nonlinear light attachment. Vibration reduction of the structure has been observed for selected characteristics of the attachment. Here, the use of a hysteretic absorber is exploited. The device, made of light mass on rubber elements, has the advantage of directly representing the elastic and damping elements. The Bouc-Wen model describes the absorber behavior and its parameters are determined by the experimental results. Due to the dependence of the nonlinear system response on the oscillation amplitude, an optimal tuning is adjusted. The system is calibrated to behave around the 1:1 internal resonance condition. Numerical and experimental results show that the absorber effectively reduces the amplitude and the number of vibration cycles

Glutathione infusion before primary percutaneous coronary intervention: A randomised controlled pilot study

Objective: In the setting of reperfused ST-elevation myocardial infarction (STEMI), increased production of reactive oxygen species (ROS) contributes to reperfusion injury. Among ROS, hydrogen peroxide (H2O2) showed toxic effects on human cardiomyocytes and may induce microcirculatory impairment. Glutathione (GSH) is a water-soluble tripeptide with a potent oxidant scavenging activity. We hypothesised that the infusion of GSH before acute reoxygenation might counteract the deleterious effects of increased H2O2 generation on myocardium. Methods: Fifty consecutive patients with STEMI, scheduled to undergo primary angioplasty, were randomly assigned, before intervention, to receive an infusion of GSH (2500 mg/25 mL over 10 min), followed by drug administration at the same doses at 24, 48 and 72 hours elapsing time or placebo. Peripheral blood samples were obtained before and at the end of the procedure, as well as after 5 days. H2O2 production, 8-iso-prostaglandin F2α (PGF2α) formation, H2O2 breakdown activity (HBA) and nitric oxide (NO) bioavailability were determined. Serum cardiactroponin T (cTpT) was measured at admission and up to 5 days. Results: Following acute reperfusion, a significant reduction of H2O2 production (p=0.0015) and 8-iso-PGF2α levels (p=0.0003), as well as a significant increase in HBA (p<0.0001)and NO bioavailability (p=0.035), was found in the GSH group as compared with placebo. In treated patients, attenuated production of H2O2 persisted up to 5 days from the index procedure (p=0.009) and these changes was linked to those of the cTpT levels (r=0.41, p=0.023). Conclusion: The prophylactic and prolonged infusion of GSH seems to determine a rapid onset and persistent blunting of H2O2 generation improving myocardial cell survival. Nevertheless, a larger trial, adequately powered for evaluation of clinical endpoints, is ongoing to confirm the current finding

Behavioral analysis for virtualized network functions: A som-based approach

In this paper, we tackle the problem of detecting anomalous behaviors in a virtualized infrastructure for network function virtualization, proposing to use self-organizing maps for analyzing historical data available through a data center. We propose a joint analysis of system-level metrics, mostly related to resource consumption patterns of the hosted virtual machines, as available through the virtualized infrastructure monitoring system, and the application-level metrics published by individual virtualized network functions through their own monitoring subsystems. Experimental results, obtained by processing real data from one of the NFV data centers of the Vodafone network operator, show that our technique is able to identify specific points in space and time of the recent evolution of the monitored infrastructure that are worth to be investigated by a human operator in order to keep the system running under expected conditions

The gamma-ray burst monitor for Lobster-ISS

Lobster-ISS is an X-ray all-sky monitor experiment selected by ESA two years ago for a Phase A study (now almost completed) for a future flight (2009) aboard the Columbus Exposed Payload Facility of the International Space Station. The main instrument, based on MCP optics with Lobster-eye geometry, has an energy passband from 0.1 to 3.5 keV, an unprecedented daily sensitivity of 2x10^{-12} erg cm^{-2}s$^{-1}, and it is capable to scan, during each orbit, the entire sky with an angular resolution of 4--6 arcmin. This X-ray telescope is flanked by a Gamma Ray Burst Monitor, with the minimum requirement of recognizing true GRBs from other transient events. In this paper we describe the GRBM. In addition to the minimum requirement, the instrument proposed is capable to roughly localize GRBs which occur in the Lobster FOV (162x22.5 degrees) and to significantly extend the scientific capabilities of the main instrument for the study of GRBs and X-ray transients. The combination of the two instruments will allow an unprecedented spectral coverage (from 0.1 up to 300/700 keV) for a sensitive study of the GRB prompt emission in the passband where GRBs and X-Ray Flashes emit most of their energy. The low-energy spectral band (0.1-10 keV) is of key importance for the study of the GRB environment and the search of transient absorption and emission features from GRBs, both goals being crucial for unveiling the GRB phenomenon. The entire energy band of Lobster-ISS is not covered by either the Swift satellite or other GRB missions foreseen in the next decade.Comment: 6 pages, 4 figures. Paper presented at the COSPAR 2004 General Assembly (Paris), accepted for publication in Advances in Space Research in June 2005 and available on-line at the Journal site (http://www.sciencedirect.com/science/journal/02731177), section "Articles in press

A smo/gli multitarget hedgehog pathway inhibitor impairs tumor growth

Pharmacological Hedgehog (Hh) pathway inhibition has emerged as a valuable anticancer strategy. A number of small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector glioma-associated oncogene 1 (Gli1) has been designed and developed. In a recent study, we exploited the high versatility of the natural isoflavone scaffold for targeting the Hh signaling pathway at multiple levels showing that the simultaneous targeting of Smo and Gli1 provided synergistic Hh pathway inhibition stronger than single administration. This approach seems to effectively overcome the drug resistance, particularly at the level of Smo. Here, we combined the pharmacophores targeting Smo and Gli1 into a single and individual isoflavone, compound 22, which inhibits the Hh pathway at both upstream and downstream level. We demonstrate that this multitarget agent suppresses medulloblastoma growth in vitro and in vivo through antagonism of Smo and Gli1, which is a novel mechanism of action in Hh inhibition