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

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

Abstract. 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 1.7–1.9 m water depth yield a preferred time-of-death age at 1766–1807 AD, while a dryland podocarp and kahikatea stumps at 2.4–2.6 m 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. 1230 AD ± 50 yr. Kahikatea trees growing on rangefront fans give ages of up to 270 yr, which is consistent with alluvial fan aggradation following the 1717 AD 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

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

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

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

A smoothed stochastic earthquake rate model considering seismicity and fault moment release for Europe

We present a time-independent gridded earthquake rate forecast for the European region including Turkey. The spatial component of our model is based on kernel density estimation techniques, which we applied to both past earthquake locations and fault moment release on mapped crustal faults and subduction zone interfaces with assigned slip rates. Our forecast relies on the assumption that the locations of past seismicity is a good guide to future seismicity, and that future large-magnitude events occur more likely in the vicinity of known faults. We show that the optimal weighted sum of the corresponding two spatial densities depends on the magnitude range considered. The kernel bandwidths and density weighting function are optimized using retrospective likelihood-based forecast experiments. We computed earthquake activity rates (a- and b-value) of the truncated Gutenberg-Richter distribution separately for crustal and subduction seismicity based on a maximum likelihood approach that considers the spatial and temporal completeness history of the catalogue. The final annual rate of our forecast is purely driven by the maximum likelihood fit of activity rates to the catalogue data, whereas its spatial component incorporates contributions from both earthquake and fault moment-rate densities. Our model constitutes one branch of the earthquake source model logic tree of the 2013 European seismic hazard model released by the EU-FP7 project ‘Seismic HAzard haRmonization in Europe' (SHARE) and contributes to the assessment of epistemic uncertainties in earthquake activity rates. We performed retrospective and pseudo-prospective likelihood consistency tests to underline the reliability of our model and SHARE's area source model (ASM) using the testing algorithms applied in the collaboratory for the study of earthquake predictability (CSEP). We comparatively tested our model's forecasting skill against the ASM and find a statistically significant better performance for testing periods of 10-20yr. The testing results suggest that our model is a viable candidate model to serve for long-term forecasting on timescales of years to decades for the European regio

The role of pre-existing discontinuities in the development of extensional faults: an analog modeling perspective

Several mountainous regions are currently affected by syn- or post-orogenic active extension. We investigate how a newly-formed normal fault interacts with structures inherited from a previous contractional phase. To this end, we use analog models that adopt an innovative technique for performing a precut that mimics such inherited structures into a clay layer; this clay layer is laid on top of a master fault simulated by two rigid blocks sliding along an inclined plane. We carry out six experiments with variously oriented precuts and compare the results with those obtained in a reference isotropic experiment. All other conditions are identical for all seven realizations. Fault evolution is monitored by taking closely-spaced snapshots analyzed through the Digital Image Correlation method. We find that the upward propagation of the normal fault can be either accelerated or decelerated depending on the presence of a precut and its orientation. Such precuts can also promote or inhibit the formation of bending-moment faults. These interactions between master fault and precut also affect the shape of the fault-related syncline-anticline pair

New results on focusing of gamma-rays with Laue lenses

We report on new results on the development activity of broad band Laue lenses for hard X-/gamma-ray astronomy (70/100-600 keV). After the development of a first prototype, whose performance was presented at the SPIE conference on Astronomical Telescopes held last year in Marseille (Frontera et al. 2008), we have improved the lens assembling technology. We present the development status of the new lens prototype that is on the way to be assembled.Comment: 8 pages, 11 figures, to be Published in SPIE Proceedings, vol.7437-19, 200