The westward lithospheric drift, its role on the subduction and transform zones surrounding Americas. Andean to cordilleran orogenic types cyclicity

We investigate the effect of the westerly rotation of the lithosphere on the active margins that surround the Americas and find good correlations between the inferred easterly-directed mantle counterflow and the main structural grain and kinematics of the Andes and Sandwich arc slabs. In the Andes, the subduction zone is shallow and with low dip, because the mantle flow sustains the slab; the subduction hinge converges relative to the upper plate and generates an uplifting doubly verging orogen. The Sandwich Arc is generated by a westerly-directed SAM (South American) plate subduction where the eastward mantle flow is steepening and retreating the subduction zone. In this context, the slab hinge is retreating relative to the upper plate, generating the backarc basin and a low bathymetry single-verging accretionary prism. In Central America, the Caribbean plate presents a more complex scenario: a) To the East, the Antilles Arc is generated by westerly directed subduction of the SAM plate, where the eastward mantle flow is steepening and retreating the subduction zone. b) To the West, the Middle America Trench and Arc are generated by the easterly-directed subduction of the Cocos plate, where the shallow subduction caused by eastward mantle flow in its northern segment gradually steepens to the southern segment as it is infered by the preexisting westerly-directed subduction of the Caribbean Plateau. In the frame of the westerly lithospheric flow, the subduction of a divergent active ridge plays the role of introducing a change in the oceanic/continental plate's convergence angle, such as in NAM (North American) plate with the collision with the Pacific/Farallon active ridge in the Neogene (Cordilleran orogenic type scenario). The easterly mantle drift sustains strong plate coupling along NAM, showing at Juan de Fuca easterly subducting microplate that the subduction hinge advances relative to the upper plate. This lower/upper plate convergence coupling also applies along strike to the neighbor continental strike slip fault systems where subduction was terminated (San Andreas and Queen Charlotte). The lower/upper plate convergence coupling enables the capture of the continental plate ribbons of Baja California and Yakutat terrane by the Pacific oceanic plate, transporting them along the strike slip fault systems as para-autochthonous terranes. This Cordilleran orogenic type scenario, is also recorded in SAM following the collision with the Aluk/Farallon active ridge in the Paleogene, segmenting SAM margin into the eastwardly subducting Tupac Amaru microplate intercalated between the proto-Liquiñe-Ofqui and Atacama strike slip fault systems, where subduction was terminated and para-autochthonous terranes transported. In the Neogene, the convergence of Nazca plate with respect to SAM reinstalls subduction and the present Andean orogenic type scenario

Confirmation of antiphospholipid antibody positivity: a year's results in a cohort of 113 patients

Objective: To evaluate the confirmation rate of antiphospholipid antibodies (aPL), to analyze their behaviour at confirmation time, and to study the clinical value of their confirmation. Methods: Blood samples from 380 subjects, enrolled in this study from June 1, 2007 to May 31, 2008, were tested for anti-cardiolipin (aCL) and anti-beta2glycoprotein (aβ2GPI) antibodies using an ELISA method and for Lupus anticoagulant (LA) using a series of clotting tests. The samples of the 113 subjects resulting positive at the first testing time were assayed again to confirm antiphospholipid positivity. Results: aPL positivity was confirmed in 67 out of the 113 subjects (59.3%). Medium-high antibody levels of all, except IgM aCL, aPL/ELISA had a significantly higher confirmation rate with respect to that in subjects with low levels. The confirmation rate in the category I antibody patients (multiple positivity) was higher than that in the category II antibody subjects (single positivity). LA positivity was confirmed only when it was associated to other aPL. The cut-off of 40 GPL produced a confirmation rate equal to that resulting from a 99th percentile cut-off. Confirmation of aPL positivity made it possible for us to confirm the diagnosis of antiphospholipid syndrome (APS) in 8 out of the 113 subjects originally resulting positive (7,1%). APS clinical features were vascular thrombosis in 4 of these and pregnancy morbidity in the other 4. Conclusions: Our data emphasize aPL positivity confirmation selectivity, and medium-high antibody levels and category I antibodies (multiple positivity) had the best confirmation rates

The metalloproteinase ADAM10 requires its activity to sustain surface expression

The metalloproteinase ADAM10 critically contributes to development, inflammation, and cancer and can be controlled by endogenous or synthetic inhibitors. Here, we demonstrate for the first time that loss of proteolytic activity of ADAM10 by either inhibition or loss of function mutations induces removal of the protease from the cell surface and the whole cell. This process is temperature dependent, restricted to mature ADAM10, and associated with an increased internalization, lysosomal degradation, and release of mature ADAM10 in extracellular vesicles. Recovery from this depletion requires de novo synthesis. Functionally, this is reflected by loss and recovery of ADAM10 substrate shedding. Finally, ADAM10 inhibition in mice reduces systemic ADAM10 levels in different tissues. Thus, ADAM10 activity is critically required for its surface expression in vitro and in vivo. These findings are crucial for development of therapeutic ADAM10 inhibition strategies and may showcase a novel, physiologically relevant mechanism of protease removal due to activity loss

Identification of histone deacetylase inhibitors with (arylidene)aminoxy scaffold active in uveal melanoma cell lines

Uveal melanoma (UM) represents an aggressive type of cancer and currently, there is no effective treatment for this metastatic disease. In the last years, histone deacetylase inhibitors (HDACIs) have been studied as a possible therapeutic treatment for UM, alone or in association with other chemotherapeutic agents. Here we synthesised a series of new HDACIs based on the SAHA scaffold bearing an (arylidene)aminoxy moiety. Their HDAC inhibitory activity was evaluated on isolated human HDAC1, 3, 6, and 8 by fluorometric assay and their binding mode in the catalytic site of HDACs was studied by molecular docking. The most promising hit was the quinoline derivative VS13, a nanomolar inhibitor of HDAC6, which exhibited a good antiproliferative effect on UM cell lines at micromolar concentration and a capability to modify the mRNA levels of HDAC target genes similar to that of SAHA

Identification of a Novel p53 Modulator Endowed with Antitumoural and Antibacterial Activity through a Scaffold Repurposing Approach

Intracellular pathogens, such as Chlamydia trachomatis, have been recently shown to induce degradation of p53 during infection, thus impairing the protective response of the host cells. Therefore, p53 reactivation by disruption of the p53-MDM2 complex could reduce infection and restore pro-apoptotic effect of p53. Here, we report the identification of a novel MDM2 inhibitor with potential antitumoural and antibacterial activity able to reactivate p53. A virtual screening was performed on an in-house chemical library, previously synthesised for other targets, and led to the identification of a hit compound with a benzo[a]dihydrocarbazole structure, RM37. This compound induced p53 up-regulation in U343MG glioblastoma cells by blocking MDM2-p53 interaction and reduced tumour cell growth. NMR studies confirmed its ability to dissociate the MDM2-p53 complex. Notably, RM37 reduced Chlamydia infection in HeLa cells in a concentration-dependent manner and ameliorated the inflammatory status associated with infection

The Bortoluzzi Mud Volcano (Ionian Sea, Italy) and its potential for tracking the seismic cycle of active faults

The Ionian Sea in southern Italy is at the center of active interaction and convergence between the Eurasian and African-Adriatic plates in the Mediterranean. This area is seismically active with instrumentally and/or historically recorded Mw > 7:0 earthquakes, and it is affected by recently discovered long strike-slip faults across the active Calabrian accretionary wedge. Many mud volcanoes occur on top of the wedge. A recently discovered one (called the Bortoluzzi Mud Volcano or BMV) was surveyed during the Seismofaults 2017 cruise (May 2017). High-resolution bathymetric backscatter surveys, seismic reflection profiles, geochemical and earthquake data, and a gravity core are used here to geologically, geochemically, and geophysically characterize this structure. The BMV is a circular feature ' 22 m high and ' 1100 m in diameter with steep slopes (up to a dip of 22). It sits atop the Calabrian accretionary wedge and a system of flower-like oblique-slip faults that are probably seismically active as demonstrated by earthquake hypocentral and focal data. Geochemistry of water samples from the seawater column on top of the BMV shows a significant contamination of the bottom waters from saline (evaporite-type) CH4-dominated crustal-derived fluids similar to the fluids collected from a mud volcano located on the Calabria mainland over the same accretionary wedge. These results attest to the occurrence of open crustal pathways for fluids through the BMV down to at least the Messinian evaporites at about-3000 m. This evidence is also substantiated by helium isotope ratios and by comparison and contrast with different geochemical data from three seawater columns located over other active faults in the Ionian Sea area. One conclusion is that the BMV may be useful for tracking the seismic cycle of active faults through geochemical monitoring. Due to the widespread diffusion of mud volcanoes in seismically active settings, this study contributes to indicating a future path for the use of mud volcanoes in the monitoring and mitigation of natural hazards

The tectonic puzzle of the Messina area (Southern Italy): Insights from new seismic reflection data

The Messina Strait, that separates peninsular Italy from Sicily, is one of the most seismically active areas of the Mediterranean. The structure and seismotectonic setting of the region are poorly understood, although the area is highly populated and important infrastructures are planned there. New seismic reflection data have identified a number of faults, as well as a crustal scale NE-trending anticline few km north of the strait. These features are interpreted as due to active right-lateral transpression along the north-eastern Sicilian offshore, coexisting with extensional and right-lateral transtensional tectonics in the southern Messina Strait. This complex tectonic network appears to be controlled by independent and overlapping tectonic settings, due to the presence of a diffuse transfer zone between the SE-ward retreating Calabria subduction zone relative to slab advance in the western Sicilian side