Targeting striatal metabotropic glutamate receptor type 5 in Parkinson's disease: bridging molecular studies and clinical trials

Metabotropic glutamate (mGlu) receptors are G protein-coupled receptors expressed primarily on neurons and glial cells modulating the effects of glutamatergic neurotransmission. The pharmacological manipulation of these receptors has been postulated to be valuable in the management of some neurological disorders. Accordingly, the targeting of mGlu5 receptors as a therapeutic approach for Parkinson's disease (PD) has been proposed, especially to manage the adverse symptoms associated to chronic treatment with classical PD drugs. Thus, the specific pharmacological blocking of mGlu5 receptors constitutes one of the most attractive non-dopaminergic-based strategies for PD management in general and for the L-DOPA-induced diskynesia (LID) in particular. Overall, we provide here an update of the current state of the art of these mGlu5 receptor-based approaches that are under clinical study as agents devoted to alleviate PD symptoms

Influence of cratonic lithosphere on the formation and evolution of flat slabs : insights from 3-D time-dependent modeling.

Several mechanisms have been suggested for the formation of flat slabs including buoyant features on the subducting plate, trenchward motion and thermal or cratonic structure of the overriding plate. Analysis of episodes of flat subduction indicate that not all flat slabs can be attributed to only one of these mechanisms and it is likely that multiple mechanisms work together to create the necessary conditions for flat slab subduction. In this study we examine the role of localized regions of cratonic lithosphere in the overriding plate in the formation and evolution of flat slabs. We explicitly build on previous models, by using time-dependent simulations with three-dimensional variation in overriding plate structure. We find that there are two modes of flat subduction: permanent underplating occurs when the slab is more buoyant (shorter or younger), while transient flattening occurs when there is more negative buoyancy (longer or older slabs). Our models show how regions of the slab adjacent to the subcratonic flat portion continue to pull the slab into the mantle leading to highly contorted slab shapes with apparent slab gaps beneath the craton. These results show how the interpretation of seismic images of subduction zones can be complicated by the occurrence of either permanent or transient flattening of the slab, and how the signature of a recent flat slab episode may persist as the slab resumes normal subduction. Our models suggest that permanent underplating of slabs may preferentially occur below thick and cold lithosphere providing a built-in mechanism for regeneration of cratons

Differential body composition effects of protease inhibitors recommended for initial treatment of HIV infection: A randomized clinical trial

This article has been accepted for publication in Clinical Infectious Diseases ©2014 The Authors .Published by Oxford University Press on Clinical Infectious Disease 60.5. DOI: 10.1093/cid/ciu898Background. It is unclear whether metabolic or body composition effects may differ between protease inhibitor-based regimens recommended for initial treatment of HIV infection. Methods. ATADAR is a phase IV, open-label, multicenter randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Pre-defined end-points were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. Results. At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95%CI -0.6 to 21.6); and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95%CI -0.5 to 17.6). Seven vs. five patients discontinued atazanavir/ritonavir or darunavir/ritonavir due to adverse effects. Total and HDL cholesterol similarly increased in both arms, but triglycerides increased more in atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95%CI 726.7 to 4997.7; P=0.0090), limb fat (estimated difference 1403.3 gr; 95%CI 388.4 to 2418.2; P=0.0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm2; 95%CI 1.9 to 55.0; P=0.0362) increased more in atazanavir/ritonavir than in darunavir/ritonavir arm. Body fat changes in atazanavir/ritonavir arm were associated with higher insulin resistance. Conclusions. We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically-relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and total and subcutaneous fat than darunavir/ritonavir and fat gains with atazanavir/ritonavir were associated with insulin resistanceThis is an Investigator Sponsored Research study. It was supported in part by research grants from Bristol‐Myers Squibb and Janssen‐Cilag; Instituto de Salud Carlos III (PI12/01217) and Red Temática Cooperativa de Investigación en SIDA G03/173 (RIS‐EST11), Ministerio de Ciencia e Innovación, Spain. (Registration number: NCT01274780; registry name: ATADAR; EUDRACT; 2010‐021002‐38)

Neotectonics of the SW Iberia margin, Gulf of Cadiz and Alboran Sea: a reassessment including recent structural, seismic and geodetic data

We use a thin-shell approximation for the lithosphere to model the neotectonics of the Gulf of Cadiz, SW Iberia margin and the westernmost Mediterranean, in the eastern segment of the Azores-Gibraltar plate boundary. In relation to previous neotectonic models in the region, we utilize a better constrained structural map offshore, and the recent GPS measurements over NW Africa and Iberia have been taken into account, together with the seismic strain rate and stress data, to evaluate alternative geodynamic settings proposed for the region. We show that by assuming a relatively simple, two-plate tectonic framework, where Nubia and Eurasia converge NW-SE to WNW-ESE at a rate of 4.5-6 mm yr-1, the models correctly predict the amount of shortening and wrenching between northern Algeria-Morocco and southern Spain and between NW Morocco and SW Iberia, as estimated from both GPS data and geological constraints. The consistency between modelled and observed velocities in the vicinity of Gibraltar and NW Morocco indicates that forcing by slab sinking beneath Gibraltar is not required to reproduce current horizontal deformation in these areas. In the Gulf of Cadiz and SW Iberia, the modelling results support a diffuse Nubia-Eurasia Plate boundary, where the convergence is accommodated along NNE-SSW to NE-SW and ENE-WSW thrust faults and WNW-ESE right-lateral strike-slip faults, over an area >200 km wide, in good general agreement with the distribution of the seismic strain rate and associated faulting mechanisms. The modelling results are robust to regional uncertainties in the structure of the lithosphere and have important implications for the earthquake and tsunami hazard of Portugal, SW Spain and Morocco. We predict maximum, long-term average fault slip rates between 1-2 mm yr-1, that is, less than 50 per cent the average plate relative movement, suggesting very long return periods for high-magnitude (Mw > 8) earthquakes on individual structures.publishe

The role of the overriding plate thermal state on slab dip variability and on the occurrence of flat subduction

Slab dip varies significantly, both between different, and along single subduction zones. Provided that old subducting plates are colder and denser than young plates, variations in the slab dip should correlate with slab age. However, recent statistical analyses do not show this expected correlation. We present the results of non-Newtonian numerical dynamic models where subduction is driven by means of a kinematic boundary condition. We systematically vary the age of both the overriding and subducting plates in order to test these effects on the slab dip at different depth ranges. We find that colder overriding plates result in shallower slab dips and episodes of flat slab subduction, as a result of the increased suction force in the mantle wedge. The influence of the thermal state of the overriding plate on slab dip is shown here to be more important than that of the age of subducting lithosphere. Modeling results are qualitatively compared to the large dip variability of the Cocos slab including a flat-slab segment. We suggest that this variability is likely related to the change of the thermal state of the overriding plates, with flat subduction occurring under cold lithosphere in southwestern Mexico and steep subduction under the warmer lithosphere of the northwestern Caribbean plate.Peer reviewe

Modelling the possible interaction between edge-driven convection and the Canary Islands mantle plume

Trabajo presentado en el AGU (American Geophysical Union) Fall Meeting: Advancing Earth and Space Science, celebrado en New Orleans. (Estados Unidos), del 11 al 15 de diciembre de 2017The close location between many hotspots and the edges of cratonic lithosphere has led to the hypothesis that these hotspots could be explained by small-scale mantle convection at the edge of cratons (Edge Driven Convection, EDC). The Canary Volcanic Province hotspot represents a paradigmatic example of this situation due to its close location to the NW edge of the African Craton. Geochemical evidence, prominent low seismic velocity anomalies in the upper and lower mantle, and the rough NE-SW age-progression of volcanic centers consistently point out to a deep-seated mantle plume as the origin of the Canary Volcanic Province. It has been hypothesized that the plume material could be affected by upper mantle convection caused by the thermal contrast between thin oceanic lithosphere and thick (cold) African craton. Deflection of upwelling blobs due to convection currents would be responsible for the broader and more irregular pattern of volcanism in the Canary Province compared to the Madeira Province. In this study we design a model setup inspired on this scenario to investigate the consequences of possible interaction between ascending mantle plumes and EDC. The Finite Element code ASPECT is used to solve convection in a 2D box. The compositional field and melt fraction distribution are also computed. Free slip along all boundaries and constant temperature at top and bottom boundaries are assumed. The initial temperature distribution assumes a small long-wavelength perturbation. The viscosity structure is based on a thick cratonic lithosphere progressively varying to a thin, or initially inexistent, oceanic lithosphere. The effects of assuming different rheologies, as well as steep or gradual changes in lithospheric thickness are tested. Modelling results show that a very thin oceanic lithosphere (< 30 km) is needed to generate partial melting by EDC. In this case partial melting can occur as far as 700 km away from the edge of the craton. The size of EDC cells is relatively small (diameter about 300 km) for lithosphere/asthenosphere viscosity contrasts of 1000. In contrast, models assuming temperature-dependent viscosity and large viscosity variations evolve to large-scale (upper mantle) convection cells, with upwelling of hot material being enhanced by cold downwellings at the edge of cratonic lithosphere.Peer reviewe

Modelling the interaction between edge-driven convection and mantle plumes: Preliminary results using ASPECT code

Trabajo presentado en el XV International Workshop on Modelling of Mantle and Lithosphere Dynamics, celebrado en Putten (Países Bajos), del 27 al 31 de agosto de 2017Peer reviewe

Tracking volume changes at intereruptive stage near South Sister Volcano (Oregon, USA)

Trabajo presentado en la European Geosciences Union General Assembly, celebrada en Viena (Austria), del 8 al 13 de abril de 2018The cluster of glaciated stratovolcanoes called the Three Sisters spreads out 20 km along the crest of the Cascade Range in Oregon (USA). The Three Sisters volcanic region extends about 40 km north and south of the Three Sisters, and contains at least 466 Quaternary volcanoes, being one of the most active volcanic areas in the Cascade Range. Scientific interest in the Three Sisters volcanic cluster was aroused in 2001, when an uplift process centered about 5 km west of South Sisters was identified, first noticed by Interferometric Synthetic Aperture Radar (InSAR). The extensively monitored area by this technique has been actively uplifting since about 1998. InSAR data from 1992 through 2001 showed an uplift rate in the area of 3-4 cm/yr. Then the deformation rate considerably decreased between 2004 and 2006 as shown by both InSAR and continuous GPS measurements. In order to analyze these features, the magmatic system geometry and location are determined. Then, a linear inversion of available deformation data (GPS and InSAR data) is performed to estimate the volume changes of the source along the analyzed time period. The strength of the methodology resides in allowing the joint inversion of InSAR measurements from multiple tracks with different look angles and three component GPS measurements from multiple sites. For this purpose, we apply a technique based on the Truncated Singular Value Decomposition (TSVD) of the Green’s function matrix representing the linear inversion. We provide a cut-off criteria for truncation without too much loose of resolution against the stability of the method. Furthermore, a strategy for the quantification of the uncertainty of the volume change time series is developed. Finally, the temporal behavior of the source volume changes is analyzed using a dynamic model based on HagenPoiseuille flow through a vertical conduit that leads to an increase in pressure within a spherical reservoir and time-dependent surface deformation. To consider the viscoelastic effects the reservoir is surrounded by a viscoelastic Maxwell shell. The volume time series are compared to predictions from the dynamic model to constrain model parameters, namely characteristic Poiseuille and Maxwell time scales, inlet and outlet injection pressure, and source and shell geometries. The modeling approach used here could be used to develop a mathematically rigorous strategy for including time-series of deformation data in the interpretation of volcanic unrest at intereruptive periods.Peer reviewe

On the origin of the Canary Islands: Insights from mantle convection modelling

The Canary Islands hotspot consists of seven volcanic islands, mainly of Neogene age, rooted on oceanic Jurassic lithosphere. Its complex structure and geodynamic setting have led to different hypotheses about its origin and evolution, which is still a matter of a vivid debate. In addition to the classic mantle plume hypothesis, a mechanism of small-scale mantle convection at the edge of cratons (Edge Driven Convection, EDC) has been proposed due to the close proximity of the archipelago to the NW edge of the NW African Craton. A combination of mantle plume upwelling and EDC has also been hypothesized. In this study we evaluate these hypotheses quantitatively by means of numerical two-dimensional thermo-mechanical models. We find that models assuming only EDC require sharp edges of the craton and predict too narrow areas of partial melting. Models where the ascent of an upper-mantle plume is forced result in an asymmetric mantle flow pattern due to the interplay between the plume and the strongly heterogeneous lithosphere. The resulting thermal anomaly in the asthenosphere migrates laterally, in agreement with the overall westward decrease of the age of the islands. We suggest that laterally moving plumes related to strong lithospheric heterogeneities could explain the observed discrepancies between geochronologically estimated hotspot rates and plate velocities for many hotspots

Some Insights about inversion of volcano deformation based on finite element models: An application to Kilauea volcano, Hawaii

Trabajo presentado en la 19th European Conference on Mathematics for Industry, celebrada en Santiago de Compostela (España), del 13 al 17 de junio de 2016Geodetic techniques, as Interferometric Synthetic Aperture Radar (InSAR), are being extensively used to monitor ground deformation at volcanic areas. The quantitative interpretation of such surface ground deformation measurements using geodetic data requires both, mathematical modelling to simulate the observed signals and inversion approaches to estimate the magmatic source parameters. In this study, we provide a numerical tool for interpreting deformation measurements by solving the inverse problem to estimate the optimal parameters for magmatic sources in an efficient and accurate way. We propose a Finite Element Model (FEM) for the calculation of Green functions in a mechanically heterogeneous domain. The key aspect of the methodology lies in applying the reciprocity relationship of the Green functions between the station and the source. In our approach, deformation sources are independent of the simulation mesh being incorporated as a source term in the model equations. The search for the best-fitting magmatic (point) source(s) is conducted for an array of 3-D locations extending below a predefined volume region. However, the total number of Green functions is reduced to the number of the observation points by using the, above mentioned, reciprocity relationship. We apply this methodology to the recent inflation episode observed at Kilauea’s summit and Southwest Rift Zone in May 2015. We measured the volcano ground displacements using data from the new Sentinel-1 radar interferometry satellite mission. This new methodology is able to accurately represent magmatic processes using physical models capable of simulating volcano deformation in non-uniform material properties distribution domains, which eventually will lead to better description of the status of the volcano.This work has been partially supported by the research project CGL2014-58821- C2-1-R.Peer reviewe