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

Primary Human Lung Alveolus-on-a-chip Model of Intravascular Thrombosis for Assessment of Therapeutics

Pulmonary thrombosis is a significant cause of patient mortality; however, there are no effective in vitro models of thrombi formation in human lung microvessels that could also assess therapeutics and toxicology of antithrombotic drugs. Here, we show that a microfluidic lung alveolus-on-a-chip lined by human primary alveolar epithelium interfaced with endothelium and cultured under flowing whole blood can be used to perform quantitative analysis of organ-level contributions to inflammation-induced thrombosis. This microfluidic chip recapitulates in vivo responses, including platelet-endothelial dynamics and revealed that lipopolysaccharide (LPS) endotoxin indirectly stimulates intravascular thrombosis by activating the alveolar epithelium, rather than acting directly on endothelium. This model is also used to analyze inhibition of endothelial activation and thrombosis due to a protease activated receptor-1 (PAR-1) antagonist, demonstrating its ability to dissect complex responses and identify antithrombotic therapeutics. Thus, this methodology offers a new approach to study human pathophysiology of pulmonary thrombosis and advance drug development

Assessment of whole blood thrombosis in a microfluidic device lined by fixed human endothelium

The vascular endothelium and shear stress are critical determinants of physiological hemostasis and platelet function in vivo, yet current diagnostic and monitoring devices do not fully incorporate endothelial function under flow in their assessment and, therefore, they can be unreliable and inaccurate. It is challenging to include the endothelium in assays for clinical laboratories or point-of-care settings because living cell cultures are not sufficiently robust. Here, we describe a microfluidic device that is lined by a human endothelium that is chemically fixed, but still retains its ability to modulate hemostasis under continuous flow in vitro even after few days of storage. This device lined with a fixed endothelium supports formation of platelet-rich thrombi in the presence of physiological shear, similar to a living arterial vessel. We demonstrate the potential clinical value of this device by showing that thrombus formation and platelet function can be measured within minutes using a small volume (0.5 mL) of whole blood taken from subjects receiving antiplatelet medications. The inclusion of a fixed endothelial microvessel will lead to biomimetic analytical devices that can potentially be used for diagnostics and point-of-care applications. Electronic supplementary material The online version of this article (doi:10.1007/s10544-016-0095-6) contains supplementary material, which is available to authorized users

Loss of α-hemoglobin–stabilizing protein impairs erythropoiesis and exacerbates β-thalassemia

Hemoglobin (Hb) A production during red blood cell development is coordinated to minimize the deleterious effects of free α- and β-Hb subunits, which are unstable and cytotoxic. The α-Hb–stabilizing protein (AHSP) is an erythroid protein that specifically binds α-Hb and prevents its precipitation in vitro, which suggests that it may function to limit free α-Hb toxicities in vivo. We investigated this possibility through gene ablation and biochemical studies. AHSP(–/–) erythrocytes contained hemoglobin precipitates and were short-lived. In hematopoietic tissues, erythroid precursors were elevated in number but exhibited increased apoptosis. Consistent with unstable α-Hb, AHSP(–/–) erythrocytes contained increased ROS and evidence of oxidative damage. Moreover, purified recombinant AHSP inhibited ROS production by α-Hb in solution. Finally, loss of AHSP worsened the phenotype of β-thalassemia, a common inherited anemia characterized by excess free α-Hb. Together, the data support a model in which AHSP binds α-Hb transiently to stabilize its conformation and render it biochemically inert prior to Hb A assembly. This function is essential for normal erythropoiesis and, to a greater extent, in β-thalassemia. Our findings raise the possibility that altered AHSP expression levels could modulate the severity of β-thalassemia in humans