Genetic Diversity of Toscana Virus

Distribution of Toscana virus (TOSV) is evolving with climate change, and pathogenicity may be higher in nonexposed populations outside areas of current prevalence (Mediterranean Basin). To characterize genetic diversity of TOSV, we determined the coding sequences of isolates from Spain and France. TOSV is more diverse than other well-studied phleboviruses (e.g.,Rift Valley fever virus)

Implication of type 4 NADPH oxidase (NOX4) in tauopathy.

Aggregates of the microtubule-associated protein tau are a common marker of neurodegenerative diseases collectively termed as tauopathies, such as Alzheimer’s disease (AD) and frontotemporal dementia. Therapeutic strategies based on tau have failed in late stage clinical trials, suggesting that tauopathy may be the consequence of upstream causal mechanisms. As increasing levels of reactive oxygen species (ROS) may trigger protein aggregation or modulate protein degradation and, we had previously shown that the ROS producing enzyme NADPH oxidase 4 (NOX4) is a major contributor to cellular autotoxicity, this study was designed to evaluate if NOX4 is implicated in tauopathy. Our results show that NOX4 is upregulated in patients with frontotemporal lobar degeneration and AD patients and, in a humanized mouse model of tauopathy induced by AVV-TauP301L brain delivery. Both, global knockout and neuronal knockdown of the Nox4 gene in mice, diminished the accumulation of pathological tau and positively modified established tauopathy by a mechanism that implicates modulation of the autophagy-lysosomal pathway (ALP) and, consequently, improving the macroautophagy flux. Moreover, neuronal-targeted NOX4 knockdown was sufficient to reduce neurotoxicity and prevent cognitive decline, even after induction of tauopathy, suggesting a direct and causal role for neuronal NOX4 in tauopathy. Thus, NOX4 is a previously unrecognized causative, mechanism-based target in tauopathies and blood-brain barrier permeable specific NOX4 inhibitors could have therapeutic potential even in established disease.post-print5895 K

Chikungunya virus infections among travellers returning to Spain, 2008 to 2014

Since the first documented autochthonous transmission of chikungunya virus in the Caribbean island of Saint Martin in 2013, the infection has been reported within the Caribbean region as well as North, Central and South America. The risk of autochthonous transmission of chikungunya virus becoming established in Spain may be elevated due to the large numbers of travellers returning to Spain from countries affected by the 2013 epidemic in the Caribbean and South America, as well as the existence of the Aedes albopictus vector in certain parts of Spain. We retrospectively analysed the laboratory diagnostic database of the National Centre for Microbiology, Institute of Health Carlos III (CNM-ISCIII) from 2008 to 2014. During the study period, 264 confirmed cases, of 1,371 suspected cases, were diagnosed at the CNM-ISCIII. In 2014 alone, there were 234 confirmed cases. The highest number of confirmed cases were reported from the Dominican Republic (n = 136), Venezuela (n = 30) and Haiti (n = 11). Six cases were viraemic in areas of Spain where the vector is present. This report highlights the need for integrated active case and vector surveillance in Spain and other parts of Europe where chikungunya virus may be introduced by returning travellers

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)

Pasados y presente. Estudios para el profesor Ricardo García Cárcel

Ricardo García Cárcel (Requena, 1948) estudió Historia en Valencia bajo el magisterio de Joan Reglà, con quien formó parte del primer profesorado de historia moderna en la Universidad Autónoma de Barcelona. En esta universidad, desde hace prácticamente cincuenta años, ha desarrollado una extraordinaria labor docente y de investigación marcada por un sagaz instinto histórico, que le ha convertido en pionero de casi todo lo que ha estudiado: las Germanías, la historia de la Cataluña moderna, la Inquisición, las culturas del Siglo de Oro, la Leyenda Negra, Felipe II, Felipe V, Austrias y Borbones, la guerra de la Independencia, la historia cultural, los mitos de la historia de España... Muy pocos tienen su capacidad para reflexionar, ordenar, analizar, conceptualizar y proponer una visión amplia y llena de matices sobre el pasado y las interpretaciones historiográficas. A su laboriosidad inimitable se añade una dedicación sin límites en el asesoramiento de alumnos e investigadores e impulsando revistas, dosieres, seminarios o publicaciones colectivas. Una mínima correspondencia a su generosidad lo constituye este volumen a manera de ineludible agradecimiento

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

Seismic anisotropy in subduction zones: numerical modeling and infinite strain axis calculations

Trabajo presentado en el AGU (American Geophysical Union) Fall Meeting: Advancing Earth and Space Science, celebrado en San Francisco (Estados Unidos), del 12 al 16 de diciembre de 2016Subduction zones show significant variability in shear wave splitting, both above and below the slab, and along-strike. For example, in the Peruvian flat slab region, where the slab has a 3D morphology, shear wave splitting shows complex patterns that indicate that the anisotropic structure varies both laterally and vertically. Above the flat-slab, fast directions measured on shear wave splitting of local S phases are dominantly trench-parallel north of the Nazca Ridge, but become more complicated towards the south as the slab steepens. For SKS phases that sample the whole subduction zone, there is an intriguing and pronounced region of nulls measurements, which could indicate either an apparent lack of mantle anisotropy or seismic anisotropy with a vertically aligned symmetry axis. Seismic anisotropy is often interpreted as the result of lattice preferred orientation (LPO) of olivine due to flow in the mantle. We provide some insight into the relationship between mantle flow and seismic anisotropy using 3D numerical modeling and infinite strain axis (ISA) calculations. Our models include a slab with along-strike variable geometry that changes rapidly with time. The changing geometry of the slab induces a complex mantle flow with both vertical and trench-parallel components. Trench-parallel flow is intense in broad regions in the mantle wedge (~1 cm/yr) and in the sub-slab mantle (>2 cm/yr). We obtain some regions of trench-parallel ISA in the supra-slab mantle, compatible with observations. However, below the slab, the ISA is mostly vertical, with trench-parallel ISA present only in narrow regions. Vertical ISA in broad regions could potentially offer an explanation for the null SKS splitting measurements found below the Peruvian flat-slab region.Peer reviewe

The Hog1 Mitogen-Activated Protein Kinase Is Essential in the Oxidative Stress Response and Chlamydospore Formation in Candida albicans

Candida albicans mutants with mutations in mitogen-activated protein (MAP) kinase HOG1 displayed an increased sensitivity to agents producing reactive oxygen species, such as oxidants (menadione, hydrogen peroxide, or potassium superoxide), and UV light. Consistent with this finding, C. albicans Hog1 was activated not only in response to an increase in external osmolarity, as happens with its Saccharomyces cerevisiae homologue, but also in response to hydrogen peroxide. The Hog1-mediated response to oxidative stress was different from that of transcription factor Cap1, the homologue of S. cerevisiae Yap1, as shown by the different sensitivities to oxidants and the kinetics of cell death of cap1Δ, hog1, and hog1 cap1Δ mutants. Deletion of CAP1 did not influence the level of Hog1 phosphorylation, and deletion of HOG1 did not affect Cap1 nuclear localization. Moreover, we show that the HOG1 gene plays a role in chlamydospore formation, another oxygen-related morphogenetic event, as demonstrated by the fact that hog1 cells were unable to generate these thick-walled structures in several media through a mechanism different from that of the EFG1 regulator. This is the first demonstration of the role of the Hog1-mediated MAP kinase pathway in resistance to oxidative stress in pathogenic fungi, and it allows us to propose a molecular model for the oxidative stress response in C. albicans