Mortalidad entre los pacientes en tratamiento con metadona e infectados con el virus de la inmunodeficiencia humana y/o hepatitis C [Mortality rate in patients on methadone treatment and infected with the human immunodeficiency virus and/or the hepatitis C virus ]

Sr. Director: La adicción a la heroína es una enfermedad recidivante crónica con graves consecuencias, particularmente en términos de prematura y alta mortalidad (Hser, Hoffman, Grella y Anglin, 2001). Los programas de tratamiento de mantenimiento con metadona (TMM) han demostrado ser eficaces para reducir el uso ilícito de opioides, y el riesgo de infección por el virus de la inmunodeficiencia humana (VIH) y/o virus de la hepatitis C (VHC), entre otras variables (Kleber, 2008; Pedrero-Pérez y MethaQoL, 2017). A pesar de todo, la tasa de mortalidad anual entre los pacientes incluidos en programas de TMM, aproximadamente del 1%, es más de 10 veces superior al de la población general (Zanis y Woody, 1998); constituyendo la sobredosis y la infección por VIH y otros virus transmitidos por la sangre (p.e. VHC) las causas más comunes de muerte (Roncero, Vega, Martinez-Raga y Torrens, 2017). En efecto, entre los drogodependientes por vía parenteral e infectados por VIH, la co-infección por VIH y VHC se observa en el 50% -95% de los casos (Muga, Roca, Egea, Tor, Sirera y Rey-Joly, 2000); pudiendo provocar, dicha infección simultanea por VIH, una mayor carga viral del VHC y una evolución más rápida a la cirrosis hepática y sus complicaciones (Santos y Sanz, 22004; Elizalde, Iñarrairaegui, Rodríguez y Zozaya, 2004)... Dear Director, Heroin addiction is a chronic, relapsing disease with serious consequences, particularly in terms of premature and high mortality (Hser, Hoffman, Grella & Anglin, 2001). Methadone maintenance treatment programs (MMT’s) have shown to be effective in reducing illicit opioid use and the risk of infection with human immunodeficiency virus (HIV) and/or Hepatitis C virus (HCV), among other (Kleber, 2008; Pedrero-Pérez & MethaQoL, 2017). Nevertheless, the approximately 1% annual mortality among MMT patients is more than 10 times that of the general population (Zanis &y Woody, 1998); and overdose, HIV infection (VIH), and other viruses transmitted by blood (e.g., HCV infection) constitute the most common causes of death (Roncero, Vega, Martinez-Raga & Torrens, 2017). In fact, among HIV-infected patients, HIV–HCV co-infection is observed in 50–95% of cases (Muga, Roca, Egea, Tor, Sirera & Rey-Joly, 2000); this simultaneous HIV infection can cause an increased viral load of HCV and a more rapid evolution to liver cirrhosis and its complications (Santos & Sanz, 2004; Elizalde, Iñarrairaegui, Rodríguez & Zozaya, 2004)..

Propuesta de evaluación del aprendizaje en materias científico-técnicas

El presente trabajo pretende mostrar un sistema de evaluación que se lleva acabo en materias científico-técnicas donde el contenido práctico es considerable. Se pretende considerar los distintos instrumentos y formas de evaluación del aprendizaje de los estudiantes. El objetivo principal de este trabajo pretende entender que examinar y calificar no son actos de menor importancia, sino que suponen una gran influencia en todo el proceso y pueden o no, ayudar y animar a los estudiantes en su principal tarea del aprendizaje y su progreso. La propuesta permite desarrollar las siguientes técnicas docentes: sesiones académicas teóricas, prácticas, exposición y debate, seminarios y jornadas, tutorías colectivas y además visitas facultativas

Cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy.

After allotransplantation, cytomegalovirus (CMV) may be transmitted from the donor organ, giving rise to primary infection in a CMV negative recipient or reinfection in one who is CMV positive. In addition, latent CMV may reactivate in a CMV positive recipient. In this study, serial blood samples from 689 kidney or liver transplant recipients were tested for CMV DNA by quantitative PCR. CMV was managed using preemptive antiviral therapy and no patient received antiviral prophylaxis. Dynamic and quantitative measures of viremia and treatment were assessed. Median peak viral load, duration of viremia and duration of treatment were highest during primary infection, followed by reinfection then reactivation. In patients who experienced a second episode of viremia, the viral replication rate was significantly slower than in the first episode. Our data provide a clear demonstration of the immune control of CMV in immunosuppressed patients and emphasize the effectiveness of the preemptive approach for prevention of CMV syndrome and end organ disease. Overall, our findings provide quantitative biomarkers which can be used in pharmacodynamic assessments of the ability of novel CMV vaccines or antiviral drugs to reduce or even interrupt such transmission

PELIGROSIDAD A LOS MOVIMIENTOS DE LADERA EN LA VERTIENTE MERIDIONAL DE SIERRA NEVADA (GRANADA) A PARTIR DE LA ESTIMACIÓN MULTI-TÉCNICA DE LA ACTIVIDAD

El presente trabajo aborda la cartografía de la susceptibilidad y la peligrosidad a los movimientos de ladera, en un ambiente montañoso, con información limitada sobre su actividad. El análisis y validación de la susceptibilidad se realizada mediante un modelo elaborado a partir del ModelBuilder™ de ArcGIS basado en el Método de la Matriz en un SIG. Dicho modelo necesita una cartografía previa de los movimientos, un MDE y un análisis discriminante de los factores determinantes de la estabilidad. Los datos del análisis reflejan que el 15% de la zona estudiada muestra una susceptibilidad a los movimientos de moderada a muy alta que, a su vez, coincide con lugares donde se encuentran la mayoría de las infraestructuras públicas de la región. Además, los valores registrados en la validación mediante el grado de ajuste están por encima del 83% para las zonas de susceptibilidad alta y muy alta. Estas zonas que presentan un mayor grado de susceptibilidad y, por tanto, una mayor exposición potencial al riesgo, son las seleccionadas para el análisis detallado de la peligrosidad. El principal problema, que, por otra parte, suele ser generalizado en este tipo de áreas para la estimación de la frecuencia con la que se suceden movimientos de ladera, es la falta de información sobre su ocurrencia. Por tanto, y con el objetivo de obtener la mayor información posible, los datos relativos a la actividad de los movimientos se extraen de diversas fuentes y técnicas, de forma que interactivamente solventen sus correspondientes limitaciones. Estos datos se extraen de una documentación previa, tanto en prensa como bibliografía específica, donde se presentan trabajos sobre DInSAR, fotogrametría aérea y LIDAR, y TLS. Además, se realiza de forma específica un análisis dendrogeomorfológico de árboles en movimientos de ladera y se revisa la ortofotografía aérea histórica de la zona de estudio. Posteriormente, con los datos de actividad, se realiza un análisis de los factores desencadenantes, que refleja que los movimientos de ladera están relacionados con episodios de precipitaciones intensas y prolongadas, y no tanto con la actividad sísmica del área. Por último, de forma indirecta, se estima la peligrosidad de la zona de estudio a los movimientos de ladera, asociando los resultados obtenidos de actividad con los factores desencadenantes; esto es, con periodos de precipitaciones intensas. Así, se establece un periodo de retorno que se extrapola a toda el área, con la asunción de que los grandes deslizamientos se generan o reactivan, conjuntamente con movimientos superficiales, tras periodos lluviosos intensos y prolongados, y que las lluvias torrenciales generan movimientos de ladera superficiales tipo flujo y desprendimientos. Los resultados obtenidos indican que la frecuencia con la que se generan los movimientos es de 5 años para los flujos superficiales y desprendimientos (F=0,2), y de 18 años para los deslizamientos y movimientos complejos (F=0,06). La zona, en términos generales, presenta determinados sectores con susceptibilidad moderada a muy alta, sin embargo la peligrosidad a los movimientos de ladera es de moderada a muy baja. En términos de probabilidad temporal, los flujos y desprendimientos son los movimientos con mayor peligrosidad

Propuesta de evaluación del aprendizaje en materias científico-técnicas

El presente trabajo pretende mostrar un sistema de evaluación que se lleva acabo en materias científico-técnicas donde el contenido práctico es considerable. Se pretende considerar los distintos instrumentos y formas de evaluación del aprendizaje de los estudiantes. El objetivo principal de este trabajo pretende entender que examinar y calificar no son actos de menor importancia, sino que suponen una gran influencia en todo el proceso y pueden o no, ayudar y animar a los estudiantes en su principal tarea del aprendizaje y su progreso. La propuesta permite desarrollar las siguientes técnicas docentes: sesiones académicas teóricas, prácticas, exposición y debate, seminarios y jornadas, tutorías colectivas y además visitas facultativas

Physiological and genetic control of transpiration efficiency in African rice, Oryza glaberrima Steud

Improving crop water use efficiency, the amount of carbon assimilated as biomass per unit of water used by a plant, is of major importance as water for agriculture becomes scarcer. In rice, the genetic bases of transpiration efficiency, the derivation of water use efficiency at the whole-plant scale, and its putative component trait transpiration restriction under high evaporative demand remain unknown. These traits were measured in 2019 in a panel of 147 African rice (Oryza glaberrima) genotypes known to be potential sources of tolerance genes to biotic and abiotic stresses. Our results reveal that higher transpiration efficiency is associated with transpiration restriction in African rice. Detailed measurements in a subset of highly contrasted genotypes in terms of biomass accumulation and transpiration confirmed these associations and suggested that root to shoot ratio played an important role in transpiration restriction. Genome wide association studies identified marker-trait associations for transpiration response to evaporative demand, transpiration efficiency, and its residuals, with links to genes involved in water transport and cell wall patterning. Our data suggest that root-shoot partitioning is an important component of transpiration restriction that has a positive effect on transpiration efficiency in African rice. Both traits are heritable and define targets for breeding rice with improved water use strategies.This work was supported by the Institut de Recherche pour le Développement, the CGIAR Research Program (CRP) on rice-agrifood systems (RICE, 2017-2022) and the Agence Nationale de la Recherche (grant ANR-17-MPGA-0011 to VV). Financial support by the Access to Research Infrastructures activity in the Horizon 2020 Programme of the EU (EPPN2020 Grant Agreement 731013) is gratefully acknowledged. PA was supported by a doctoral fellowship from the French Ministry of Higher Education. BEE was supported by the Centre National de la Recherche Scientifique et Technologique of Gabon. The authors acknowledge the IRD iTrop HPC (South Green Platform) at IRD Montpellier for providing HPC resources (https://bioinfo.ird.fr, http://www.southgreen.fr)

In Silico Analysis of the Apolipoprotein E and the Amyloid β Peptide Interaction: Misfolding Induced by Frustration of the Salt Bridge Network

The relationship between Apolipoprotein E (ApoE) and the aggregation processes of the amyloid β (Aβ) peptide has been shown to be crucial for Alzheimer's disease (AD). The presence of the ApoE4 isoform is considered to be a contributing risk factor for AD. However, the detailed molecular properties of ApoE4 interacting with the Aβ peptide are unknown, although various mechanisms have been proposed to explain the physiological and pathological role of this relationship. Here, computer simulations have been used to investigate the process of Aβ interaction with the N-terminal domain of the human ApoE isoforms (ApoE2, ApoE3 and ApoE4). Molecular docking combined with molecular dynamics simulations have been undertaken to determine the Aβ peptide binding sites and the relative stability of binding to each of the ApoE isoforms. Our results show that from the several ApoE isoforms investigated, only ApoE4 presents a misfolded intermediate when bound to Aβ. Moreover, the initial α-helix used as the Aβ peptide model structure also becomes unstructured due to the interaction with ApoE4. These structural changes appear to be related to a rearrangement of the salt bridge network in ApoE4, for which we propose a model. It seems plausible that ApoE4 in its partially unfolded state is incapable of performing the clearance of Aβ, thereby promoting amyloid forming processes. Hence, the proposed model can be used to identify potential drug binding sites in the ApoE4-Aβ complex, where the interaction between the two molecules can be inhibited

3D Mapping of the SPRY2 Domain of Ryanodine Receptor 1 by Single-Particle Cryo-EM

The type 1 skeletal muscle ryanodine receptor (RyR1) is principally responsible for Ca2+ release from the sarcoplasmic reticulum and for the subsequent muscle contraction. The RyR1 contains three SPRY domains. SPRY domains are generally known to mediate protein-protein interactions, however the location of the three SPRY domains in the 3D structure of the RyR1 is not known. Combining immunolabeling and single-particle cryo-electron microscopy we have mapped the SPRY2 domain (S1085-V1208) in the 3D structure of RyR1 using three different antibodies against the SPRY2 domain. Two obstacles for the image processing procedure; limited amount of data and signal dilution introduced by the multiple orientations of the antibody bound in the tetrameric RyR1, were overcome by modifying the 3D reconstruction scheme. This approach enabled us to ascertain that the three antibodies bind to the same region, to obtain a 3D reconstruction of RyR1 with the antibody bound, and to map SPRY2 to the periphery of the cytoplasmic domain of RyR1. We report here the first 3D localization of a SPRY2 domain in any known RyR isoform

A Major Role for Side-Chain Polyglutamine Hydrogen Bonding in Irreversible Ataxin-3 Aggregation

The protein ataxin-3 consists of an N-terminal globular Josephin domain (JD) and an unstructured C-terminal region containing a stretch of consecutive glutamines that triggers the neurodegenerative disorder spinocerebellar ataxia type 3, when it is expanded beyond a critical threshold. The disease results from misfolding and aggregation, although the pathway and structure of the aggregation intermediates are not fully understood. In order to provide insight into the mechanism of the process, we monitored the aggregation of a normal (AT3Q24) ataxin-3, an expanded (AT3Q55) ataxin-3, and the JD in isolation. We observed that all of them aggregated, although the latter did so at a much slower rate. Furthermore, the expanded AT3Q55 displayed a substantially different behavior with respect to the two other variants in that at the latest stages of the process it was the only one that did the following: i) lost its reactivity towards an anti-oligomer antibody, ii) generated SDS-insoluble aggregates, iii) gave rise to bundles of elongated fibrils, and iv) displayed two additional bands at 1604 and 1656 cm−1 in FTIR spectroscopy. Although these were previously observed in other aggregated polyglutamine proteins, no one has assigned them unambiguously, yet. By H/D exchange experiments we show for the first time that they can be ascribed to glutamine side-chain hydrogen bonding, which is therefore the hallmark of irreversibly SDS-insoluble aggregated protein. FTIR spectra also showed that main-chain intermolecular hydrogen bonding preceded that of glutamine side-chains, which suggests that the former favors the latter by reorganizing backbone geometry

A Major Role for Side-Chain Polyglutamine Hydrogen Bonding in Irreversible Ataxin-3 Aggregation

The protein ataxin-3 consists of an N-terminal globular Josephin domain (JD) and an unstructured C-terminal region containing a stretch of consecutive glutamines that triggers the neurodegenerative disorder spinocerebellar ataxia type 3, when it is expanded beyond a critical threshold. The disease results from misfolding and aggregation, although the pathway and structure of the aggregation intermediates are not fully understood. In order to provide insight into the mechanism of the process, we monitored the aggregation of a normal (AT3Q24) ataxin-3, an expanded (AT3Q55) ataxin-3, and the JD in isolation. We observed that all of them aggregated, although the latter did so at a much slower rate. Furthermore, the expanded AT3Q55 displayed a substantially different behavior with respect to the two other variants in that at the latest stages of the process it was the only one that did the following: i) lost its reactivity towards an anti-oligomer antibody, ii) generated SDS-insoluble aggregates, iii) gave rise to bundles of elongated fibrils, and iv) displayed two additional bands at 1604 and 1656 cm−1 in FTIR spectroscopy. Although these were previously observed in other aggregated polyglutamine proteins, no one has assigned them unambiguously, yet. By H/D exchange experiments we show for the first time that they can be ascribed to glutamine side-chain hydrogen bonding, which is therefore the hallmark of irreversibly SDS-insoluble aggregated protein. FTIR spectra also showed that main-chain intermolecular hydrogen bonding preceded that of glutamine side-chains, which suggests that the former favors the latter by reorganizing backbone geometry