New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Implementación de dispositivos tecnológicos usados por terapeutas ocupacionales en la rehabilitación de extremidad superior posterior a un accidente cerebro vascular

Rehabilitation with exoskeletons in people with acquired brain injury is a topic of interest for researchers, since these robotic devices seek to recover the sensorimotor sequelae caused by the injury and improve the performance of the injured patient in activities of daily living. The objective of this study was to identify the contributions provided by the implementation of exoskeleton devices used by occupational therapy in the rehabilitation of upper limb in patients with stroke sequelae. The method used was a narrative review, with search strategies in the following databases: Scopus, Science Direct, Google Scholar and Pubmed. Articles published in English, Spanish and Portuguese were considered, with keywords in the titles and/or abstract. A total of 578 articles were identified and 7 were those that met the criteria for inclusion in this research. The results showed that exoskeleton-type devices enhance conventional rehabilitation, with glove-type exoskeletons, assisted limb and brain-computer interface powered exoskeletons standing out in this process. These devices, when incorporated by occupational therapists in rehabilitation, have shown to generate improvements in motor functionality and manipulative dexterity, which have been evidenced both in acute and chronic stages, generating an increase in the performance of users in the performance of their daily life activities.La rehabilitación con exoesqueletos en personas con daño cerebral adquirido es un tema de interés para los investigadores, ya que estos dispositivos robóticos buscan recuperar las secuelas sensoriomotrices causadas por la lesión y mejorar el desempeño del paciente secuelado en las actividades de la vida diaria. El objetivo de este estudio fue identificar los aportes que brinda la implementación de dispositivos exoesqueletos utilizados por la terapia ocupacional, en la rehabilitación de miembro superior en pacientes secuelados de accidente cerebro vascular. El método utilizado fue una revisión narrativa, con estrategias de búsqueda en las bases de datos: Scopus, Science Direct, Google Scholar y Pubmed. Se consideraron artículos publicados en inglés, español y portugués, con palabras claves en los títulos y/o resúmenes. Se identificaron 578 artículos y 7 fueron los que cumplieron los criterios para incluirse en esta investigación. Los resultados arrojaron que los dispositivos de tipo exoesqueleto potencian la rehabilitación convencional destacándose en este proceso los exoesqueletos de tipo guante, extremidad asistida y accionados mediante interfaz cerebro-computadora. Estos al ser incorporados por los terapeutas ocupacionales en la rehabilitación han demostrado generar mejoras en la funcionalidad motora y destreza manipulativa, las que se han evidenciado tanto en etapa aguda como crónica, generando un aumento en el desempeño de los usuarios en la realización de sus actividades de la vida diaria

Terrestial laser scanning digitalization in underground constructions

Spain has a large heritage in vernacular architecture among which the underground constructions can be highlighted. On many occasions these constructions were excavated hundreds of years ago and there is lack of technical information about their geometry or visual characteristics. Among the existing survey techniques, the terrestrial laser scanning technology seems one of the most appropriate and effective for these constructions. Given the high underground heritage in Spain and the lack of graphic documentation with good quality, there is a need to establish a quick and effective methodology aiming to classify these constructions in order to be included in the national heritage registers. To do so, the first step was to assess how aspects such as the scanner resolution, color and meshing strategy (post-processing phase) affect the quality of the graphic results generated. Then, the most adequate survey strategy was selected (based on a reference case study) and was further applied in seven representative underground constructions in order to validate the methodology and verify its effectiveness. Results indicate that a higher density of points is not always associated with a higher graphic quality in both the digital model and graphic information. The type of mesh used in the post-processing stage affects insignificantly the meshing surface, the graphic quality and the processing time of the digital model. On the contrary, it helps to filter unnecessary points in the cloud and thus obtain less heavy digital models. The resolution strategy can considerably increase the processing time of the models, however a lower resolution strategy combined with a higher number of shots is recommended to improve the graphic quality of the results. © 2019 Elsevier Masson SA

Natural ventilation analysis in an underground construction: CFD simulation and experimental validation

This work evaluates the thermal and natural ventilation behaviour in an underground construction and explains the passive behavior of the building components (tunnel, chimney and cave) in different periods of the year. The CFD models developed take into account the temperature gradients of the terrain, which allows a more realistic simulation of the natural ventilation in underground constructions. The role of the building components in the regulation of the indoor environment vary dramatically in each period. Results show that thermal stability with zero energy consumption is reached in the cave despite the extreme outdoor temperatures. Further, the access tunnel is the key element in the ventilation of the underground construction, where the ground temperature plays an essential role in regulating natural ventilation. By contrast, the ventilation chimney plays a less important role due to lower air velocities. The approach and adjustments of CFD models presented here could be useful as a reference for other underground projects as a decision-making in the design of optimized ventilation and energy management systems. © 201

TNF-α Plus IL-1β Induces Opposite Regulation of Cx43 Hemichannels and Gap Junctions in Mesangial Cells through a RhoA/ROCK-Dependent Pathway

Connexin 43 (Cx43) is expressed in kidney tissue where it forms hemichannels and gap junction channels. However, the possible functional relationship between these membrane channels and their role in damaged renal cells remains unknown. Here, analysis of ethidium uptake and thiobarbituric acid reactive species revealed that treatment with TNF-α plus IL-1β increases Cx43 hemichannel activity and oxidative stress in MES-13 cells (a cell line derived from mesangial cells), and in primary mesangial cells. The latter was also accompanied by a reduction in gap junctional communication, whereas Western blotting assays showed a progressive increase in phosphorylated MYPT (a target of RhoA/ROCK) and Cx43 upon TNF-α/IL-1β treatment. Additionally, inhibition of RhoA/ROCK strongly antagonized the TNF-α/IL-1β-induced activation of Cx43 hemichannels and reduction in gap junctional coupling. We propose that activation of Cx43 hemichannels and inhibition of cell–cell coupling during pro-inflammatory conditions could contribute to oxidative stress and damage of mesangial cells via the RhoA/ROCK pathway

CHLSOC: the Chilean Soil Organic Carbon database, a multi-institutional collaborative effort

A critical aspect of predicting soil organic carbon (SOC) concentrations is the lack of available soil information; where information on soil characteristics is available, it is usually focused on regions of high agricultural interest. To date, in Chile, a large proportion of the SOC data have been collected in areas of intensive agricultural or forestry use; however, vast areas beyond these forms of land use have few or no soil data available. Here we present a new SOC database for the country, which is the result of an unprecedented national effort under the framework of the Global Soil Partnership. This partnership has helped build the largest database of SOC to date in Chile, named the Chilean Soil Organic Carbon database (CHLSOC), comprising 13 612 data points compiled from numerous sources, including unpublished and difficult-to-access data. The database will allow users to fill spatial gaps where no SOC estimates were publicly available previously. Presented values of SOC range from 6 x 10(-5) % to 83.3 %, reflecting the variety of ecosystems that exist in Chile. The database has the potential to inform and test current models that predict SOC stocks and dynamics at larger spatial scales, thus enabling benefits from the richness of geochemical, topographic and climatic variability in Chile.Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 11160372 Convenio CONAF-UDeC 2015 Perturbaciones Araucaria ERANet-LAC joint program ELAC2014/DCC-0092 Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) CONICYT FONDECYT 1161492 Global Soil Partnership - Food and Agriculture Organization of the United Nations (FAO) South America Soil Partnership - Food and Agriculture Organization of the United Nations (FAO