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Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Programme, Neurodegenerative Disease Research (JPND). Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Part of the work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI was part of and funded by the Dutch Federation of University Medical Centers and has received initial funding from the Dutch Government (from 2007-2011). Since 2020, this work was carried out in the context of Parelsnoer clinical biobanks at Health-RI (https://www.health-ri.nl/initiatives/parelsnoer).Part of the genotyping included in this work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Alfredo Ramirez is also supported by the German Research Foundation (DFG) grants Nr: RA 1971/6-1, RA1971/7-1, and RA 1971/8-1. We would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria 'La Caixa', Fundacio ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'). The position held by I.dR. is funded by grant. FI20/00215. PFIS Contratos Predoctorales de Formacion en Investigacion en Salud. We would like to thank UCL Genomics, London, UK, for performing the genotyping analyses of the samples within the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444, and P01AG003991. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenom ics.wustl.edu/)and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Research at the Belgian EADB site is funded in part by the Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund. The work of Valdecilla was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigacion Sanitario, PI08/0139, PI12/02288, PI16/01652, and PI20/01011), the JPND (DEMTEST PI11/03028), the CIBERNED, and the Siemens Healthineers. We thank the Valdecilla Biobank (PT17/0015/0019), integrated into the Spanish Biobank Network, for their support and collaboration in sample collection and management. Our heartfelt thanks to the participants of the Valdecilla Cohort for their generosity. The work of ADGEN was supported by EU Joint Programme-Neurodegenerative Disease Research (301220) and the Academy of Finland (338182). The DELCODE study (Study-ID:BN012) was supported and conducted by the German Center for Neurodegenerative Diseases (DZNE). The data samples were provided by the DELCODE study group. Details and participating sites can be found at www.dzne.de/en/research/studies/clinical-studies/delco de. The German Dementia Competence Network (KND) is funded by the German Federal Ministry of Education and Research (BMBF) grants Number: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711. WF, SvdL, HHolstege, CT and PhS are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and HealthHolland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD (www.aboard-project.nl).ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds and Gieskes-Strijbisfonds. IEJ was partially supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). AZ was supported by the Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361), and the Dementia Foundation (2020-04-13, 2021-0417). ISk was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALFagreement (ALF 716681), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 20050762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 20132496), Swedish Brain Power, Hjarnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163), the Alzheimer's Association Zenith Award (ZEN-01-3151), the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159), the Alzheimer's Association (IIRG-03-6168, IIRG-09-131338) and the Bank of Sweden Tercentenary Foundation. SK was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALF GBG-771071), the Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825), and the Swedish Research Council (2019-02075). MW was supported by the Swedish Research Council 2016-01590. DP was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (2018092016862), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB was supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG06839801), and the Alzheimer's Association 2021 Zenith Award (ZEN-21848495). CC receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614), and the Chuck Zuckerberg Initiative (CZI).

The original version of this Article omitted from the author list the 212th author Patrizia Mecocci, who is from the Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy. Consequently, the “Sample Contribution” section of Author Contributions was updated to add “P.M” between “P.D.” and “R.C.”. Additionally, the original version of this Article contained the incorrect affiliation for author Patrick Gavin Kehoe, which incorrectly read “German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany”. The correct version replaces this affiliation with “Bristol Medical School (THS), University of Bristol, Southmead Hospital, Bristol, UK”. This has been corrected in both the PDF and HTML versions of the Article. CA extern

Este informe, elaborado por el equipo del Centro Tecnológico Naval y del Mar, tiene como finalidad ofrecer al tejido empresarial una mejora en el conocimiento del entorno que permita detectar tendencias y desarrollar estrategias adecuadas, basadas en niveles superiores de certidumbre a través de la captación y divulgación de información y conocimiento de importancia estratégica en los ámbitos social, tecnológico y económico, que incidan en la detección de nuevas oportunidades de desarrollo regional. Los contenidos de este informe están estrechamente relacionados con el desarrollo del proyectoInvestigación de múltiples tecnologías de comunicación para la mejora de re-des de sensores inalámbricos en la monitorización del medio marino. MODEMaplicaredes de comunicación inalámbrica e IoT (Internet de las Cosas) para el desarrollo de sistemas de seguimiento y medición a bajo coste aptos para el medio marino.

Este informe, elaborado por el equipo del Centro Tecnológico Naval y del Mar, tiene como finalidad ofrecer al tejido empresarial una mejora en el conocimiento del entorno que permita detectar tendencias y desarrollar estrategias adecuadas, basadas en niveles superiores de certidumbre a través de la captación y divulgación de información y conocimiento de importancia estratégica en los ámbitos social, tecnológico y económico, que incidan en la detección de nuevas oportunidades de desarrollo regional. Los contenidos de este informe están estrechamente relacionados con el desarrollo del proyecto Investigación y optimización de técnicas de modelización, clasificación y predicción de series temporales, con aplicación al entorno marino. FORECAST aplica modelos basados en IA (Inteligencia Artificial) para encontrar una metodología óptima para el estudio de series temporales. Busca desarrollar un modelo de análisis ágil y certero que permita optimizar las tareas de predicción a través del uso de series temporales y mediante la caracterización y modelización de datos del medio marino.

This case study is devoted to the rising phenomenon of corporate universities. Since organizations can only be competitive and successful with the right approach by investing in the training and development of their employees, there is a need for learning institutions. By analyzing the most famous corporate universities – namely Hamburger University and Disney University – the key success factors of such institutes are shown. The aim of this work ist to show the different approaches of each corporate university - with focus on training leadership or excellent customer service.

Resumen Los trazos de la canción podría definirse como la biografía espiritual del autor británico Bruce Chatwin (1940-1989). En esta obra vuelca todas sus obsesiones y se da cuenta en ella de que llegó la hora de explicar la naturaleza de su desasosiego, ese impulso inexplicable que le alejaba de casa insistentemente. Publicada dos años antes de su muerte, en ella vierte todas las ideas que habían estado madurando desde su niñez. La aventura de dos hombres explorando los lugares más remotos de la Australia aborigen logró, además, un gran éxito de público y crítica. Encontró en el mito indígena de la creación un espejo de todas sus preocupaciones sobre el nomadismo. Escribió sobre gente que da origen a su mundo en movimiento. Con el fin de analizar cómo el autor conjuga estas ideas, el presente artículo indaga, en primer lugar, en el nacimiento de su interés por el nomadismo y Australia. En segundo lugar, profundiza en cómo la filosofía aborigen le sirve como vehículo para explicar su propio impulso nómada. Finalmente, examina el capítulo de Los trazos de la canción titulado De las libretas de apuntes, puesto que constituye la columna vertebral de su filosofía personal. Abstract The Songlines could be defined as the spiritual biography of British writer Bruce Chatwin (1940-1989). In this book he reveals his obsessions and he realizes that it is time to explain the root of his restlessness, that unexplainable urge to flee from home. Published two years before his death, he brings to light the ideas he had been nurturing since childhood. The adventure of two men exploring the virgin territory of Australia reaped enormous critical and public success. He found in the aboriginal creation myth a representation of his concern on nomadism. He wrote about people who create their world in motion. In order to analyze how the author incorporates all these ideas, the first section of the present article examines the origin of his interest in nomadism and Australia. Secondly, it deepens on how the aboriginal philosophy helps him explain his own nomadic urge. Finally, the article considers the chapter titled From the Notebooks, because it constitutes the backbone of his personal philosophy.

Los contenidos sobre la Responsabilidad Social que se enseñan en las universidades impactan indirectamente sobre su aplicación en las empresas, porque esos contenidos influyen en la forma como los futuros líderes empresariales interpretan y aplican este concepto. La investigación se diseñó con el objetivo de evaluar si coinciden o divergen los conocimientos y opiniones sobre la Responsabilidad Social Interna adquiridos por estudiantes de diferentes universidades. Se aplicó, en forma auto-administrada, un cuestionario estructurado a una muestra no probabilística de estudiantes de tres universidades radicadas en: Colombia, España y Uruguay. Se utilizaron baterías de indicadores que miden: 1) la forma como los estudiantes interpretan el concepto de Responsabilidad Social Interna, 2) su conocimiento sobre las funciones que debe cumplir el área de recursos humanos cuando se aplica la Responsabilidad Social y 3) sus opiniones sobre los beneficios que genera la Responsabilidad Social Interna para la relación de las empresas con sus empleados. En este documento se presentan resultados basados en información preliminar. Se encontró que existen, entre los estudiantes de las tres universidades, diferencias estadísticamente significativas en la forma de interpretar la Responsabilidad Social Interna, pero no ocurre lo mismo con su conocimiento sobre las funciones del área de Recursos y Humanos y en su opinión sobre los beneficios que ella genera.

The manuscript refers to the challenge and the uncertainty in Ciudad Juarez, Chihuahua, and San Luis Rio Colorado, Sonora, for the pandemic (COVID 19). Like border cities. They have a geostrategic position because of their closeness to the United States. Both destinations have the necessary tourist infrastructure to serve and receive national and international visitors. Both cities have health restrictions, the slowdown in the economy, and the closure of borders, situations that have put the entire tourism industry in social, economic ambiguity. Other realities are the similarities on issues their territory; mutually, cities seek bi-national collaboration. And have experienced in the field of medical tourism, which allows them to generate attractive tourist products that motivate binational mobility. Although which aims to create interdependent agreements in the Buffer Zone (Paso del Norte Region) and position the city brand, reinforcing from an operational approach for workers and tourism service providers. To analyze the ambiance, we use the SWOT and Semantic Networks. This quality technics, it could display the Sustainable Dynamic Strategic Lines related in these two cities in the north of Mexico.

Weitere Nicht-UDE Autoren sind nicht genannt. Importance: The behavioral and cognitive symptoms of severe psychotic disorders overlap with those seen in dementia. However, shared brain alterations remain disputed, and their relevance for patients in at-risk disease stages has not been explored so far. Objective: To use machine learning to compare the expression of structural magnetic resonance imaging (MRI) patterns of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer disease (AD), and schizophrenia; estimate predictability in patients with bvFTD and schizophrenia based on sociodemographic, clinical, and biological data; and examine prognostic value, genetic underpinnings, and progression in patients with clinical high-risk (CHR) states for psychosis or recent-onset depression (ROD). Design, Setting, and Participants: This study included 1870 individuals from 5 cohorts, including (1) patients with bvFTD (n = 108), established AD (n = 44), mild cognitive impairment or early-stage AD (n = 96), schizophrenia (n = 157), or major depression (n = 102) to derive and compare diagnostic patterns and (2) patients with CHR (n = 160) or ROD (n = 161) to test patterns' prognostic relevance and progression. Healthy individuals (n = 1042) were used for age-related and cohort-related data calibration. Data were collected from January 1996 to July 2019 and analyzed between April 2020 and April 2022. Main Outcomes and Measures: Case assignments based on diagnostic patterns; sociodemographic, clinical, and biological data; 2-year functional outcomes and genetic separability of patients with CHR and ROD with high vs low pattern expression; and pattern progression from baseline to follow-up MRI scans in patients with nonrecovery vs preserved recovery. Results: Of 1870 included patients, 902 (48.2%) were female, and the mean (SD) age was 38.0 (19.3) years. The bvFTD pattern comprising prefrontal, insular, and limbic volume reductions was more expressed in patients with schizophrenia (65 of 157 [41.2%]) and major depression (22 of 102 [21.6%]) than the temporo-limbic AD patterns (28 of 157 [17.8%] and 3 of 102 [2.9%], respectively). bvFTD expression was predicted by high body mass index, psychomotor slowing, affective disinhibition, and paranoid ideation (R2= 0.11). The schizophrenia pattern was expressed in 92 of 108 patients (85.5%) with bvFTD and was linked to the C9orf72 variant, oligoclonal banding in the cerebrospinal fluid, cognitive impairment, and younger age (R2= 0.29). bvFTD and schizophrenia pattern expressions forecasted 2-year psychosocial impairments in patients with CHR and were predicted by polygenic risk scores for frontotemporal dementia, AD, and schizophrenia. Findings were not associated with AD or accelerated brain aging. Finally, 1-year bvFTD/schizophrenia pattern progression distinguished patients with nonrecovery from those with preserved recovery. Conclusions and Relevance: Neurobiological links may exist between bvFTD and psychosis focusing on prefrontal and salience system alterations. Further transdiagnostic investigations are needed to identify shared pathophysiological processes underlying the neuroanatomical interface between the 2 disease spectra.

La elaboración del vino base es fundamental para obtener vinos espumosos tintos de calidad. Para ello hay que partir de una vendimia que se realice de manera anticipada. El problema radica en que si se vendimia antes de su maduración óptima la uva presentará baja concentración de antocianos y alto contenido en taninos verdes, lo que se traducirá en vinos base con poca intensidad de color, desequilibrados, con notas demasiado amargas y astringentes, y la estructura en boca no será la adecuada. Este problema se puede mitigar, entre otras técnicas, realizando una crianza sobre lías del vino base. En este proceso las lías propias de la fermentación se adicionan al vino para que aporten al mismo, compuestos que mejoran la estabilidad colorante, reduciendo la astringencia y aumentando el cuerpo y la untuosidad en boca. El mayor inconveniente de este proceso es que requiere bastante mano de obra y puede conllevar un largo periodo de tiempo para lograr los efectos deseados, por lo que se han planteado otras técnicas alternativas como el uso de ultrasonidos para reducir el tiempo de crianza sobre lías aumentando la concentración de los compuestos de interés. El objetivo de este trabajo es estudiar el efecto de la crianza sobre lías tratadas con ultrasonidos sobre los parámetros químicos y sensoriales de un vino base tinto destinado a la elaboración de un vino espumoso. Para ello, a partir de un vino base elaborado con uvas de la variedad Tempranillo que ha permanecido en contacto con lías tratadas con ultrasonidos durante 4 meses se realizará en cada uno de los lotes (2 controles + 3 tratamientos con ultrasonidos a distintas frecuencias), un análisis químico y sensorial con un panel de catadores entrenado. Todos los análisis se realizarán por duplicado. Finalmente, se realizará un tratamiento de los datos utilizando diferentes técnicas estadísticas. Los resultados obtenidos muestran desde el punto de vista tanto fisicoquímico como sensorial apenas diferencias entre las muestras. Sin embargo, se han aumentado ciertos atributos sensoriales. Por lo que se deben realizar más estudios., The preparation of the base wine is essential to obtaining high-quality red sparkling wines. To do so, it is necessary to start from a harvest that is made in advance. The problem is that if it is harvested before its optimal ripening, the grapes will present a low concentration of anthocyanins and high content of green tannins. As a result, we will obtain base wines with little intensity of colour, unbalanced, with bitter and astringent notes, and the structure in the mouth will not be adequate. This problem can be mitigated, among other techniques, by making aging on the lees of the base wine. In this process, the lees of fermentation are added to the wine to provide the wine compounds that improve colouring stability, by reducing astringency and increasing body and smoothness in the mouth. The major drawback of this process is that it requires a lot of manpower and it can take a long time to achieve the desired effects, so other alternative techniques have been proposed such as the use of ultrasound to reduce the aging time on lees by increasing the concentration of the compounds of interest. This work aims to study the effect of aging on lees treated with ultrasound on the chemical and sensory parameters of a red base wine intended to produce sparkling wine. To do this, a base wine made with grapes of the Tempranillo variety that has remained in contact with lees treated with ultrasound for 4 months will be conducted in each of the lots (2 controls + 3 treatments with ultrasound at different frequencies), and a chemical and sensory analysis with a trained panel of tasters. All analyses will be undertaken in duplicate. Finally, the data will be processed using different statistical techniques. The results obtained show few differences between the samples from a chemical or sensory point of view. However, certain sensory attributes have been increased. So, more studies need to be done., Grado en Enología

Una de las dimensiones más significativas en el proceso de incorporación de los descendientes de migrados es la lingüística, tanto en sociedades oficialmente monolingües como, especialmente, bilingües. Ubicados en Cataluña, el modelo de convivencia e integración propuesto aboga por la creación de un proyecto común de convivencia plurilingüe y pluricultural, en el que la lengua catalana sea su eje vertebrador. Sin duda uno de los más importantes procesos de cara a la obtención de este fin, son las actitudes lingüísticas que los hijos e hijas de las migraciones construyen, debido a su comprobada influencia tanto en el aprendizaje lingüístico como en la integración sociocultural. Con este marco de fondo, el objetivo de este artículo es analizar los predictores sociodemográficos, sociofamiliares, psicosociales y lingüísticos que producen que las actitudes se ubiquen por encima o por debajo de la media, en el caso de descendientes de ecuatorianos, de otros países de Hispanoamérica y Marruecos en Cataluña. Los datos presentados son fruto de la aplicación de un cuestionario actitudinal y autoidentificatorio, así como de sendas pruebas de competencias lingüísticas (en catalán y español). Los principales resultados apuntan a que, si bien de manera bivariada las variables influyentes son numerosas, al introducirlas en Modelos de Regresión Logística, las más importantes conectan con la esfera autoidentificatoria, el lugar de nacimiento (e implícitamente la lengua familiar) y los usos lingüísticos. Las implicaciones de estos resultados son discutidas.

RESUMEN : La pseudoartrosis del escafoides es una patología muy prevalente en nuestra socie dad, sobre todo entre las personas jóvenes con una vida activa. Esto es debido a que se trata de la principal complicación de la fractura del escafoides carpiano, la segunda fractura en frecuencia de la extremidad superior, solo superada por la fractura de radio distal. El retraso en el diagnóstico de la fractura, la precaria vascularización ósea del escafoi des, la localización de la fractura previa y la presencia de inestabilidad o colapso articular son algunos de los predisponentes a padecer esta complicación traumatológica. Las principales técnicas quirúrgicas que se llevan a cabo para corregir esta pseudoartrosis son: la técnica de Matti-Ruse, la técnica de Fisk-Fernández y las técnicas que utilizan injertos óseos vasculariza dos, como la técnica de Mathoulin o la técnica de Zaidemberg. A lo largo de este trabajo se lleva a cabo un estudio comparativo entre la tasa de con solidación obtenida en el tratamiento quirúrgico de las pseudoartrosis del escafoides car piano en el Hospital Universitario Marqués de Valdecilla (HUMV) entre los años 2010-2020 y una serie de variables recogidas en las bases de datos de las historias clínicas que intervienen en el proceso de curación de dicha pseudoartrosis. ABSTRACT : Pseudarthrosis of the scaphoid is a very prevalent pathology in our society, particularly among young people with an active life. This is because it is the main complication of carpal scaphoid fracture, the second most frequent fracture of the upper extremity, which is only surpassed by distal radius fracture. The delay in the diagnosis of the fracture, the precarious bony vascularization of the scaphoid, the location of the previous fracture and the presence of joint instability or articular collapse are some of the predisposing factors to suffer this traumatic complication. The main surgical techniques used to correct this pseudarthrosis are: the Matti-Ruse technique, the Fisk-Fernandez technique and techniques that use vascularized bone grafts with volar ap proaches, such as the Mathoulin technique or the Zaidemberg technique. Throughout this work, a comparative study is carried out between the rate of consol idation that is obtained in the surgical treatment of carpal scaphoid pseudarthrosis at the Marqués de Valdecilla University Hospital (HUMV) between 2010-2020 and a series of varia bles that have been collected in the databases of the medical records, that are involved in the healing process of this pseudarthrosis. Grado en Medicina

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis., We would like to thank patients and controls who participated in this project. The present work has been performed as part of the doctoral program of I. de Rojas at the Universitat de Barcelona (Barcelona, Spain) supported by national grant from the Instituto de Salud Carlos III FI20/00215. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria ‘La Caixa’, Fundació ACE, and CIBERNED. The Vallecas Project is supported by Queen Sofia Foundation and the Instituto de Salud Carlos III. The position held by SA-L is funded by Instituto de Salud Carlos III (Co-funded by European Social Fund “Investing in your future”) Sara Borrell Contract (CD19/00232). A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)–Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER–‘Una manera de hacer Europa’). Some control samples and data from patients included in this study were provided in part by the National DNA Bank Carlos III (www.bancoadn.org, accessed date: 1 October 2021, University of Salamanca, Spain) and Hospital Universitario Virgen de Valme (Sevilla, Spain); they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. This research has been conducted using the COVID-19 Host Genetic Initiative public resource obtained through the web site (https://www.covid19hg.org/results/, accessed date: 1 October 2021).

Identifying the mechanisms through which genetic risk causes dementia is an imperative for new therapeutic development. Here, we apply a multistage, systems biology approach to elucidate the disease mechanisms in frontotemporal dementia. We identify two gene coexpression modules that are preserved in mice harboring mutations in MAPT, GRN and other dementia mutations on diverse genetic backgrounds. We bridge the species divide via integration with proteomic and transcriptomic data from the human brain to identify evolutionarily conserved, disease-relevant networks. We find that overexpression of miR-203, a hub of a putative regulatory microRNA (miRNA) module, recapitulates mRNA coexpression patterns associated with disease state and induces neuronal cell death, establishing this miRNA as a regulator of neurodegeneration. Using a database of drug-mediated gene expression changes, we identify small molecules that can normalize the disease-associated modules and validate this experimentally. Our results highlight the utility of an integrative, cross-species network approach to drug discovery.

La presente investigación presenta un programa didáctico de preparación dirigido a la formación inicial de estudiantes de Educación Preescolar que los prepara para la atención inclusiva a los sujetos con hipoacusia bilateral en situación de aislamiento. Por estas razones, se ofrecen saberes y procederes didácticos para la atención inclusiva a los sujetos con dicha discapacidad, que contribuye a su inclusión en las modalidades de atención educativa de la Primera Infancia en condiciones de aislamiento. En tal sentido, se tuvieron en cuenta para la elaboración de la propuesta los métodos del nivel teórico: analítico – sintético, modelación; nivel empírico experimental, análisis de documentos, observación, encuesta, entrevista,talleres de opinión crítica y construcción colectiva y preexperimento; del estadístico-matemático el cálculo porcentual, tablas y gráficos. Los resultados del preexperimento realizado en el Departamento de Educación Preescolar de Camagüey, perteneciente a la Universidad Ignacio Agramonte Loynaz, demostraron su validez, al promover el desarrollo cognoscitivo de las estudiantes en formación inicial para desarrollar el proceso educativo inclusivo de los sujetos con hipoacusia bilateral en el Nivel Educativo de la Primera Infancia en condiciones de aislamiento.

The commercialization of health services in international markets has generated a phenomenon called medical and health tourism (TMyS). In a sense, it is an exploratory study with a qualitative approach that seeks, through in-depth interviews as information gathering strategies, to build a network of opportunities for the development of medical and health tourism in the city of San Luis Río Colorado, Sonora. The informants are government actors, tourism and health service providers, and researchers from the area, whose contributions analyze under the discourse interpretation methodology with qualitative support from the Atlas. ti software. The conclusions allow demonstrating the interest of the tourism and health system actors in applying different creativity and innovation actions to develop economic activity in this pandemic era that requires dialogue between the institutions of power and the sectors involved in its growth., La comercialización de los servicios de salud en los mercados internacionales ha generado un fenómeno denominado turismo médico y de salud (TMyS) En sentido es estudio exploratorio con enfoque cualitativo que busca, a través de entrevistas a profundidad como estrategias de recolección de información, construir una red de oportunidades de desarrollo del turismo médico y de salud en la ciudad de San Luis Río Colorado, Sonora. Los informantes son actores gubernamentales, prestadores de servicios turísticos y de salud e investigadores del área, cuyas aportaciones se analizan bajo la metodología de interpretación del discurso con apoyo cualitativo del software Atlas.ti. Las conclusiones permiten demostrar el interés de los actores del sistema turístico y de salud en aplicar diferentes acciones de creatividad e innovación para el desarrollo de la actividad económica, en esta época de pandemia que requiere el diálogo entre las instituciones de poder y los sectores involucrados en su crecimiento., A comercialização de serviços de saúde em mercados internacionais gerou um fenômeno denominado turismo médico e de saúde (TMyS) Em certo sentido, é um estudo exploratório com abordagem qualitativa que busca, por meio de entrevistas em profundidade como estratégias de coleta de informações, a construção de um rede de oportunidades para o desenvolvimento do turismo médico e de saúde na cidade de San Luis Río Colorado, Sonora. Os informantes são atores governamentais, prestadores de serviços de turismo e saúde e pesquisadores da área, cujas contribuições são analisadas sob a metodologia de interpretação do discurso com apoio qualitativo do software Atlas.ti. As conclusões permitem demonstrar o interesse dos atores do turismo e do sistema de saúde em aplicar diferentes ações de criatividade e inovação para o desenvolvimento da atividade econômica, nesta era de pandemia que exige diálogo entre as instituições de poder e os setores envolvidos. seu crescimento.

Emerging studies have suggested several chromosomal regions as potential host genetic factors involved in the susceptibility to SARS-CoV-2 infection and disease outcome. We nested a COVID-19 genome-wide association study using the GR@ACE/DEGESCO study, searching for susceptibility factors associated with COVID-19 disease. To this end, we compared 221 COVID-19 confirmed cases with 17,035 individuals in whom the COVID-19 disease status was unknown. Then, we performed a meta-analysis with the publicly available data from the COVID-19 Host Genetics Initiative. Because the APOE locus has been suggested as a potential modifier of COVID-19 disease, we added sensitivity analyses stratifying by dementia status or by disease severity. We confirmed the existence of the 3p21.31 region (LZTFL1, SLC6A20) implicated in the susceptibility to SARS-CoV-2 infection and TYK2 gene might be involved in COVID-19 severity. Nevertheless, no statistically significant association was observed in the COVID-19 fatal outcome or in the stratified analyses (dementia-only and non-dementia strata) for the APOE locus not supporting its involvement in SARS-CoV-2 pathobiology or COVID-19 prognosis.

Additional file 6.

Título, resumen, palabras clave y texto en español y en inglés Resumen basado en el de la publicación Monográfico con el título: “Competencias digitales en educación para los ciudadanos del siglo XXI” Título del monográfico en inglés: “Digital competence in education for 21st citizens” Se pretende, por una parte, crear un instrumento para evaluar las habilidades digitales de alumnos de educación infantil (3 a 6 años de edad) partiendo de sus prácticas de aula; y por otra, valorar los niveles de autonomía adquiridos por los alumnos respecto de dichas habilidades. El estudio se realizó durante dos años escolares, recopilando datos de un total de 254 alumnos de 17 aulas con un recurso TIC en ocho escuelas. En primer lugar, los resultados ofrecen un instrumento diseñado y verificado en la práctica para la evaluación de las habilidades digitales. En segundo lugar, los resultados sobre autonomía destacan la importancia que tienen factores como la madurez, el contenido curricular y la naturaleza de la práctica en el aula para explicar la adquisición de habilidades digitales. Es importante subrayar la necesidad de realizar más estudios de evaluación de habilidades adoptando un enfoque centrado en las prácticas. ESP

El siguiente trabajo tiene como objetivo el cálculo de la capacidad de carga de Alquézar, concretamente se va a estudiar el caso del sendero de las pasarelas ya que es el recurso turístico que más presión turística soporta. Se ha elaborado un inventario de infraestructuras que ha sido georreferenciado mediante el software Q-GIS, posteriormente se ha procedido al cálculo de la capacidad de carga física y de la capacidad de carga real, aplicándole a esta ultima los factores de corrección “social” y “accesibilidad”. La capacidad de carga física se ha cifrado en 9.960 personas y la capacidad de carga real en 439 personas. Finalmente se comparan estos resultados con los datos de afluencia existentes.

Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer’s disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a finescale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [βAVROH (CI 95%) = 0.070 (0.037–0.104); P = 3.91 × 10−5; βFROH (CI95%) = 0.043 (0.009–0.076); P = 0.013]. ROHs increasing the risk of AD (OR > 1) were significantly overrepresented compared to ROHs increasing protection (p < 2.20 × 10−16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482‒11,305,456), (β (CI 95%) = 1.09 (0.48 ‒ 1.48), p value = 9.03 × 10−4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in wholeexome sequencing data (N = 1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability. Consejería de Salud de la Junta de Andalucía PI-0001/2017

Additional file 4.

Additional file 5.

ObjectiveWe sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.MethodsWe evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.ResultsWe found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10-5; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10-2; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.ConclusionsOur results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

Resumen El escritor británico Bruce Chatwin (1940-1989) convierte a un coleccionista compulsivo en eje central de su novela Utz. A través de su protagonista, reflexiona acerca del mundo del arte, rememorando su pasado cuando trabajaba en la casa de subastas Sotheby´s. Su experiencia allí le proporcionó unos conocimientos y una mirada que determinarían su vida, aprendió a estudiar una obra de arte, a describirla en pocas palabras y valorar su precio en el mercado. Todo ello se percibe en su estilo narrativo, donde persigue la precisión de las descripciones típicas de los catalogadores. Desarrolló un estilo propio. Además, adquirió una red de contactos trascendental alrededor del mundo. Fijó su interés en personalidades peculiares que desembocaron en la creación de Utz, personificación de ese entramado de marchantes y coleccionistas que le facilitó su puesto de director en el departamento de impresionistas y arte moderno. Al mismo tiempo, su época en Sotheby´s despertó en él la eterna disyuntiva entre la posesión, la búsqueda de la inmortalidad y la creación artística. El presente artículo examina cómo el autor aborda todos estos temas en la novela. Abstract British writer Bruce Chatwin (1940-1989) makes a compulsive collector the central axis of his novel Utz. Through that character, he reflects on the art world remembering his work at the auction house Sotheby´s. His experience there gave him the knowledge and look that would condition his life. He learnt to analyze a work of art, to describe it in just a few words and to value it in the market. All of it can be noticed in his writing style, in which he pursues the kind of the precision observed in cataloguers. He developed his own technique. Besides, he acquired a strong contact network around the world. He put his eyes on peculiar personalities that led to the creation of Utz, personification of all those art dealers and collectors that he met during his time as the head of the firm's Impressionist and Modern Art department. Moreover, his work at Sotheby´s awakened his eternal dilemma between possession, search for immortality and creation. This article examines how the author treats the above topics in his novel.

Background The Adult Treatment Panel III (ATPIII) guidelines aim to reduce cardiovascular morbidity and mortality. In Ecuador, 20% of people have high LDL cholesterol levels, and 39% have high triglyceride levels. Objective To analyze lipid-lowering regimens in Ecuadorian patients and determine the achievement rate of the ATPIII goals for lipid profile. Methods Using a retrospective analysis, 385 subjects older than 30 years, who received pharmacological treatment for dyslipidemia for at least three months was randomly selected from institutions at two large cities in Ecuador. Data were collected from patients’ medical records and analyzed by chi-square test or paired t-test; p-values less than 0.05 were considered significant. Results Baseline total cholesterol values were above 200 mg/dL in 75% of subjects, LDL-c values above 129 mg/dL in 83% of subjects and triglycerides values above 150 mg/dL in 79% of subjects. Most (n = 253, 95.8%) patients at very high cardiovascular risk were taking statins, 50% of them atorvastatin. Considering the ATPIII guidelines’ goals, only 24 subjects (19%) at high CV risk achieved an LDL-c < 100 mg/dl, while a significantly lower percentage (p = 0.04) of patients at very high risk reached an LDL-c < 70mg/dl (11%; n = 30). Conclusion These data indicate a low rate of compliance with the ATPIII guidelines, independent of the medication used or duration of the treatment. This may be attributed to the prescription of low doses of medication and a therapy targeting isolated lipid fractions rather than a complete lipid profile. (Int J Cardiovasc Sci. 2020; 33(4):371-376)

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer’s disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aβ1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aβ1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

British writer Bruce Chatwin (1940-1989) makes a compulsive collector the central axis of his novel Utz. Through that character, he reflects on the art world remembering his work at the auction house Sotheby´s. His experience there gave him the knowledge and look that would condition his life. He learnt to analyze a work of art, to describe it in just a few words and to value it in the market. All of it can be noticed in his writing style, in which he pursues the kind of the precision observed in cataloguers. He developed his own technique. Besides, he acquired a strong contact network around the world. He put his eyes on peculiar personalities that led to the creation of Utz, personification of all those art dealers and collectors that he met during his time as the head of the firm's Impressionist and Modern Art department. Moreover, his work at Sotheby´s awakened his eternal dilemma between possession, search for immortality and creation. This article examines how the author treats the above topics in his novel. El escritor británico Bruce Chatwin (1940-1989) convierte a un coleccionista compulsivo en eje central de su novela Utz. A través de su protagonista, reflexiona acerca del mundo del arte, rememorando su pasado cuando trabajaba en la casa de subastas Sotheby´s. Su experiencia allí le proporcionó unos conocimientos y una mirada que determinarían su vida, aprendió a estudiar una obra de arte, a describirla en pocas palabras y valorar su precio en el mercado. Todo ello se percibe en su estilo narrativo, donde persigue la precisión de las descripciones típicas de los catalogadores. Desarrolló un estilo propio. Además, adquirió una red de contactos trascendental alrededor del mundo. Fijó su interés en personalidades peculiares que desembocaron en la creación de Utz, personificación de ese entramado de marchantes y coleccionistas que le facilitó su puesto de director en el departamento de impresionistas y arte moderno. Al mismo tiempo, su época en Sotheby´s despertó en él la eterna disyuntiva entre la posesión, la búsqueda de la inmortalidad y la creación artística. El presente artículo examina cómo el autor aborda todos estos temas en la novela.

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

Se cumple un año de la aprobación por parte de la Asamblea General de Naciones Unidas de los Objetivos de Desarrollo Sostenible (ODS). Una Agenda mundial para conseguir en los próximos 15 años una sociedad próspera, justa e igualitaria. Se trata de 17 ODS que recogen la transparencia de manera explícita en tres de ellos y de modo transversal en todos como factor fundamental para su consecución. Entre las novedades, la nueva Agenda asigna al sector privado un papel clave como agente de desarrollo, invitándole a restaurar la confianza, la justicia y la igualdad en el mundo trabajando por una sociedad y una economía más transparentes. El Pacto Mundial ha apostado desde hace más de quince años por la transparencia en el tejido empresarial a través del Principio 10 "las empresas deben trabajar contra la corrupción en todas sus formas, incluidas extorsión y soborno" y, en la actualidad, ostenta el mandato de promover los ODS en el sector privado, Shortly it will be the first year anniversary since the United Nations General Assembly approved the Sustainable Development Goals (SDGs). A global agenda that is working to build a prosper, fair and egalitarian society. While cutting across all of them, transparency is explicitly stated in three out of the 17 SDGs, being one of the main factors that compromises their fulfilment. Among the novelties, the new Agenda provides a key role to the private sector as an agent of development, conveying it to restore confidence, justice and equality in the world by working towards a more transparent economy and society. The UN Global Compact has been working for more than 15 years now to promote transparency within the business community through the 10th Principle “Businesses should work against corruption in all its forms, including extortion and bribery” and, today, has the mandate to promote the SDGs within the private sector

Little information exists about the role of anemia in patients with acute coronary syndromes (ACS) admitted to Intensive Cardiac Care Units (ICCU). The aim of this study was to assess the prevalence of anemia and its impact on management and outcomes in this clinical setting. All consecutive patients admitted to eight different ICCUs with diagnosis of non-ST segment elevation ACS (NSTEACS) were prospectively included. Anemia was defined as hemoglobin < 130 g/L in men and < 120 g/L in women. The association between anemia and mortality or readmission at six months was assessed by the Cox regression method. A total of 629 patients were included. Mean age was 66.6 years. A total of 197 patients (31.3%) had anemia. Coronary angiography was performed in most patients (96.2%). Patients with anemia were significantly older, with a higher prevalence of comorbidities, poorer left ventricle ejection fraction and higher GRACE score values. Patients with anemia underwent less often coronary angiography, but underwent more often intraaortic counterpulsation, non-invasive mechanical ventilation and renal replacement therapies. Both ICCU and hospital stay were significantly longer in patients with anemia. Both the incidence of mortality (HR = 3.36, 95% CI: 1.43-7.85, P = 0.001) and the incidence of mortality/readmission were significantly higher in patients with anemia (HR = 2.80, 95% CI: 2.03-3.86, P = 0.001). After adjusting for confounders, the association between anemia and mortality/readmission remained significant (P = 0.031). Almost one of three NSTEACS patients admitted to ICCU had anemia. Most patients underwent coronary angiography. Anemia was independently associated to poorer outcomes at 6 months.

El manuscrito explora la vestimenta habitual y tradicional del pueblo Rarámuri, más conocida por tarahumara. Su cosmovisión se impregna en los atuendos, diseños y colores elegidos, simple, adusta, pero de una belleza que la relaciona con la inmediatez. Al igual que su relación con la naturaleza, basada en el respeto, esta situación lo enmarca como atractivo en la actividad del turismo, en el sentido de diferenciación del patrimonio cultural. En definitiva, el carácter histórico y las condiciones ambientales conforman patrones culturales que se reflejan en la indumentaria, entendida la cultura como un conjunto de creencias, actitudes y costumbres, que influyen en la forma de proceder, pensar y de festejar. Los cambios por la dinámica social y la migración de los tarahumaras han constituido cambios en el estilo de vida y en la adopción de materiales, como el uso de ropa de confección industrial, influenciados por la globalización.

[ES] A medida que la población mundial crece exponencialmente, las tasas de consumo y la demanda de nuevos productos también aumentan drásticamente. Como resultado, un gran número de productos al final de la vida útil (EoL) se están eliminando continuamente, lo que da lugar a una serie de problemas ambientales. Este proyecto de final de máster tiene por objeto llevar a cabo el desarrollo y la caracterización de compuestos de polímeros reforzados con fibra de vidrio a partir del reciclaje de los residuos de las turbinas eólicas, concretamente mediante el reciclaje mecánico de las palas de las turbinas eólicas de EoL. Esta tesis forma parte de las iniciativas pertenecientes a la estrategia Europa 2020 para generar un crecimiento sostenible, inteligente e inclusivo, es decir, una Europa que utilice los recursos de manera eficiente. El trabajo de tesis se realizó en el marco de un proyecto europeo Horizonte 2020 titulado "FiberEUse, Large scale demonstration of new circular economy value-chains based on the re-use of end-of-life fibre reinforced composites" (Proyecto Nº 730323). Por consiguiente, el objetivo final de esta tesis es la fabricación de un nuevo material compuesto para aplicaciones posteriores, logrando el principio de Economía Circular a los compuestos de EoL. En primer lugar, se prepararon muestras de compuestos de polímeros reforzados con fibra de vidrio. Los compuestos se fabricaron a partir de un 60% en peso de fibras de vidrio recicladas junto con la resina epoxídica comercial AralditeBY158 y el reactivo comercial Aradur21 que modifica la viscosidad y el tiempo de gelificación de la resina, ya que según estudios anteriores la cantidad óptima de fibras de vidrio recicladas era del 60% en peso. Estas muestras de material se caracterizaron a través de diferentes propiedades como la resistencia a la tracción, la temperatura de transición vítrea, las mediciones del ángulo de contacto por el método de la gota sésil entre otros. Finalmente, gracias a los resultados positivos obtenidos del material compuesto, la superficie del material fue recubierta para optimizar sus propiedades. Se utilizarán diferentes tipos de reactivos comerciales como el Omnicat440, el anhídrido succínico y el anhídrido ftálico, y diferentes tecnologías para la deposición de soluciones de recubrimiento como el aerógrafo y el pincel. Se empleó especialmente el método de curado con luz ultravioleta. Los mejores resultados de revestimiento se obtuvieron con una tecnología de pretratamiento por plasma de la superficie del compuesto antes de la etapa de revestimiento y utilizando el aerógrafo para la deposición de las soluciones de revestimiento. Sin embargo, debido a la situación actual causada por el virus Covid-19 no ha sido posible obtener una solución de revestimiento óptima para el acabado de la superficie del material remanufacturado. Para llevar a cabo esta labor se han utilizado varias técnicas de caracterización, como la calorimetría de barrido diferencial (DSC) y UV-DSC, ensayos de tracción y mediciones del ángulo de contacto., [EN] As the world population grows exponentially, consumption rates and demand for new products also increase dramatically. As a result, a large number of end-of-life (EoL) products are continuously being phased out, resulting in a number of environmental problems. This Final Master's Degree Project aims to perform the development and characterisation of fibreglass reinforced polymer composites from the recycling of wind turbine waste, specifically through the mechanical recycling of the blades of EoL wind turbines. This thesis is part of the initiatives belonging to the Europe 2020 strategy to generate sustainable, intelligent and inclusive growth, that is, a Europe that uses resources efficiently. The thesis work was performed in the framework of a Horizon 2020 European project entitled ¿FiberEUse, Large scale demonstration of new circular economy value-chains based on the reuse of end-of-life fibre reinforced composites¿ (Project Number 730323). Therefore, the final objective of this thesis is the manufacture of a new composite material for subsequent applications, achieving the principle of Circular Economy to EoL compounds. First, samples of glass-fibre reinforced polymer composites were prepared. The composites were made from 60% by weight of recycled glass fibres together with the commercial epoxy resin AralditeBY158 and the commercial reagent Aradur21 which modifies the viscosity and gelling time of the resin, since according to previous studies the optimal amount of recycled glass fibres was 60% by weight. These material samples were characterized through different properties such as tensile strength, glass transition temperature, contact angle measurements by sessile drop method among others. Finally, thanks to the positive results obtained from the composite material, the surface of the material was coated to optimize its properties. Different types of commercial reagents such as Omnicat440, succinic anhydride and phthalic anhydride and different technologies for the deposition of coating solutions such as airbrush and brush will be used. Especially the method of curing with UV light was employed. The best coating results were obtained with a plasma pre-treatment technology of the surface of the composite prior to the coating stage and by using the airbrush for the deposition of the coating solutions. However, due to the current situation caused by the Covid-19 virus it has not been possible to obtain an optimal coating solution for the surface finishing of the remanufactured material. In order to carry out this work, several characterization techniques have been used, such as differential scanning calorimetry (DSC) and UV-DSC, tensile tests and contact angle measurements.

Objective We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.Methods We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD–motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.Results We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10−5; odds ratio (OR) 6.4; confidence interval (CI) 2.31–24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10−2; OR 2.5; CI 1.17–5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.Conclusions Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes. Objective We sought to characterize C9orf72 expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.Methods We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD–motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.Results We found C9orf72 pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [p = 2.17 × 10−5; odds ratio (OR) 6.4; confidence interval (CI) 2.31–24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [p = 1.1 × 10−2; OR 2.5; CI 1.17–5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.Conclusions Our results indicate correlation between pathogenic C9orf72 expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.

“The authors would like to thank the Norwegian Dementia Genetics Network (DemGene), the European DLB Consortium (E-DLB), Dementia Genetics Spanish Consortium (DEGESCO) and Genomic Research at Fundació ACE (GR@ACE) Consortium. Fundació ACE would like to thank patients and controls who participated in this project. We are indebted to private donors for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). The study was founded by the Research Council of Norway, Norwegian Regional Health Authorities and Norwegian Health Association and 237250/EU/JPND (APGeM). The Cohort 2 results were generated with the assistance of financial support of grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). GR@ACE project has been funded by Fundación bancaria “La Caixa”, Grifols SA, Fundació ACE. The funding sources did not in any way affect the results or presentation of the results.” should read: “The authors would like to thank the Norwegian Dementia Genetics Network (DemGene), the European DLB Consortium (E-DLB), Dementia Genetics Spanish Consortium (DEGESCO) and Genomic Research at Fundació ACE (GR@ACE) Consortium. Fundació ACE would like to thank patients and controls who participated in this project. We are indebted to private donors for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). The study was founded by the Research Council of Norway, Norwegian Regional Health Authorities and Norwegian Health Association and 237250/EU/JPND (APGeM). The Cohort 2 results were generated with the assistance of financial support of grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). GR@ACE project has been funded by Fundación bancaria “La Caixa”, Grifols SA, Fundació ACE. The funding sources did not in any way affect the results or presentation of the results. This paper represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author and not necessarily those of the NIHR or the Department of Health and Social Care”.

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target. The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer's disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients. The Fundació ACE (ACE) study with 20 Pr-aMCI-storage subtype subjects (MCI) were analyzed. All subjects underwent a neuropsychological assessment, a structural MRI, FDG-PET, and PIB-PET. The adjusted hippocampal volume (aHV) on MRI, the standard uptake value ratio (SUVR) on FDG-PET and PIB-PET SUVR measures were analyzed. The construction of the CCs domain scores, and the aHV on MRI and FDG-PET SUVR measures, were replicated in the parental AB255 study database (n = 133 MCI). Partial correlations adjusted by age, gender, and education were calculated with the associated p -value among every CC domain score and the neuroimaging biomarkers. The results were replicated in the "MCI due to AD" with memory storage impairments from ADNI. Delayed Recall CC domain score was significantly correlated with PIB-PET SUVR (β= -0.61, p = 0.003) in the ACE study and also with aHV on MRI (β= 0.27, p = 0.01) and FDG-PET SUVR (β= 0.27, p = 0.01) in the AB255 study. After a median survival time of 20.6 months, 85% from the ACE MCI converted to AD. The replication of our results in the ADNI dataset also confirmed our findings. Delayed Recall is the CC domain score best correlated with neuroimaging biomarkers associated with prodromal AD diagnosis.

The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLCγ2 pathway as drug-target.

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.

Resumen tomado de la publicación Monográfico con el título: “Alimentación y educación saludable” La alimentación ejerce un papel esencial en nuestras vidas. Nos alimentamos a diario, del mismo modo que respiramos o dormimos, pero alimentarse va mucho más allá de un acto de supervivencia. Lo que elijamos para comer y para beber, y cómo lo hagamos tendrá una repercusión directa en nuestra salud, nuestro bienestar y también en nuestro entorno. Por todo ello, es fundamental instaurar buenos hábitos de alimentación y estilos de vida desde edades tempranas para lograr un cambio sostenible. Biblioteca del Ministerio de Educación y Formación Profesional; Calle San Agustín, 5; 28014 Madrid; Tel. +34917748000; biblioteca@educacion.gob.es ESP

En la actualidad, todavía prima la concepción de las matemáticas como algo aburrido, es por ello por lo que los alumnos, en muchas ocasiones, asisten a clase desmotivados. Por lo tanto, cambiar la percepción hacia las mismas podría ayudar a cambiar la motivación del alumno. Por otra parte, los juegos son herramientas con un alto nivel motivacional, así pues, se va a investigar la potencialidad de utilizar este recurso en el aula como elemento motivador y eje vertebrador en la planificación de sesiones. Se estudiará el valor educativo del juego para la adquisición y el aprendizaje de contenidos matemáticos y su efectividad al combinar aspectos educativos y lúdicos. Se va a realizar un análisis bibliográfico acerca del tema destacando algunas definiciones y clasificaciones de autores importantes, las ventajas e inconvenientes del uso de esta herramienta metodológica en el aula y el diseño y análisis de una serie de encuestas para maestros y alumnos. Además, se llevará a cabo el diseño y experimentación en el aula de Educación Primaria de una serie de juegos con el objetivo enseñar contenidos relativos a la geometría.

ATENCIÓ: la correcció està també al DDD, cal relacionar??? https://ddd.uab.cat/record/226203 Altres ajuts: The following studies and consortia have contributed to this manuscript. Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). 100-Plus study: We are grateful for the collaborative efforts of all participating centenarians and their family members and/or relations. This work was supported by Stichting Alzheimer Nederland (WE09.2014-03), Stichting Diorapthe, horstingstuit foundation, Memorabel (ZonMW projectnumber 733050814) and Stichting VUmc Fonds. Genotyping of the 100-Plus Study was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW projectnumber 733051061). German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe): This study/publication is part of the German Research Network on Dementia (KND), the German Research Network on Degenerative Dementia (KNDD; German Study on Ageing, Cognition and Dementia in Primary Care Patients; AgeCoDe), and the Health Service Research Initiative (Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+; AgeQualiDe)) and was funded by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716; grants Health Service Research Initiative: 01GY1322A, 01GY1322B, 01GY1322C, 01GY1322D, 01GY1322E, 01GY1322F, 01GY1322G). Alfredo Ramirez was partly supported by the ADAPTED consortium: Alzheimer's disease Apolipoprotein Pathology for Treatment Elucidation and Development, which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115975. Brain compendium: This work was funded by the UK Medical Research Council (13044). P.F.C. is a Wellcome Trust principal Fellow (212219/Z/18/Z) and a UK NIHR Senior Investigator, who receives support from the Medical Research Council Mitochondrial Biology Unit (MC_UU_00015/9), and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.Clinical AD, Sweden: We would like to thank UCL Genomics for performing the genotyping analyses. Danish data: The studies behind the Danish long-lived cases received funding from The National Program for Research Infrastructure 2007 (grant no. 09-063256), the Danish Agency for Science Technology and Innovation, the Velux Foundation, the US National Institute of Health (P01 AG08761), the Danish Agency for Science, Technology and Innovation/The Danish Council for Independent Research (grant no. 11-107308), the European Union's Seventh Framework Programme (FP7/2007-2011) under grant agreement no. 259679, the INTERREG 4 A programme Syddanmark-Schleswig-K.E.R.N. (by EU funds from the European Regional Development Fund), the CERA Foundation (Lyon), the AXA Research Fund, Paris, and The Health Foundation (Helsefonden), Copenhagen, Denmark. The GOYA study was conducted as part of the activities of the Danish Obesity Research Centre (DanORC, www.danorc.dk) and The MRC centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). The genotyping for GOYA was funded by the Wellcome Trust (WT 084762). GOYA is a nested study within The Danish National Birth Cohort which was established with major funding from the Danish National Research Foundation. Additional support for this cohort has been obtained from the Pharmacy Foundation, the Egmont Foundation, The March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. Fundació ACE (FACE): We would like to thank patients and controls who participated in this project. We are indebted to Trinitat Port-Carbó and her family for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). Agustín Ruiz has received support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ADAPTED Grant No. 115975 and by grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- "Una manera de Hacer Europa"), by Fundación bancaria "La Caixa" and Grifols SA (GR@ACE project). Genetics of Healthy Ageing Study (GEHA - NL): The work described in this paper was funded mainly by the EU GEHA Project contract no. LSHM-CT-2004-503-270. Gothenburg Birth Cohort (GBC) Studies: We would like to thank UCL Genomics for performing the genotyping analyses. The studies were supported by The Stena Foundation, The Swedish Research Council (2015-02830, 2013-8717), The Swedish Research Council for Health, Working Life and Wellfare (2013-1202, 2005-0762, 2008-1210, 2013-2300, 2013-2496, 2013-0475), The Brain Foundation, Sahlgrenska University Hospital (ALF), The Alzheimer's Association (IIRG-03-6168), The Alzheimer's Association Zenith Award (ZEN-01-3151), Eivind och Elsa K:son Sylvans Stiftelse, The Swedish Alzheimer Foundation. International FTD-Genomics Consortium (IFGC): International FTD-Genomics Consortium (IFGC): The authors thank the IFGC for providing relevant data to support the analyses presented in this manuscript. Further acknowledgments for IFGC (https://ifgcsite.wordpress.com/), e.g. full members list and affiliations, are found in the online supplementary files. IPDGC (​The International Parkinson Disease Genomics Consortium): We also would like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). See for a complete overview of members, acknowledgements and funding http://pdgenetics.org/partners. Kompetenznetz Multiple Sklerose (KKNMS): This work was supported by the German Ministry for Education and Research (BMBF) as part of the "German Competence Network Multiple Sclerosis" (KKNMS) (grant nos. 01GI0916 and 01GI0917) and the Munich Cluster for Systems Neurology (SyNergy). TA was supported by the BMBF through the Integrated Network IntegraMent, under the auspices of the e:Med Programme (01ZX1614J). BH was supported by the EU Horizon 2020 project MultipleMS.Longitudinal Aging Study Amsterdam (LASA) is largely supported by a grant from the Netherlands Ministry of Health, Welfare and Sports, Directorate of Long-Term Care. The authors are grateful to all LASA participants, the fieldwork team and all researchers for their ongoing commitment to the study. Leiden Longevity Study: This study was supported by a grant from the Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007), the Centre for Medical Systems Biology, and the Netherlands Consortium for Healthy Ageing (Grant 050-060-810), all in the framework of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) and by Unilever Colworth.Maria Carolina Dalmasso: Georg Forster Research Award (Alexander von Humboldt Foundation). Mayo Clinic AD, DLB, PD, PSP: We thank the patients and their families for their participation, without whom these studies would not have been possible. Funding for this work was supported by National Institute on Aging [RF AG051504 to NET.; U01 AG046139 to NET]; and National Institute of Neurological Disorders and Stroke [R01 NS080820 to NET; P50 NS072187]. The Mayo Clinic is a Lewy Body Dementia Association (LBDA) Research Center of Excellence, American Parkinson Disease Association (APDA) Information and Referral Center and Center for Advanced Research, NINDS Tau Center without Walls (U54-NS100693) and is supported by Mayo Clinic AD and related dementias genetics program, The Little Family Foundation, the Mangurian Foundation for Lewy body research and NINDS R01 NS078086 (to OAR). The PD program at the Mayo Clinic Florida is also supported by the Mayo Clinic Center for Regenerative Medicine, Mayo Clinic Center for Individualized Medicine, Mayo Clinic Neuroscience Focused Research Team (Cecilia and Dan Carmichael Family Foundation, and the James C. and Sarah K. Kennedy Fund for Neurodegenerative Disease Research at Mayo Clinic in Florida), the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch, and The Sol Goldman Charitable Trust. Samples included in this study are from the brain bank at Mayo Clinic in Jacksonville which is supported by CurePSP The online version of this article (10.1007/s00401-019-02026-8) contains supplementary material, which is available to authorized users.

Figure S1. miRNA levels in human entorhinal cortex (A), hippocampus (B) and cerebellum (C) at different stages of AD pathology compared with cognitively healthy controls. Figure S2. Correlation plots for plasma miRNAs expression levels vs age. Figure S3. Circulating miRNAs levels comparison between sexes. Figure S4. NPTX1 and NPTXR protein levels in AD human entorhinal cortex. Table S1. Tissue samples information. Table S2. Validated miRNA-target interactions for candidate miRNAs based on miRWalk2.0 database. Only selected synaptic-related targets are shown. Table S3. Follow-up of MCI patients. (PDF 1295 kb)

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA’s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.