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The concept of safe-by-design (SbD) can help toxicologists and risk assessors to keep pace with the rapidly expanding field of nanotechnology. As part of SbD, the hazard potential of a new nanomaterial (NM) is identified at the first stages of product development. For this, simple yet predictive toxicity assays are crucial. We investigated the suitability of several in vitro models and exposure methods to predict the human (pulmonary) inflammation potential of NMs. Four silica NMs were selected of which in vivo pulmonary toxicity ranking had previously been established: DQ12 (quartz) > NM-203 (fumed silica) > Colloidal silica > Silanized colloidal silica. Several cell types including a 3D human airway epithelial model, lung epithelial cell lines, and immune cell lines, either in mono- or co-culture were exposed to the four materials either in a submerged setting or at the air-liquid interface (ALI). After 24 hours of exposure, cytokine response was assessed using either 13-plex LegendPlex, ELISA, or qPCR, and toxicity rankings were compared. The results indicate differences in sensitivity between cell models and exposure methods. Submerged exposure of a cell-line seems a suitable first tier for SbD hazard testing in case of NMs that can easily be dispersed. For NMs that are not compatible with submerged testing, ALI exposure might be needed. Higher tier testing might be used to confirm the ranking.

Throughout their whole life cycle from production to waste disposal, nanomaterials (NMs) and nano-enabled products (NEPs) are in contact with humans by different exposure routes and may induce adverse health effects. After oral exposure they may give rise to local or even systemic toxic effects associated to their dissolution behaviour, intestinal absorption or by being trapped into the gastrointestinal barrier Safe and sustainable-by-design (SSbD) interventions to reduce or mitigate NM/NEP risks along their life cycle have been suggested in the last years. However, no clear physico-chemical (PC) properties modulating the hazard by the oral route have been identified. Based on published practical examples of successful SSbD strategies, key PC properties determining the technical function of the NM in the NEP as well as those modified by the SSbD intervention are identified. In addition, oral IATAs from the GRACIOUS project are used to identify which PC properties could be relevant to determine the fate of NMs/NEPs after oral exposure. A further literature search on the specific NM/NEP may help to unravel the relationships among key PC properties and associated mechanisms of hazards. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 862419.

No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.

El presente artículo trata de analizar la legislación penal aplicable tanto en el ordenamiento español como en el británico, a los incidentes islamófobos que se están produciendo en los estadios de futbol. Por ello, además de consignar los principales incidentes registrados, se realiza un amplio recorrido por las principales disposiciones de naturaleza penal que abordan nuestro objeto de investigación en las dos localizaciones geográficas indicadas. De manera complementaria, también se hace referencia a normas provenientes de otros sectores de ambos ordenamientos que persiguen erradicar el discurso de odio hacia los musulmanes en el conocido como deporte rey, This article tries to analyze the criminal legislation applicable both in the Spanish and British legal systems to the Islamophobic incidents that are taking place in football stadiums. For this reason, in addition to recording the main incidents, an extensive review is made of the main provisions of a criminal nature about our object of investigation in the two indicated geographical locations. In a complementary way, we also insert a reference to rules from other sectors of the two legal systems that seek to eradicate hate speech towards Muslims in football

Un intérprete de lenguaje natural o modelo del lenguaje (ML) es una red neuronal que sigue la arquitectura de los transformers, que a día de hoy son el estado del arte en muchas técnicas de NLP (Natural Language Processing). El objetivo de un modelo del lenguaje probabilístico es aprender la probabilidad conjunta de secuencias de palabras sobre un vocabulario. Sin embargo esto se vuelve cada vez más complicado conforme aumenta el número de palabras debido a la maldición de la dimensionalidad. Una ontología es una estructura orientada a un área temática que guarda información sobre propiedades y relaciones entre una serie de conceptos y categorías. Los modelos de lenguaje no son capaces de procesar conocimiento estructurado como el contenido por una ontología, por ello buscamos implementar un método multilingüe que extraiga el contenido explicito en las ontologías obteniendo una descripción escrita en lenguaje ingles natural. El objetivo principal de este trabajo es emplear un corpus de verbalizaciones de distintas ontologías para ser procesado por un modelo del lenguaje capaz de encontrar nuevas relaciones de equivalencia entre las ontologías empleadas. Adicionalmente el método busca hacer más accesible y explicable el conocimiento que contiene la ontología a humanos no expertos en ontologías. Existen en la web varios métodos de verbalización ya implementados, han sido utilizados como fuente de inspiración con objeto de no reinventar la rueda e implementar un método de verbalización útil y de buena calidad. Los resultados obtenidos indican que el corpus de verbalizaciones ha sido útil para encontrar nuevas relaciones de equivalencia, la mejoría de la medida F1-score depende del modelo del lenguaje empleado, se ha conseguido un aumento medio del 8.361% en modelos BERT base y de un 4.5% en modelos BERT large. Palabras clave: ontología, transformers, modelo del lenguaje, red neuronal, procesamiento de lenguaje natural, OWL, Word embedding, BERT, Roberta.

Objectives: Since the results of the RECOVERY trial, WHO recommendations about the use of corticosteroids (CTs) in COVID-19 have changed. The aim of the study is to analyse the evolutive use of CTs in Spain during the pandemic to assess the potential influence of new recommendations. Material and methods: A retrospective, descriptive, and observational study was conducted on adults hospitalised due to COVID-19 in Spain who were included in the SEMI-COVID-19 Registry from March to November 2020. Results: CTs were used in 6053 (36.21%) of the included patients. The patients were older (mean (SD)) (69.6 (14.6) vs. 66.0 (16.8) years, p &lt, 0.001), with hypertension (57.0% vs. 47.7%, 0.001), obesity (26.4% vs. 19.3%, 0.0001), and multimorbidity prevalence (20.6% vs. 16.1%, 0.001). These patients had higher values (mean (95% CI)) of C-reactive protein (CRP) (86 (32.7–160) vs. 49.3 (16–109) mg/dL, 0.001), ferritin (791 (393–1534) vs. 470 (236–996) µg/dL, 0.001), D dimer (750 (430–1400) vs. 617 (345–1180) µg/dL, 0.001), and lower Sp02/Fi02 (266 (91.1) vs. 301 (101), 0.001). Since June 2020, there was an increment in the use of CTs (March vs. September, 0.001). Overall, 20% did not receive steroids, and 40% received less than 200 mg accumulated prednisone equivalent dose (APED). Severe patients are treated with higher doses. The mortality benefit was observed in patients with oxygen saturation &lt, /=90%. Conclusions: Patients with greater comorbidity, severity, and inflammatory markers were those treated with CTs. In severe patients, there is a trend towards the use of higher doses. The mortality benefit was observed in patients with oxygen saturation &lt, /=90%.

Objective We evaluated pain in leucine-rich glioma inactivated1(LGI1) and contactin-associated protein2(CASPR2)-antibody positive(Ab+) patients, to evaluate clinical associations and pathophysiology of treatable pain syndromes. Methods 108 LGI-Ab+, 33 CASPR2-Ab+, and 6 LGI1/CASPR-Ab+patients were phenotyped. Pain questionnaires were undertaken to identify neuropathic pain using the Douleur Neuropathique(DN4), patient reported outcome measurement information system(PROMIS), and quality of life(EQ5D). Skin biopsies, and serum binding to cell-based assays, sensory neuronal cocultures, and dorsal root ganglion(DRG) cultures were undertaken. Results 39/147 patients described pain, including 17/33 CASPR2-Ab+(52%), 20/108 LGI1-Ab+(19%), and 2 LGI/CASPR2-Ab+patients. Questionnaires completed in 23/39(59%) revealed comparable DN4 scores(p=0.319) with 58% of LGI1-Ab+ and 67% of CASPR2-Ab+patients having neuropathic pain. Patients rated >50% response in 8/30(27%) analgesia trials, versus 20/40(55%) immunotherapy trials(p=0.045). PROMIS ratings were similar between LGI1-Ab+ and CASPR2-Ab+patients at nadir(p=0.662), but showed more improvement following immunotherapy in LGI1-Ab+(p=0.008) than CASPR2-Ab+patients(p=0.125). At follow-up(median 57 months) CASPR2-Ab+patients showed more impairment in mobility(p=0.014), daily activities(p=0.019), and anxiety/depression(p=0.043); and lower overall health(p=0.019) on the EQ5D compared to LGI1-Ab+patients. Intraepidermal nerve fibre density was reduced in 2 LGI1-Ab+ and 1 CASPR2-Ab+patients. Serum immunoglobulin G(IgG) from 6/16 CASPR2-Ab+patients bound to sensory neuronal cocultures compared to 0/14 LGI1-Ab+patients(p=0.019) and 0/12 healthy controls. Serum IgG from 10/16 CASPR2-Ab+patients bound to DRG cultures compared to 1/14 LGI1-Ab+patients(p=0.0024) and 1/12 healthy controls. Conclusion Neuropathic pain may be present in both LGI-Ab+ and CASPR2-Ab+patients, and is immunotherapy responsive. Serum IgG from CASPR2-Ab+patients more frequently bound sensory neurons and dorsal root ganglia, suggesting pathophysiological differences which may underlie the more severe pain in these patients.

The connection between sport and nationalism is unquestionable. However, it is a matter of debate whether and to what extent this should be the case, given the potential danger involved. Cases of chauvinist exacerbation and even violence are well known. From a normative philosophical approach, we start with the hypothesis of a thermometer of sports nationalism that allows us to evaluate when these expressions are tolerable or not. As a proposal, we distinguish between assertive, aggressive and violent nationalism. Having examined the pros and cons of sporting nationalism in terms of foreign policy, it seems to us that there are not sufficient reasons to establish a causal link or to claim that it contributes to violence. It follows that there do not seem to us to be any moral or political reasons to eliminate international competitions or to even substantially change their current structure.

El presente artículo trata de analizar el último pronunciamiento del Tribunal de Justicia de la Unión Europea en materia de sacrificio ritual. En el mismo se aborda la controvertida cuestión del aturdimiento previo de animales como fórmula para fomentar la protección del bienestar de los mismos, aunque para ello puede apreciarse la concurrencia de una vulneración de las tradiciones rituales judías y musulmanas y, con ellas, las del derecho de libertad religiosa prevista por la Carta de Derechos Fundamentales de la Unión., This article tries to analyze the latest judgment of the Court of Justice of the European Union on ritual slaughter. In it, the controversial issue of stunning in animals is addressed as a way to promote the protection of their welfare, although for this, can be appreciated the concurrence of an infringement of Jewish and Muslim ritual traditions and, with them, the violation of the religious freedom provided by the Charter of Fundamental Rights of the European Union., 1. INTRODUCCIÓN. 2. LOS ORÍGENES DEL CONFLICTO: EL MARCO NORMATIVO EUROPEO EN MATERIA DE SACRIFICIO DE ANIMALES. 3. ANTECEDES DE LA SENTENCIA: LA CUESTIÓN DEL ATURDIMIENTO PREVIO EN BÉLGICA. 3.1. La nueva regulación en materia de sacrificio de animales introducida por los decretos de Flandes y Valonia. 3.2. Planteamiento de la cuestión prejudicial. 4. INTERPRETACIÓN DEL TJUE EN SU SENTENCIA DE 17 DE DICIEMBRE DE 2020. 4.1.- Consideraciones previas. 4.2. Análisis de las cuestiones prejudiciales primera y segunda. 4.3. Pronunciamiento en torno a la tercera cuestión prejudicial. 5. REFLEXIONES FINALES. 6. BIBLIOGRAFÍA. 7. WEBGRAFÍA.

Els crims sempre han estat fenòmens de gran interès social. D'una manera o d'una altra en tots els tipus de formats en els quals es relaten aquests successos, sempre s'ha donat espai a aquests esdeveniments. El present treball es dedica a l'anàlisi d'un gènere televisiu cada vegada més en auge: el true crime. Amb la finalitat d'aprofundir en aquest fenomen, es formula el següent objectiu d'investigació: l'estudi de la construcció social del crim, és a dir, la configuració d'aquest a través dels mitjans de comunicació. La metodologia emprada es divideix en dues fases: 1) la realització d'una anàlisi de contingut, tenint en compte els següents corrents sociològics en relació amb el crim - els factors socials (Ferri, 1990), la Teoria Funcionalista (Durkheim, 1993), el llibre Vigilar y Castigar de Foucault, la Teoria de la Desviació Social (Merton, 1959), la Teoria de l'Associació Diferencial (Sutherland, 1924) i la Tipologia de Comportament Desviat proposada per Becker l'any 1963 - d'un capítol de la sèrie de televisió Crims i d'una emissió de ràdio també de true crime i 2) l'elaboració d'una entrevista al presentador, guionista i director de Crims de TV3. Els resultats obtinguts mostren que molts dels corrents sociològics analitzats coincideixen amb les característiques dels capítols analitzats. Finalment, es conclou que el crim és un fet social, ja que, aquest és definit moralment per la societat i que, per tant, reflecteix un conjunt de valors i creences compartits. D'altra banda, fent referència al canvi de percepció en la narració del fenomen del true crime, l'èxit, en el cas concret de Crims, està directament relacionat amb la metodologia de realització dels seus programes. Los crímenes siempre han sido fenómenos de gran interés social. De una manera u otra en todos los tipos de formatos en los que se relatan estos sucesos, siempre se ha dado espacio a estos acontecimientos. El presente trabajo se dedica al análisis de un género televisivo cada vez más en auge: el true crime. Con la finalidad de profundizar en este fenómeno, se formula el siguiente objetivo de investigación: el estudio de la construcción social del crimen, es decir, la configuración de este a través de los medios de comunicación. La metodología utilizada se divide en dos fases: 1) la realización de un análisis de contenido, teniendo en cuenta las siguientes corrientes sociológicas en relación con el crimen - los factores sociales (Ferri, 1990), la Teoría Funcionalista (Durkheim, 1993), el libro Vigilar y Castigar de Foucault, la Teoría de la Desviación Social (Merton, 1959), la Teoría de la Asociación Diferencial (Sutherland, 1924) y la Tipología de Comportamiento Desviado propuesta por Becker en 1963 - de un capítulo de la serie de televisión Crims y de una emisión de radio también de true crime y 2) la elaboración de una entrevista al presentador, guionista y director de Crims de TV3. Los resultados obtenidos muestran que muchas de las corrientes sociológicas analizadas coinciden con las características de los capítulos analizados. Finalmente, se concluye que el crimen es un hecho social, ya que, éste es definido moralmente por la sociedad y que, por tanto, refleja un conjunto de valores y creencias compartidos. Por otro lado, haciendo referencia al cambio de percepción en la narración del fenómeno del true crime, el éxito, en el caso concreto de Crims, está directamente relacionado con la metodología de realización de sus programas. Crimes have always been phenomena of great social interest. In one way or another in all types of formats in which these events are recounted, space has always been given to these events. This work is dedicated to the analysis of an increasingly booming television genre: true crime. To deepen this phenomenon, the following research objective is formulated: the study of the social construction of crime, that is, the configuration of this through the media. The methodology used is divided into two phases: 1) the realization of a content analysis, taking into account the following sociological currents in relation to crime - social factors (Ferri, 1990), the Functionalist Theory (Durkheim, 1993), the book Vigilance and Punish by Foucault, the Theory of Social Deviation (Merton, 1959), the Theory of Differential Association (Sutherland, 1924) and the Typology of Deviant Behavior proposed by Becker in 1963 - from an episode of the television series Crims and from a radio broadcast also of true crime and 2) the elaboration of an interview with the presenter, screenwriter and director of Crims of TV3. The results obtained show that many of the sociological currents analyzed coincide with the characteristics of the chapters analyzed. Finally, it is concluded that crime is a social fact, since it is morally defined by society and therefore reflects a set of shared values and beliefs. On the other hand, referring to the change of perception in the narrative of the phenomenon of true crime, success, in the specific case of Crims, is directly related to the methodology of carrying out its programs.

La autoestima se considera un elemento emocional esencial para poder afrontar situaciones complicadas que se presentan en la vida. La hospitalización infantil influye en la autoestima, tanto negativa como positivamente. Negativa porque el aspecto que la genera es la enfermedad y el distanciamiento de su vida cotidiana, y positiva porque a través de la resiliencia se puede salir fortalecido de la misma. Por tanto, es imprescindible trabajar la autoestima en el hospital para así poder fomentar la resiliencia.Trabajar la autoestima tiene múltiples beneficios, puesto que ayuda a los niños y las niñas a mejorar la salud mental y la autoconfianza. A través esta propuesta de intervención educativa se pretende aumentar la autoestima en el aula hospitalaria, mediante la mejora del autoconcepto en distintas sesiones en las que la interacción social fomenta la valoración positiva que cada niño y niña tiene de sí mismo.

The G4C2 hexanucleotide repeat expansion (HRE) in C9orf72 is the commonest cause of familial amyotrophic lateral sclerosis (ALS). A number of different methods have been used to generate isogenic control lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and non-homologous end-joining by deleting the repeat region, with the risk of creating indels and genomic instability. In this study, we demonstrate complete correction of an induced pluripotent stem cell (iPSC) line derived from a C9orf72-HRE positive ALS/frontotemporal dementia patient using CRISPR/Cas9 genome editing and homology-directed repair (HDR), resulting in replacement of the excised region with a donor template carrying the wild-type repeat size to maintain the genetic architecture of the locus. The isogenic correction of the C9orf72 HRE restored normal gene expression and methylation at the C9orf72 locus, reduced intron retention in the edited lines and abolished pathological phenotypes associated with the C9orf72 HRE expansion in iPSC-derived motor neurons (iPSMNs). RNA sequencing of the mutant line identified 2220 differentially expressed genes compared with its isogenic control. Enrichment analysis demonstrated an over-representation of ALS relevant pathways, including calcium ion dependent exocytosis, synaptic transport and the Kyoto Encyclopedia of Genes and Genomes ALS pathway, as well as new targets of potential relevance to ALS pathophysiology. Complete correction of the C9orf72 HRE in iPSMNs by CRISPR/Cas9-mediated HDR provides an ideal model to study the earliest effects of the hexanucleotide expansion on cellular homeostasis and the key pathways implicated in ALS pathophysiology.

Summary TDP-43 dysfunction is common to 97% of amyotrophic lateral sclerosis (ALS) cases, including those with mutations in C9orf72. To investigate how C9ORF72 mutations drive cellular pathology in ALS and to identify convergent mechanisms between C9ORF72 and TARDBP mutations, we analyzed motor neurons (MNs) derived from induced pluripotent stem cells (iPSCs) from patients with ALS. C9ORF72 iPSC-MNs have higher Ca2+ release after depolarization, delayed recovery to baseline after glutamate stimulation, and lower levels of calbindin compared with CRISPR/Cas9 genome-edited controls. TARDBP iPS-derived MNs show high glutamate-induced Ca2+ release. We identify here, by RNA sequencing, that both C9ORF72 and TARDBP iPSC-MNs have upregulation of Ca2+-permeable AMPA and NMDA subunits and impairment of mitochondrial Ca2+ buffering due to an imbalance of MICU1 and MICU2 on the mitochondrial Ca2+ uniporter, indicating that impaired mitochondrial Ca2+ uptake contributes to glutamate excitotoxicity and is a shared feature of MNs with C9ORF72 or TARDBP mutations., Graphical Abstract, Highlights • Mutations in C9orf72 and TDP-43 reduce Ca2+ buffering capacity in ALS motor neurons • High levels of Ca2+-permeable glutamate receptors link C9orf72 and TDP-43 • Low mitochondrial Ca2+ uptake leads to glutamate-induced cell death • Imbalance of MICU1 and MICU2 reduces mitochondrial Ca2+ uptake, In this study, Dafinca, Talbot, and colleagues provide a mechanistic link between mutations in C9orf72 and TARDBP in induced pluripotent stem cell-derived motor neurons from ALS patients. They show both mutations cause increased expression of Ca2+-permeable receptors, reduced cytosolic Ca2+ buffering, and identify that perturbations in mitochondrial calcium uptake through an imbalance of MICU1 and MICU2 link the mutations.