High-accuracy determination of the neutron flux in the new experimental area n_TOF-EAR2 at CERN

A new high flux experimental area has recently become operational at the n_TOF facility at CERN. This new measuring station, n_TOF-EAR2, is placed at the end of a vertical beam line at a distance of approximately 20m from the spallation target. The characterization of the neutron beam, in terms of flux, spatial profile and resolution function, is of crucial importance for the feasibility study and data analysis of all measurements to be performed in the new area. In this paper, the measurement of the neutron flux, performed with different solid-state and gaseous detection systems, and using three neutron-converting reactions considered standard in different energy regions is reported. The results of the various measurements have been combined, yielding an evaluated neutron energy distribution in a wide energy range, from 2meV to 100MeV, with an accuracy ranging from 2%, at low energy, to 6% in the high-energy region. In addition, an absolute normalization of the n_TOF-EAR2 neutron flux has been obtained by means of an activation measurement performed with 197Au foils in the beam.Comisión Europea FP7/2007-2011 No.605203Centro Nacional de Ciencias de Polonia UMO- 2012/04/M/ST2/00700Centro Nacional de Ciencias de Polonia UMO-2016/22/M/ST2/00183Fundación de Ciencia Croata No. 168

Papel de CPT1C en el desarrollo axonal y en el transporte de los endosomas tardíos

La paraplejía espástica hereditaria agrupa un conjunto de desórdenes neurodegenerativos caracterizados por espasticidad y rigidez muscular. Todos ellos están relacionados clínica y patológicamente con problemas en el desarrollo axonal del tracto corticoespinal y las columnas dorsales de la médula espinal. Hasta la fecha se han descrito 77 genes asociados a esta enfermedad. Sus mutaciones afectan a diversas funciones celulares como el transporte intracelular, la función mitocondrial o el metabolismo lipídico, entre otras. Entre estos genes se encuentra CPT1C. CPT1C es una carnitina palmitoil transferasa que se encuentra localizada en el RE de neuronas. A diferencias del resto de CPTs, CPT1C no presenta actividad catalítica pero mantiene la capacidad de unir malonil-CoA. El malonil-CoA es un intermediario en la síntesis de ácidos grasos, y sus niveles varían según el estado energético de la célula. Recientemente se ha sugerido que CPT1C podría ser un sensor de malonil-CoA y regular la función de otras proteínas. Entre las posibles proteínas interactoras de CPT1C se encuentra la protrudina. Se ha descrito el papel de la protrudina en el transporte y desarrollo axonal, pero no cuál es su mecanismo regulador. En esta tesis proponemos que CPT1C podría interaccionar con protrudina y, mediante la unión a malonil-CoA, regular el transporte y desarrollo axonal. Para ello se han realizado dos aproximaciones. En primer lugar se ha estudiado la implicación de CPT1C en el crecimiento axonal y dendrítico en neuronas corticales procedentes de embriones de ratones WT y KO CPT1C. En segundo lugar se ha estudiado la interacción de CPT1C con protrudina y su papel en la localización y transporte de endosomas tardíos en células HeLa. En ambas aproximaciones se ha estudiado la influencia de la unión de malonil-CoA a CPT1C. Los resultados obtenidos demuestran que CPT1C es necesaria para el correcto crecimiento axonal y ramificación dendrítica dependiendo de su unión a malonil-CoA. En este trabajo hemos podido demostrar además la interacción de CPT1C con protrudina, y describir su papel en la regulación de la localización y transporte de LEs, función que se encuentra regulada por la unión de malonil-CoA

Complement Mediated Endothelial Damage in Thrombotic Microangiopathies

Thrombotic microangiopathies (TMA) constitute a group of different disorders that have a common underlying mechanism: the endothelial damage. These disorders may exhibit different mechanisms of endothelial injury depending on the pathological trigger. However, over the last decades, the potential role of the complement system (CS) has gained prominence in their pathogenesis. This is partly due to the great efficacy of complement-inhibitors in atypical hemolytic syndrome (aHUS), a TMA form where the primary defect is an alternative complement pathway dysregulation over endothelial cells (genetic and/or adquired). Complement involvement has also been demonstrated in other forms of TMA, such as thrombotic thrombocytopenic purpura (TTP) and in Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), as well as in secondary TMAs, in which complement activation occurs in the context of other diseases. However, at present, there is scarce evidence about the efficacy of complement-targeted therapies in these entities. The relationship between complement dysregulation and endothelial damage as the main causes of TMA will be reviewed here. Moreover, the different clinical trials evaluating the use of complement-inhibitors for the treatment of patients suffering from different TMA-associated disorders are summarized, as a clear example of the entry into a new era of personalized medicine in its management

Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma

The lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models.Towards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies, K-Ras +/LSL-G12D;Trp53 LSL-R172H;Pdx1-Cre mice (KPC) and the K-Ras +/LSL-G12D;Pdx1-Cre mice (KC) were crossed with Loxl2 allele floxed mice (Loxl2 Exon2 fl/fl) or conditional Loxl2 overexpressing mice (R26Loxl2 KI/KI) to generate KPCL2 KO or KCL2 KO and KPCL2 KI or KCL2 KI mice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation. Using these PDAC mouse models, we show that while Loxl2 ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling. Loxl2 overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affects Osm and Loxl2 expression and collagen fibre alignment.Taken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic diseaseg JCL-G received support from a ’la Caixa’ Foundation (ID 100010434) fellowship (LCF/BQ/DR21/11880011). This study was supported by ISCIII FIS grants PI18/00757 and PI21/01110 (BSJ) and PI18/00267 (LG-B), and grants from the Spanish Ministry of Economy and Innovation SAF2016-76504-R (ACan and FP), PID2019-111052RB-I00 (FP), PID2019-104644RB-I00 (GM-B), a Ramón y Cajal Merit Award RYC-2012–12104 (BSJ) and ISCIII, CIBERONC, CB16/12/00446 (ACar) and CB16/12/00295 (ACan and GM-B), all of them co-financed through Fondo Europeo de Desarrollo Regional (FEDER) ’Una manera de hacer Europa’; a Fero Foundation Grant (BSJ); a Coordinated grant (GC16173694BARB) from the Fundación Científica Asociación Española Contra el Cáncer (FC-AECC) (BSJ); a Miguel Servet award (CP16/00121) (PS); a DFG, German Research Foundation Grant—Project no: 492 436 553 (KG); and a Max Eder Fellowship of the German Cancer Aid (111746) (PCH

Investment in Human Capital and Corporate Social Responsibility in SMEs providing accommodation services. The specificity of family firms

The general purpose of this paper is to investigate the effect of Human Capital Investment (HCI) on Corporate Social Responsibility (CSR) practices in small and medium-sized enterprises providing accommodation services. Thus, this study has two aims: first, analyzing the effect that HCI exerts on CSR practices; and second, examining the moderating effect of being a family firm on prior relationship. The sample is obtained from a survey carried out during 2017 in Spain to 1136 family and non-family businesses, which 41 belong to "Accommodation Services" and the methodology used is PLS-SEM.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Predicting the sources of an outbreak with a spectral technique

The epidemic spreading of a disease can be described by a contact network whose nodes are persons or centers of contagion, and links are heterogeneous relations among them. We provide a procedure to identify multiple sources of an outbreak or their closer neighbors. Our methodology is based on a simple spectral technique that requires only the definition of a undirected contact graph. The algorithm is tested on a variety of graphs collected from real influenza outbreaks, both in urban and rural areas. The proposed spectral technique is able to identify the source nodes in cases when the graph sufficiently approximates to a tree

Complement Mediated Endothelial Damage in Thrombotic Microangiopathies

Thrombotic microangiopathies (TMA) constitute a group of different disorders that have a common underlying mechanism: the endothelial damage. These disorders may exhibit different mechanisms of endothelial injury depending on the pathological trigger. However, over the last decades, the potential role of the complement system (CS) has gained prominence in their pathogenesis. This is partly due to the great efficacy of complement-inhibitors in atypical hemolytic syndrome (aHUS), a TMA form where the primary defect is an alternative complement pathway dysregulation over endothelial cells (genetic and/or adquired). Complement involvement has also been demonstrated in other forms of TMA, such as thrombotic thrombocytopenic purpura (TTP) and in Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), as well as in secondary TMAs, in which complement activation occurs in the context of other diseases. However, at present, there is scarce evidence about the efficacy of complement-targeted therapies in these entities. The relationship between complement dysregulation and endothelial damage as the main causes of TMA will be reviewed here. Moreover, the different clinical trials evaluating the use of complement-inhibitors for the treatment of patients suffering from different TMA-associated disorders are summarized, as a clear example of the entry into a new era of personalized medicine in its management

The Mitochondrial SDHD Gene Is Required for Early Embryogenesis, and Its Partial Deficiency Results in Persistent Carotid Body Glomus Cell Activation with Full Responsiveness to Hypoxia

The SDHD gene encodes one of the two membrane-anchoring proteins of the succinate dehydrogenase (complex II) of the mitochondrial electron transport chain. This gene has recently been proposed to be involved in oxygen sensing because mutations that cause loss of its function produce hereditary familiar paraganglioma, a tumor of the carotid body (CB), the main arterial chemoreceptor that senses oxygen levels in the blood. Here, we report the generation of a SDHD knockout mouse, which to our knowledge is the first mammalian model lacking a protein of the electron transport chain. Homozygous SDHD_/_ animals die at early embryonic stages. Heterozygous SDHD_/_ mice show a general, noncompensated deficiency of succinate dehydrogenase activity without alterations in body weight or major physiological dysfunction. The responsiveness to hypoxia of CBs from SDHD_/_ mice remains intact, although the loss of an SDHD allele results in abnormal enhancement of resting CB activity due to a decrease of K_ conductance and persistent Ca2_ influx into glomus cells. This CB overactivity is linked to a subtle glomus cell hypertrophy and hyperplasia. These observations indicate that constitutive activation of SDHD_/_ glomus cells precedes CB tumor transformation. They also suggest that, contrary to previous beliefs, mitochondrial complex II is not directly involved in CB oxygen sensing

Extensor Hallucis Capsularis o Tendón Accesorio del Extensor Hallucis Longus: Estudio anatómico y funcional, frecuencia y mediciones

The purpose of this study was to look closely at the anatomy of the extensor hallucis longus, ligament or tendon capsularis Accessory Extensor hallucis longus muscle; defi ne its occurrence frequency, it is a muscle that is not present in all feet and raises controversy in the reviewed literature. The ligament is a ligament capsularis dorsalis pedis group that accompanies the extensor hallucis longus muscle medial to it forever. We intend to demonstrate by our dissections, a ligament more common than it seems and where is its origin and insertion as well as their function, presentation and location by using photographs of cadaver feet and its width measures and characteristics. To achieve our object of study in this article, fi rst 50 dissected human cadaver fi ngers, making the relevant measurements.El objeto de éste estudio fue observar detenidamente la anatomía del Extensor Hallucis Longus, Ligamento Capsularis o Tendón Accesorio del músculo Extensor Hallucis Longus; definir su su frecuencia de aparición, pues es un músculo que no está presente en todos los pies y suscita controversia en la bibliografía consultada.El Ligamento Capsularis es un ligamento del grupo dorsal del pie, que acompaña al músculo Extensor Hallucis Longus siempre medial a él.Pretendemos demostrar con nuestras disecciones, que es un ligamento más habitual de lo que parece y, dónde está su origen e inserción, así como su función, presentación y ubicación mediante fotografías en pies de cadáver, así como medidas sobre su anchura y características particulares.Para conseguir nuestro objeto de estudio en éste artículo, se diseccionan 50 primeros dedos de cadáver humano, realizando las pertinentes mediciones