2D experiments and numerical simulation of the oscillatory shallow flow in an open channel lateral cavity

Steady shallow flows past an open channel lateral cavity can induce the excitation of an eigenmode of a gravity standing wave inside the cavity, called seiche, which may be coupled with the shedding of vortices at the opening of the cavity. The presence of the seiche is of fundamental interest as it enhances the mass exchange between the main channel and the cavity. Measurements of the time evolution of the water surface are not often found in the literature for this type of flows. In this work, an experimental and numerical study of a shallow flow past a channel lateral cavity is carried out. The main novelty is the use of a pioneering non-intrusive experimental technique to measure the water surface at the channel-cavity region. This optical technique offers high resolution 2D data in time and space of the water surface evolution, allowing to determine the relevant features of the seiche oscillation. Such data are supplemented with Particle Image Velocimetry measurements. Furthermore, the experiments are numerically reproduced using a high-resolution depth-averaged URANS shallow water model, under the assumption that shallow water turbulence is mainly horizontal. The experimental and numerical results are analyzed in the frequency domain. High-resolution two-dimensional amplitude oscillation maps of the seiche phenomenon, as well as velocity fields, are presented. The high quality of the experimental data reported in this work makes this data set a suitable benchmark for numerical simulation models in order to evaluate their performance in the resolution of turbulent resonant shallow flows

Repercusiones de los ritmos reproductivos en un rebaño extensivo de raza manchega de carne

Se muestra la evolución de los resultados productivos en los últimos 22 años de una explotación de ovino de carne de la raza Manchega, destinado a la producción de lechazo, en función del sistema de cubriciones aplicado, el número de machos en cubrición y la utilización de melatonina para las cubriciones en épocas de anestro. Desde 1985 a 1992 se aplicaba en la explotación un sistema de tres partos en dos años. En 1993 se comenzó a utilizar el sistema STAR, de 5 cubriciones al año. En 2000 se aumentó el número de machos a más de un 5%. A partir de 2002 se comenzó a aplicar melatonina en las cubriciones que establece el sistema STAR en anestro estacionario (marzo y junio). Todas las modificaciones han mostrado beneficios en los resultados productivos. Los resultados de los últimos 5 años muestran la eficacia y la compatibilidad del sistema STAR en nuestras explotaciones de ovino en extensivo, acompañado de un número de machos importante que asegure buenas cubriciones (>5%). La aplicación de la melatonina optimiza este sistema de manejo, estabilizando las cubriciones de anestro, lo que hace que se produzca un mayor número de corderos útiles (vendidos + reposición), una venta de corderos mayor en el segundo semestre y se estabilicen los resultados entre años

Newcastle Disease Virus (NDV) Oncolytic Activity in Human Glioma Tumors Is Dependent on CDKN2A-Type I IFN Gene Cluster Codeletion.

Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor in adults with a median overall survival of 15 months. Tumor recurrence and poor prognosis are related to cancer stem cells (CSCs), which drive resistance to therapies. A common characteristic in GBM is CDKN2A gene loss, located close to the cluster of type I IFN genes at Ch9p21. Newcastle disease virus (NDV) is an avian paramyxovirus with oncolytic and immunostimulatory properties that has been proposed for the treatment of GBM. We have analyzed the CDKN2A-IFN I gene cluster in 1018 glioma tumors and evaluated the NDV oncolytic e ect in six GBM CSCs ex vivo and in a mouse model. Our results indicate that more than 50% of GBM patients have some IFN deletion. Moreover, GBM susceptibility to NDV is dependent on the loss of the type I IFN. Infection of GBM with an NDV-expressing influenza virus NS1 protein can overcome the resistance to oncolysis by NDV of type I-competent cells. These results highlight the potential of using NDV vectors in antitumor therapies.post-print3309 K

Structural basis for substrate specificity of heteromeric transporters of neutral amino acids

Despite having similar structures, each member of the heteromeric amino acid transporter (HAT) family shows exquisite preference for the exchange of certain amino acids. Substrate specificity determines the physiological function of each HAT and their role in human diseases. However, HAT transport preference for some amino acids over others is not yet fully understood. Using cryo-electron microscopy of apo human LAT2/CD98hc and a multidisciplinary approach, we elucidate key molecular determinants governing neutral amino acid specificity in HATs. A few residues in the substrate-binding pocket determine substrate preference. Here, we describe mutations that interconvert the substrate profiles of LAT2/CD98hc, LAT1/CD98hc, and Asc1/CD98hc. In addition, a region far from the substrate-binding pocket critically influences the conformation of the substrate-binding site and substrate preference. This region accumulates mutations that alter substrate specificity and cause hearing loss and cataracts. Here, we uncover molecular mechanisms governing substrate specificity within the HAT family of neutral amino acid transporters and provide the structural bases for mutations in LAT2/CD98hc that alter substrate specificity and that are associated with several pathologies

Bevacizumab dose adjustment to improve clinical outcomes of glioblastoma.

Background Glioblastoma (GBM) is one of the most aggressive and vascularized brain tumors in adults, with a median survival of 20.9 months. In newly diagnosed and recurrent GBM, bevacizumab demonstrated an increase in progression-free survival, but not in overall survival. Methods We conducted an in silico analysis of VEGF expression, in a cohort of 1082 glioma patients. Then, to determine whether appropriate bevacizumab dose adjustment could increase the anti-angiogenic response, we used in vitro and in vivo GBM models. Additionally, we analyzed VEGFA expression in tissue, serum, and plasma in a cohort of GBM patients before and during bevacizumab treatment. Results We identified that 20% of primary GBM did not express VEGFA suggesting that these patients would probably not respond to bevacizumab therapy as we proved in vitro and in vivo. We found that a specific dose of bevacizumab calculated based on VEGFA expression levels increases the response to treatment in cell culture and serum samples from mice bearing GBM tumors. Additionally, in a cohort of GBM patients, we observed a correlation of VEGFA levels in serum, but not in plasma, with bevacizumab treatment performance. Conclusions Our data suggest that bevacizumab dose adjustment could improve clinical outcomes in Glioblastoma treatment.post-print1360 K

Oral insulin-mimetic compounds that act independently of insulin

The hallmarks of insulin action are the stimulation and suppression of anabolic and catabolic responses, respectively. These responses are orchestrated by the insulin pathway and are initiated by the binding of insulin to the insulin receptor, which leads to activation of the receptor's intrinsic tyrosine kinase. Severe defects in the insulin pathway, such as in types A and B and advanced type 1 and 2 diabetes lead to severe insulin resistance, resulting in a partial or complete absence of response to exogenous insulin and other known classes of antidiabetes therapies. We have characterized a novel class of arylalkylamine vanadium salts that exert potent insulin-mimetic effects downstream of the insulin receptor in adipocytes. These compounds trigger insulin signaling, which is characterized by rapid activation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3 independent of insulin receptor phosphorylation. Administration of these compounds to animal models of diabetes lowered glycemia and normalized the plasma lipid profile. Arylalkylamine vanadium compounds also showed antidiabetic effects in severely diabetic rats with undetectable circulating insulin. These results demonstrate the feasibility of insulin-like regulation in the complete absence of insulin and downstream of the insulin receptor. This represents a novel therapeutic approach for diabetic patients with severe insulin resistance

Graph based study of allergen cross-reactivity of plant lipid transfer proteins (LTPs) using microarray in a multicenter study.

The study of cross-reactivity in allergy is key to both understanding. the allergic response of many patients and providing them with a rational treatment In the present study, protein microarrays and a co-sensitization graph approach were used in conjunction with an allergen microarray immunoassay. This enabled us to include a wide number of proteins and a large number of patients, and to study sensitization profiles among members of the LTP family. Fourteen LTPs from the most frequent plant food-induced allergies in the geographical area studied were printed into a microarray specifically designed for this research. 212 patients with fruit allergy and 117 food-tolerant pollen allergic subjects were recruited from seven regions of Spain with different pollen profiles, and their sera were tested with allergen microarray. This approach has proven itself to be a good tool to study cross-reactivity between members of LTP family, and could become a useful strategy to analyze other families of allergens

Programa de Atención al Ictus en Aragón (PAIA). Estrategia del cambio y resultados en el periodo 2009-2014

Introducción En 2008, Aragón tenía tasas de morbimortalidad y discapacidad por ictus superiores a las del conjunto de España. Se estableció la necesidad de desarrollar un Programa de Atención al Ictus (PAIA). Material y métodos Damos a conocer la dinámica de planificación, implantación, evaluación y mejora que se ha desarrollado entre los años 2009-2014 y sus resultados a 5 años. Resultados Se ha mejorado en la estructura, en los procesos y en los resultados, con mejoría en los indicadores clave de la asistencia (audit 2008-2010-2012) y otros: tasa ictus 2013: 2, 07 (2008: 2, 36); 78% ictus atendidos en áreas/unidades en 2014 (30%, 2008); tasa fibrinólisis 8, 3% en 2014 (4, 4%, 2010); fibrinólisis hospitales secundarios (30% total); fibrinólisis con teleictus 9%; descenso de la mortalidad por ictus, 38%; años de vida prematura perdidos 67, 7 (2013)/144 (2008); capacitación de enfermería, desarrollo de la neurosonología, trabajo en red, con protocolos y buenas prácticas compartidos entre sectores sanitarios, etc. Conclusiones La gestión por procesos y equipos multidisciplinares desplegados en una distribución territorial integral, con protocolos y referencias establecidas y una dinámica de evaluación y mejora continua, ha demostrado ser una herramienta potente para garantizar la calidad y la equidad. El PAIA, por su dinámica de mejora sostenida y la implicación de los clínicos, es un buen ejemplo de gestión clínica y trabajo en red. Introduction: In 2008, stroke mortality, morbidity, and disability rates in Aragon were higher than the average in Spain. These data underscored the need to develop a stroke care programme (PAIA). Material and methods: We present the dynamics of planning, implementation, evaluation, and improvement developed between 2009 and 2014 as well as the results of the PAIA after that 5-year period. Results: Structure, processes, and outcomes have improved with reference to the key indicators of healthcare (audit: 2008, 2010, 2012) among others: stroke rate in 2013 was 2.07 (2.36 in 2008); 78% of strokes were managed in stroke units in 2014 (30% in 2008); rate of fibrinolysis was 8.3% in 2014 (4.4% in 2010); fibrinolysis was administered in secondary hospitals (30% of the total); fibrinolysis was administered by Telestroke in 9%; stroke mortality decreased (38%); 67.7 years of potential life lost (YPLL) in 2013 (144 in 2008); nurse training; development of neurosonology; networking; sharing protocols and best practices between health sectors, etc. Conclusions: Integrated process management and multidisciplinary teams distributed and deployed over an entire territory with established protocols, references, evaluations, and continuous development, have been proven powerful tools to ensure both quality and equality. The PAIA is a good example of clinical governance and networking due to its dynamic and sustained improvement and cooperation between clinicians